Clinical trial NCT03832738
Conditions: Plaque Psoriasis Psoriasis Skin Diseases
Keywords: JTE-451 Psoriasis Plaque psoriasis IMPACT-PS
Sponsor: Akros Pharma Inc.
Start date: 2019-01-17; Completion date: 2020-03-13
Enrollment: 152 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study to evaluate the efficacy and safety of JTE-451 administered for 16 weeks in subjects with moderate to severe plaque psoriasis.

Detailed description:

Arms: arm 1: JTE-451 Tablets Dose 1 daily for 16 weeks. arm 2: JTE-451 Tablets Dose 2 daily for 16 weeks. arm 3: Placebo Tablets daily for 16 weeks.
Interventions: intervention 1: JTE-451 Tablets intervention 2: Placebo Tablets
Intervention descriptions: intervention 1: Active drug tablets containing JTE-451 intervention 2: Placebo tablets matching in appearance to the active drug tablets

Protocol documents:
Prot_000.pdf: 
 
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-451 Administered for 16 Weeks in Subjects with Moderate 
to Severe Plaque Psoriasis (IMPACT-PS) 
PROTOCOL NUMBER: AE451-G-18-004 
PROTOCOL DATE:  
24 June 2019 
NCT NUMBER: 
NCT03832738 
 
 
 


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Cover Page 
Akros Pharma Inc. 
Clinical Study Protocol  
PROTOCOL TITLE: 
A Multicenter, Randomized, Double-blind, Placebo-controlled, 
Parallel-group Study to Evaluate the Efficacy and Safety of 
JTE-451 Administered for 16 Weeks in Subjects with Moderate to 
Severe Plaque Psoriasis (IMPACT-PS) 
 
PROTOCOL NUMBER: 
AE451-G-18-004 
 
DATE: 
24 June 2019 
 
IND NUMBER:  
 
EUDRACT NUMBER: 
2018-003359-40 
SPONSOR: 
Akros Pharma Inc.  
302 Carnegie Center, Suite 300 
Princeton, NJ  08540 
 
SPONSOR CONTACT: 
Akros Pharma Inc. 
 
 
 
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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Table of Contents 
COVER PAGE.................................................................................................................................1 
SIGNATURE PAGE .......................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
PROTOCOL SYNOPSIS ................................................................................................................9 
1 
INTRODUCTION .................................................................................................................13 
1.1 
Background ................................................................................................................... 13 
1.1.1 Psoriasis .................................................................................................................... 13 
1.1.2 Treatment of Psoriasis............................................................................................... 13 
1.1.3 Retinoid-related Orphan Receptor γ (RORγ) ............................................................ 14 
1.2 
JTE­451 ......................................................................................................................... 14 
1.2.1 Nonclinical Information ............................................................................................ 14 
1.2.2 Clinical Information .................................................................................................. 17 
1.3 
Justification of Study Population and Dose Selection .................................................. 20 
1.3.1 Justification for Study Population ............................................................................. 20 
1.3.2 Justification for Study Design ................................................................................... 20 
1.3.3 Justification for Dose Selection ................................................................................ 21 
2 
STUDY OBJECTIVES ..........................................................................................................23 
3 
INVESTIGATIONAL PLAN ................................................................................................23 
3.1 
Number of Sites and Subjects ....................................................................................... 23 
3.2 
Study Design ................................................................................................................. 23 
3.3 
Selection of Study Population ....................................................................................... 24 
3.3.1 Inclusion Criteria ...................................................................................................... 24 
3.3.2 Exclusion Criteria ..................................................................................................... 25 
3.4 
Removal of Subjects from the Study ............................................................................ 28 
3.5 
Study Procedures .......................................................................................................... 30 
3.5.1 Informed Consent...................................................................................................... 34 
3.5.2 Screening Period ....................................................................................................... 34 
3.5.3 Double-blind Treatment Period ................................................................................ 34 
3.5.4 Follow-up Period ...................................................................................................... 35 
3.5.5 Study Restrictions ..................................................................................................... 36 
3.5.6 Procedure Definitions ............................................................................................... 40 
3.5.7 Clinical Institutions and Laboratories ....................................................................... 48 
3.6 
Adverse Events ............................................................................................................. 49 
3.6.1 Safety Definitions ..................................................................................................... 49 
3.6.2 Assessing Adverse Events ........................................................................................ 50 
3.6.3 Reporting Adverse Events ........................................................................................ 52 
3.7 
Identification of Treatments .......................................................................................... 54 


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3.7.1 Method of Assigning Subjects to Treatment Groups ................................................ 54 
3.7.2 Identity of Investigational Products .......................................................................... 54 
3.7.3 Storage and Handling Procedures ............................................................................. 54 
3.7.4 Clinical Supplies Packaging ..................................................................................... 54 
3.7.5 Administration of Study Drug .................................................................................. 55 
3.7.6 Management of Clinical Supplies ............................................................................. 55 
3.7.7 Randomization .......................................................................................................... 56 
3.7.8 Blinding..................................................................................................................... 56 
3.7.9 Breaking the Blind .................................................................................................... 56 
3.8 
Statistical Methods ........................................................................................................ 56 
3.8.1 Subject Population for Analysis................................................................................ 57 
3.8.2 Sample Size ............................................................................................................... 57 
3.8.3 Interim Analysis ........................................................................................................ 57 
3.8.4 Efficacy Analyses ..................................................................................................... 57 
3.8.5 Safety Analyses ......................................................................................................... 59 
3.8.6 Pharmacokinetic Analyses ........................................................................................ 60 
3.9 
Quality Control and Quality Assurance ........................................................................ 61 
4 
INVESTIGATOR OBLIGATIONS ......................................................................................61 
4.1 
Institutional Review/Independent Ethics Committee ................................................... 61 
4.2 
Subject Consent ............................................................................................................ 62 
4.3 
Data Collection ............................................................................................................. 62 
4.3.1 Case Report Forms .................................................................................................... 62 
4.3.2 Source Documents .................................................................................................... 62 
4.4 
Adherence to Protocol................................................................................................... 63 
4.5 
Reporting Adverse Events ............................................................................................ 63 
4.6 
Investigator’s Final Report ........................................................................................... 63 
4.7 
Records Retention ......................................................................................................... 63 
4.8 
Confidentiality .............................................................................................................. 63 
4.9 
Publications ................................................................................................................... 64 
5 
STUDY MANAGEMENT ....................................................................................................64 
5.1 
Monitoring .................................................................................................................... 64 
5.2 
Management of Protocol Amendments and Deviations ............................................... 65 
5.3 
Study Termination ........................................................................................................ 65 
5.4 
Sponsor’s Final Report ................................................................................................. 65 
6 
REFERENCES ......................................................................................................................66 
7 
APPENDICES .......................................................................................................................68 
 
 
 


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List of Figures 
 
Figure 1. 
Study Schema............................................................................................................ 30 
Figure 2. 
Dosing and Pharmacokinetic Sample Collection Time ............................................ 33 
 
List of Tables 
 
Table 1. 
Schedule of Study Procedures .................................................................................. 31 
Table 2. 
Psoriasis Therapy and Immunomodulating Therapy Restrictions ............................ 36 
Table 8. 
The PASI Scoring ..................................................................................................... 42 
 
 


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List of Abbreviations and Definition of Terms 
Abbreviation 
Definition of term 
14C-JTE-451 
14C-labeled JTE-451 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUCinf 
Area under the concentration-time curve from the time of dosing to infinity 
BA 
Bioavailability 
BCRP 
Breast cancer resistance protein 
βhCG 
Human chorionic gonadotropin 
BID 
Twice a day 
BMI 
Body mass index 
BSA 
Body surface area 
CFR 
Code of federal regulations 
CI 
Confidence interval 
CL_F 
Apparent oral clearance of drug following extravascular administration 
(total body clearance) 
Cmax 
Maximum concentration 
CPRI 
Central Pharmaceutical Research Institute  
CRF 
Case report form 
CTCAE 
Common terminology criteria for adverse events 
CV% 
Coefficient of variation 
CYP 
Cytochrome P450 
ECG 
Electrocardiogram 
eCOA 
Electronic clinical outcome assessment 
EOT 
End of treatment 
FSH 
Follicle-stimulating hormone 
GCP 
Good clinical practice 
GI 
Gastrointestinal 
HBc 
Hepatic B core 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
hCav1.2 
L-type calcium channel 
HCV 
Hepatitis C virus 
hERG 
Human ether-a-go-go-related gene 
HIV 
Human immunodeficiency virus 
hNav1.5 
Human cardiac sodium channel 
HPLC-MS/MS 
High performance liquid chromatography/tandem mass spectrometry 
HR 
Hear rate 


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Abbreviation 
Definition of term 
IAP 
Intestine-originated alkaline phosphatase 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent ethics committee 
IL 
Interleukin 
IMP 
Investigational medicinal product 
IRB 
Institutional review board 
ITT 
Intent-to-treat 
IWRS 
Interactive web response system 
Ki 
Inhibition constant  
LOCF 
Last observation carried forward 
MATE1 
Multidrug and toxin extrusion transporter 1 
MATE2-K 
Multidrug and toxin extrusion transporter 2K  
MDR1 
Multidrug resistance protein 1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOA 
Mechanism of action 
mRNA 
Messenger ribonucleic acid 
MTX 
Methotrexate 
NOAC 
Novel anticoagulant agent 
NOAEL 
No observed adverse effect level 
NRS 
Numeric rating scale 
OAT1 
Organic anion transporter 1 
OAT3 
Organic anion transporter 3 
OATP1B1 
Organic anion transporting polypeptide 1B1 
OATP1B3 
Organic anion transporting polypeptide 1B3 
OCT2 
Organic cation transporter 2 
PASI 
Psoriasis area and severity index 
PK  
Pharmacokinetic(s) 
PLSS 
Psoriatic lesion severity sum 
PP 
Per protocol 
PR 
Interval from beginning of the P wave to the beginning of the QRS 
complex in the frontal plane  
PR 
Interval from beginning of the P wave to the beginning of the QRS 
complex in the frontal plane  
PT 
Prothrombin time 
PUVA  
Psoralen plus ultraviolet A 
QD 
Once a day 
QOL 
Quality of life 
QRS 
Duration of QRS complex in the frontal plane 


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Abbreviation 
Definition of term 
QT 
Interval from beginning of the QRS complex to end of the T wave in the 
frontal plane  
QTcF 
Fridericia-corrected QT interval 
ROR 
Retinoid-related orphan receptor 
RR 
Interval from beginning of the QRS complex in the frontal plane to the next 
QRS complex  
SAE 
Serious adverse event  
SAP 
Statistical analysis plan  
SD 
Standard deviation 
SPF 
Sun protection factor 
sPGA 
Static Physician’s Global Assessment 
SUSAR 
Suspected unexpected adverse drug reaction 
t1/2 
Elimination half-life associated with the terminal slope (λz) of a 
semilogarithmic concentration-time curve  
TB 
Tubercle bacillus 
TEAE 
Treatment-emergent adverse event 
Th cells 
T helper cells (type 1 [Th1], type 2 [Th2], type 17 [Th17]) 
TNF 
Tumor necrosis factor 
ULN 
Upper limit of normal 
UVA 
Ultraviolet A 
UVB 
Ultraviolet B 
V_F 
Apparent volume of distribution following extravascular administration 


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Protocol Synopsis 
STUDY TITLE 
A Multicenter, Randomized, Double-blind, Placebo-controlled, 
Parallel-group Study to Evaluate the Efficacy and Safety of 
JTE-451 Administered for 16 Weeks in Subjects with Moderate to 
Severe Plaque Psoriasis (IMPACT-PS) 
PROTOCOL NUMBER AE451-G-18-004 
CLINICAL PHASE 
Phase 2 
STUDY DURATION 
Approximately 24 weeks duration per subject: 
• Up to 28-day Screening Period 
• 16-week double-blind Treatment Period 
• Approximately 4-week Follow-up Period 
STUDY OBJECTIVES 
Primary Objective 
To evaluate the efficacy of JTE-451 administered for 16 weeks in 
subjects with moderate to severe plaque psoriasis compared with 
placebo. 
Secondary Objectives 
• To evaluate the safety and tolerability of JTE-451 administered 
for 16 weeks in subjects with moderate to severe plaque 
psoriasis. 
• To evaluate the pharmacokinetics (PK) of JTE-451 
administered for 16 weeks in subjects with moderate to severe 
plaque psoriasis. 
 


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STUDY DESIGN 
This is a 16-week, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study in subjects with moderate 
to severe plaque psoriasis. Eligible subjects will be randomized at 
Visit 2 to receive JTE-451 200 mg twice a day (BID) (400 mg/day), 
400 mg BID (800 mg/day) or placebo BID for 16 weeks. 
Approximately 150 subjects are planned to be randomized into 
3 treatment groups. Randomized subjects will visit the site at 
Weeks 2, 4, 8, 12 and 16 during the Treatment Period. Follow-up 
visits will take place approximately 4 weeks after the last dose of 
study drug. Randomization will be stratified based on prior exposure 
to biologic therapy (i.e., biologic-naïve vs. biologic-experienced 
subjects) and body weight (i.e., <90 kg vs. ≥90 kg at Visit 2). 
The end of the study is defined as the date of the last subject last 
visit. 
PLANNED 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 ratio) of approximately 150 subjects 
(approximately 50 subjects in each treatment group). 
KEY ELIGIBILITY 
CRITERIA 
• Male or female, ≥18 and ≤70 years of age at Visit 1; 
• Have had a history of moderate to severe plaque psoriasis for at 
least 6 months prior to Visit 1; 
• Subjects with moderate to severe plaque psoriasis covering 
≥10% body surface area (BSA), with a psoriasis area and 
severity index (PASI) ≥12 and static Physician’s Global 
Assessment (sPGA) score ≥3 at Visit 1 and Visit 2; 
• Body Mass Index (BMI) ≤40 kg/m2 at Visit 1; 
 
 
• Absence of erythrodermic psoriasis, pustular psoriasis, guttate 
psoriasis, medication-induced psoriasis or other skin conditions 
(e.g., clinically-significant eczema or severe acne) at Visit 1; 
• No history or presence of itch due to underlying conditions other 
than plaque psoriasis which cause or influence pruritus of the 
skin within 12 months prior to Visit 1; 
• Negative QuantiFERON®-TB Gold Plus test, negative chest 
radiographic findings for tubercle bacillus (TB) and no other 
evidence of active or untreated latent TB;  


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KEY ELIGIBILITY 
CRITERIA, Cont. 
• No history of a clinically-significant infection (e.g., infection 
that required oral antimicrobial therapy) within 4 weeks prior to 
Visit 2; 
Note: Subjects with treated upper respiratory tract infection or 
urinary tract infection will be permitted if it resolved prior to 
Visit 2. 
• No history of infections requiring hospitalization or parenteral 
antibiotic, antiviral, antifungal or antiparasitic therapy within 
3 months prior to Visit 2 and no history of recurrent infections 
or 
conditions 
predisposing 
to 
chronic 
infections 
(e.g., bronchiectasis, chronic osteomyelitis); 
INVESTIGATIONAL 
PRODUCT 
(STUDY DRUG), 
FORMULATION, 
DOSAGE,  
ROUTE AND TIME OF 
ADMINISTRATION 
 
 
JTE-451 
200 mg Tablets 
200 mg BID, 400 mg BID 
Oral administration for 16 weeks starting on the day of 
randomization at Visit 2, BID, at approximately 12-hour intervals, 
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 at Visit 7, when no study drug will be 
administered). 
REFERENCE 
PRODUCT 
(STUDY DRUG), 
FORMULATION, 
DOSAGE, 
ROUTE AND TIME OF 
ADMINISTRATION 
 
 
Placebo 
Tablets (identical in appearance to JTE-451 tablets)  
Not applicable (N/A) 
Oral administration for 16 weeks starting on the day of 
randomization at Visit 2, BID, at approximately 12-hour intervals, 
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 at Visit 7, when no study drug will be 
administered). 


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EVALUATION 
CRITERIA 
Primary Efficacy Parameters 
Proportion of subjects achieving a minimum 75% improvement 
from baseline in the PASI (PASI-75) at end of treatment (EOT). 
Secondary Efficacy Parameters 
The following will be evaluated at Weeks 2, 4, 8, 12, 16, 20 and 
EOT, unless otherwise stated. 
• Proportion of subjects achieving PASI-50/PASI-75/PASI-90; 
• Percent change from baseline in PASI; 
• Proportion of subjects achieving sPGA score of 0 or 1; 
• Change from baseline in sPGA score; 
• Percent change from baseline in BSA; 
• Change from baseline in Skindex-16; 
• Change from baseline in Itch Numeric Rating Scale (NRS); 
• Change from baseline in each domain score/questionnaire of the 
Skindex-16. 
Safety Assessments 
• 
Number and proportion of subjects with adverse events (AEs), 
type and severity of AEs, change from baseline in safety 
laboratory, vital sign and electrocardiogram (ECG) parameters. 
Pharmacokinetic Assessments 
• Trough plasma levels of JTE-451; 
STATISTICAL 
METHODS 
Appropriate statistical analysis will be performed using the software 
for statistical analysis by the SAS Windows®. 


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1 
Introduction 
1.1 Background 
1.1.1 Psoriasis 
Plaque psoriasis is the most common form of psoriasis. It is an intractable inflammatory skin 
disease characterized by raised, well-demarcated, itchy erythematous circular-to-oval plaques 
covered with adherent silvery white scales. In addition to the skin-related manifestation, 
concomitant joint- and nail-related signs and symptoms may be experienced by some patients. The 
number of patients with psoriasis is estimated to be approximately 7.5 million in the US, 
7.5 million in the EU and 420 thousands in Japan, and the worldwide prevalence is calculated to 
be 0.6 to 4.8%.1-4 It is also known that the quality of life (QOL) of the psoriasis patients is lower 
than that of patients with cancer or diabetes.5 As a result, psoriasis markedly restricts the social 
activities of patients. 
Various cytokines produced by Th1 and Th17 cells play a crucial role in the development of 
psoriasis. Clinical studies of biologics targeting cytokines have revealed that interleukin (IL)-17 
produced by Th17 cells and IL-23 responsible for the growth and maintenance of Th17 cells, play 
highly important roles in the disease progression and exacerbation of psoriasis.6-9 
1.1.2 Treatment of Psoriasis 
The goal of psoriasis treatment is to achieve rapid remission induction, long-term control of skin 
manifestations and improve the QOL. The pharmacotherapy for psoriasis mainly consists of 
topical vitamin D3 analogues and topical corticosteroids, and depending on the symptoms, 
systemic treatment such as cyclosporine and methotrexate (MTX) may be used. For patients with 
concomitant joint symptoms and those who have not sufficiently responded to conventional 
systemic treatment, biologics targeting such as tumor necrosis factor (TNF)-ɑ, IL-23 and IL-17 
may be prescribed. Cyclosporine and MTX, which form the core of the systemic treatment, exert 
their actions more rapidly and effectively compared with the topical drugs and can induce 
remission in many patients.10 However, these drugs raise many safety concerns: long-term 
treatment with cyclosporine may cause nephropathy or increase the blood pressure, and MTX may 
lead to myelosuppression and a wide variety of other side effects. Biologics can achieve complete 
remission in some patients, making a massive contribution to the advancement in treatment of 
psoriasis. However, biologics involve many issues that have to be resolved: (1) approximately 
30% of the patients do not respond to therapy (2) increased risks for infections and cancer 
development (3) financial burden is high and (4) the lack of availability of long-term safety data 
for these compounds.11 Additionally, it is known that psoriasis significantly impacts the QOL of 
the patients affected and there is not always a direct correlation between the severity grading of 
the disease (which is significantly related to the amount of body area covered by the rash) and its 
impact on the QOL (e.g., if the rash is limited to the face, the severity may be assessed as mild, 
although the QOL is significantly impaired). Nonetheless, highly efficacious therapeutic options, 
such as biologics may not be selected in such cases, therefore this issue is not being addressed with 
the current therapeutic options.  
Based on these reasons, next generation of therapeutic drugs for psoriasis are expected to be 
cost-effective, highly efficacious and safe oral drugs that can induce remission rapidly and achieve 


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complete remission with high probability. Unlike existing drugs for systemic treatment that are 
indicated only for severe cases, the cost, as well as the safety profile of the new generation 
therapeutics must allow prescribing those to any patient regardless of the severity of the disease. 
1.1.3 Retinoid-related Orphan Receptor γ (RORγ) 
Retinoid-related orphan receptor γ is a nuclear receptor, discovered in 199412, but its functions 
remained unclear for many years. In 2006, it was reported that RORγ is specifically expressed in 
Th17 cells and that it plays a crucial role in the differentiation of naive T cells into Th17 cells as 
well as in the activation of Th17 cells.13 Since then, RORγ has drawn attention as a target molecule 
for diseases involving Th17 cells. RORγ binds to the ROR binding element following nuclear 
translocation and enhances the transcriptional activities of target genes such as IL-17 and IL-23 
receptors. The molecule is thus considered to be a master regulator playing a central role in the 
functional regulation of Th17 cells. The biologics targeting IL-17 and IL-23 are currently indicated 
for some autoimmune diseases in clinical settings. IL-17 is produced by Th17 cells, functions of 
which are regulated by RORγ and IL-23 plays an important role in the proliferation and 
maintenance of Th17 cells. These facts suggest that RORγ, a master regulator of Th17 cells, can 
play an important role in the pathogenesis and exacerbation of various autoimmune diseases. 
1.2 JTE-451 
A brief summary of the nonclinical and clinical findings is included below. Additional details are 
described in the JTE-451 Investigator’s Brochure (IB). 
1.2.1 Nonclinical Information 


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1.2.2 Clinical Information 


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1.3 Justification of Study Population and Dose Selection 
1.3.1 Justification for Study Population 
Subjects with moderate to severe plaque psoriasis, based on several psoriasis severity criteria 
(i.e., psoriasis area and severity index [PASI], sPGA and body surface area [BSA] described in 
Section 3.3.1) will be enrolled in this study. 
 
 
 
 
 
 
 
From a safety perspective, study restrictions will be implemented based on the 
 
 
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. 
 
 
 
Other 
general 
safety-related 
restrictions 
such 
as 
cardiovascular-system-related, hepatic and renal function-related restrictions, as well as the known 
safety signals associated with other compounds with similar MOA have been implemented to 
monitor and adequately manage safety-related findings. 
1.3.2 Justification for Study Design 
A parallel group, placebo-controlled design will be employed in this study to evaluate the effect 
of JTE-451 on the efficacy and safety of JTE-451 compared to placebo in subjects with plaque 
psoriasis. Briefly, upon completion of all protocol-mandated screening procedures, qualified 
subjects will be randomized at Visit 2 in a 1:1:1 ratio to one of the following three parallel dose 
groups: JTE-451 200 mg BID (400 mg/day), JTE-451 400 mg BID (800 mg/day) or placebo BID 
(approximately 50 subjects to be randomized per group) and will receive the double-blind 
treatment for 16 weeks followed by a 4-week Follow-up Period. To minimize potential 
confounders in efficacy responses, randomization will be stratified based on prior exposure to 
biologic therapy (i.e., biologic-naïve vs. biologic-experienced subjects) and body weight 
(i.e., <90 kg vs. ≥90 kg at Visit 2). No clinically meaningful food effect on the PK of JTE-451 was 
shown in the single ascending dose study 
 thus, study drug will be 
administered regardless of meals. Based on the PK charac eristics of the compound, the protocol 
requires the study drug administration twice a day, at approximately 12-hour intervals. The 
duration of the double-blind treatment period is sufficient to obtain the proof-of-efficacy for 
JTE-451 in subjects with plaque psoriasis. The duration of the Follow-up Period is set to 
approximately 4 weeks; standard duration for similar outpatient studies administered an 


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investigational product. Based on the PK characteristics of JTE-451, this period is considered 
conservative, as JTE-451 clears the human body within approximately one day after the last dose. 
The efficacy parameters assessed in this study are consistent with the standards in the industry in 
similar psoriasis trials (e.g., PASI, sPGA, BSA). 
 
ps
 
 
 
 
. To minimize the chances of 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. 
With respect to study entry restrictions, 
 
 screening procedures and exclusion criteria to mitigate and minimize 
the risk of infections, including tuberculosis and viral infections have been included to ensure the 
safety of subjects. To minimize the risks to the subjects and to facilitate further characterization of 
the safety profile of JTE-451, standard safety evaluations, such as AE collection, physical 
examination, vital sign, laboratory (including biochemistry, hematology, coagulation and 
urinalysis) and ECG assessments are included in the study as part of ongoing safety monitoring 
activities. Data for these parameters will be collected throughout the study and will be evaluated 
on an ongoing basis.  
1.3.3 Justification for Dose Selection 
Selection of JTE-451 doses in this study (200 mg BID and 400 mg BID) is based on the collective 
data from nonclinical studies and Phase 1 clinical studies in healthy subjects 
1 
 and in subjects with plaque psoriasis 
.  
 
 
 


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2 
Study Objectives 
Primary Objective 
To evaluate the efficacy of JTE-451 administered for 16 weeks in subjects with moderate to severe 
plaque psoriasis compared with placebo. 
Secondary Objectives 
• To evaluate the safety and tolerability of JTE-451 administered for 16 weeks in subjects with 
moderate to severe plaque psoriasis. 
• To evaluate the pharmacokinetics (PK) of JTE-451 administered for 16 weeks in subjects with 
moderate to severe plaque psoriasis. 
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 ratio) approximately 150 subjects (approximately 50 subjects per treatment group). 
3.2 Study Design 
This is a 16-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study 
in subjects with moderate to severe plaque psoriasis.  
Eligible subjects will be randomized at Visit 2 to receive JTE-451 200 mg BID (400 mg/day), 
400 mg BID (800 mg/day) or placebo BID for 16 weeks. Approximately 150 subjects are planned 
to be randomized into 3 treatment groups. Randomized subjects will visit the site at Weeks 2, 4, 8, 
12 and 16 during the Treatment Period. A follow-up visit will take place approximately 4 weeks 
after the last dose of study drug. Randomization will be stratified based on prior exposure of 
subjects to biologic therapy (i.e., biologic-naïve vs. biologic-experienced subjects) and body 
weight (i.e., <90 kg vs. ≥90 kg at Visit 2). 
The study duration will be of approximately 24 weeks per subject: 
• Up to 28-day Screening Period 
• 16-week double-blind Treatment Period 
• 4-week Follow-up Period 
The end of the study is defined as the date of the last subject last visit. 
 
 


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3.3 Selection of Study Population 
Written informed consent must be obtained prior to performing any study-related procedures 
including washout of previous medications to participate in the study. A copy of the informed 
consent will be provided to the subject. 
3.3.1 Inclusion Criteria 
To qualify for the study, the subject must satisfy the following criteria: 
1. Male or female, ≥18 and ≤70 years of age at the time of Visit 1 (Screening Visit); 
2. Have a history of moderate to severe plaque psoriasis for at least 6 months prior to Visit 1; 
3. Subjects with moderate to severe plaque psoriasis covering ≥10% BSA, with a PASI ≥12 and 
sPGA score ≥3 at Visit 1 and Visit 2 (baseline); 
4. Body Mass Index (BMI) ≤40 kg/m2 at Visit 1; 
5. Female subjects may participate if they meet one of the following criteria:  
• Surgically sterile (e.g., hysterectomy or bilateral oophorectomy), 
• Post-menopausal; 
o Female subjects with a documented history of lack of menses for ≥12 consecutive 
months prior to Visit 1 with no other reversible medical etiology, 
o Female subjects with a history of lack of menses but onset <12 months prior to Visit 1 
and a serum follicle-stimulating hormone (FSH) >40 mIU/mL, or 
• If of childbearing potential (all female subjects other than above), with a negative 
pregnancy test at Visit 1 and Visit 2, and if participates in heterosexual intercourse, agrees 
to be compliant with consistent and correct use of acceptable methods of contraception as 
described below for the duration of the study and for at least 30 days after the last dose of 
study drug. Acceptable methods of birth control for this study are: 
a) at least one highly effective contraceptive method, which includes intrauterine 
devices, tubal ligation, bilateral tubal occlusion, partner sterilization (with appropriate 
post-vasectomy documentation of the absence of sperm in the ejaculate), intrauterine 
hormone-releasing systems, or 
b) at least two effective methods, which include male condom, female condom, 
cervical cap, diaphragm or contraceptive sponge; all with spermicide  
Notes: 
• Female subjects of childbearing potential must agree to undergo urine pregnancy 
testing from Visit 2 until Visit 8.  
• Hormonal methods (except for intrauterine hormone-releasing systems) are not 
considered an acceptable method of contraception for the study. 
• Concomitant use of a female condom and a male condom is not considered an 
acceptable method of contraception for the study. 
Note: Female subjects must not donate eggs for the duration of the study and for at least 
12 weeks after the last dose of study drug. 
6. Male subjects must agree to practice abstinence from heterosexual intercourse, use a barrier 
contraceptive method with spermicide if his partner is of childbearing potential for the duration 


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of the study and for at least 30 days after the last dose of study drug or be sterilized (with 
appropriate post-vasectomy documentation of the absence of sperm in the ejaculate): 
• Male subjects should be informed about the risks involved if pregnancy in female partners 
occurs while he is taking an investigative product and for at least 30 days after the last dose 
of study drug.  
• Counseling on appropriate contraception methods for their female partners should be given 
as follows: female partners of male subjects randomized in this study must be surgically 
sterile or post-menopausal, or in case of female partner of childbearing potential, they must 
agree to use at least one effective method of birth control (in addition to the method utilized 
by the male subject) for the duration of the study and for at least 30 days after the last dose 
of study drug. Please see inclusion criterion # 5 a) and # 5 b) for a list of acceptable forms 
of birth control for the study (hormonal methods will be allowed as one of two effective 
method for female partners of male subjects); 
• Male subjects must not donate sperm for the duration of the study and within 12 weeks of 
the last dose of study drug. 
7. 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. 
2. 
 
3. Presence of erythrodermic psoriasis, pustular psoriasis, guttate psoriasis, medication-induced 
psoriasis or other skin conditions (e.g., clinically-significant eczema or severe acne) that could 
interfere with study evaluations at Visit 1; 
 
4. History or presence of any itch due to underlying conditions other than plaque psoriasis which 
cause or influence pruritus of the skin (e.g., drug-induced pruritus, significant other systemic 
diseases with itch) within 12 months prior to Visit 1; 
5. Does not meet all study restrictions, including previous/concomitant medication restriction 
criteria, as described in Section 3.5.5.1; 
6. Leucocyte 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 Visit 1; 
7. Hemoglobin <11 g/dL or platelet count <100,000/mm3 at Visit 1; 
8. ALT >2.0 X the upper limit of normal (ULN) or AST >2.0 X the ULN at Visit 1; 
9. Serum creatinine >1.5 X the ULN at Visit 1; 


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10. Hemoglobin A1c (HbA1c) >8.5% at Visit 1; 
11. Positive viral serology at Visit 1 for: 
• HIV: positive HIV antibodies (Ab), 
• HBV: positive hepatitis B surface antigen (HBsAg), 
• HCV: positive HCV Ab; 
Note: Subjects who test negative for HBsAg and test positive for hepatic B core (HBc) Ab will 
not be excluded from the study. 
12. Positive drug of abuse test results at Visit 1, unless results are due to a medically relevant 
reason; 
Note: Subjects who test positive for only cannabinoids or opiates, and have had no evidence 
of substance dependence or substance abuse problem that could interfere with study 
evaluations may participate in the study according to the Investigator’s judgment, if all other 
study restrictions required by the protocol are met. 
13. History or presence of substance abuse, drug addiction or alcoholism within 1 year prior to 
Visit 1; 
Note: Alcoholism is defined as the consumption of more than 28 units of alcohol a week (an 
alcohol unit is defined as 300 mL of beer, 100 mL of wine, or 25 mL of hard liquor). 
14. Positive QuantiFERON®-TB Gold Plus test, positive chest radiographic findings for tubercle 
bacillus (TB) or any other evidence of active or untreated latent TB; 
• The QuantiFERON®-TB Gold Plus test should not be performed within 4 weeks from the 
date of a live vaccination; 
• If QuantiFERON®-TB Gold Plus test is indeterminate, a retest is allowed if results can be 
obtained within the timeframe allowed between Visit 1 and Visit 2. If the retest is also 
indeterminate, the subject will be excluded from the study; 
• Subjects with positive QuantiFERON®-TB Gold Plus test and a history of treated latent TB 
who have documented evidence of completed adequate treatment at least 12 months prior 
to Visit 2 may participate in the study, if all other study restrictions required by the protocol 
are met; 
• Subjects who have had household contact with a person with active TB are excluded, unless 
appropriate and documented prophylactic treatment for TB, as recommended by local 
guidelines, was completed at least 30 days prior to Visit 2. 
15. History of live vaccination within 4 weeks prior to Visit 2 or have a live vaccination planned 
during the study or within 6 weeks after the last dose of study drug; 
16. Have donated or received blood or blood products within 4 weeks prior to Visit 1; 
17. History of a clinically-significant infection (e.g., infection that required oral antimicrobial or 
antiviral therapy) within 4 weeks prior to Visit 2; 
  
Note: Subjects with treated upper respiratory tract infection or urinary tract infection will be 
permitted if the infection resolved prior to Visit 2. 
18. History of opportunistic infections or infection requiring hospitalization or parenteral 
antibiotic, antiviral, antifungal or antiparasitic therapy within 3 months prior to Visit 2 or 
history of recurrent infections or conditions predisposing subject to chronic infections 
(e.g., bronchiectasis, chronic osteomyelitis); 


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19. History or presence of any lymphoproliferative disorder (e.g., Epstein Barr Virus-related 
lymphoproliferative disorder, lymphoma, leukemia, multiple myeloma) or signs and symptoms 
suggestive of current lymphatic disease, such as Hodgkin's or Non-Hodgkin's lymphoma; 
20. History or presence of 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 
more than 6 months prior to Visit 1; 
21. History of organ transplantation; 
22. History of decompensated heart failure, fluid overload, myocardial infarction, uncontrolled 
arterial hypertension or evidence of ischemic heart disease or other serious cardiac disease 
within 12 months prior to Visit 1; 
23. Pregnant or nursing at Visit 1 or Visit 2 or plan to become pregnant or initiate breastfeeding 
during the study or within 30 days after the last dose of study drug; 
24. History of clinically-significant hypersensitivities (e.g., multiple drug allergies or severe 
allergic reactions, including angioedema); 
25. History or presence of significant uncontrolled depressive disorder (e.g., manic-depressive 
disorders, treatment-resistant major depression), history of suicidal ideation or behavior or 
presence of risk for suicide by Investigator’s judgment; 
26. History or presence of any other clinically relevant medical condition or disease or laboratory 
abnormality including hepatic, renal, gastroenterologic, respiratory, cardiovascular, 
endocrinologic, neurologic (e.g., epilepsy), psychiatric (e.g., schizophrenia), immunologic 
(e.g., immunocompromised subjects or subjects with autoimmune conditions other than 
psoriasis, such as rheumatoid arthritis, systemic lupus erythematosus, type I diabetes), 
metabolic bone (e.g., osteoporosis) 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; 
27. Cannot communicate reliably with the Investigator (including inability to complete the 
self-assessment questionnaire) 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. Death 
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 such as bathing, dressing, undressing, feeding self, 
using the toilet, taking medication, but not bedridden), according to the common terminology 
criteria for adverse events (CTCAE)14, are noted in a subject, he/she must be promptly 
evaluated by the Investigator (e.g., repeat tests, evaluation of the baseline parameters, 
concomitant medications) for potential withdrawal from the study. Every effort should be made 
to discuss this with the Medical Monitor prior to final decision, unless not feasible, based on 
safety considerations.  
3. 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 an adverse event. 
4. Non-compliance with Study Drug (i.e., <80% or >120% compliance at two consecutive study 
visits; exceptions on a case-by-case basis may be permitted if approved by Sponsor or 
designee). 
Note: Compliance will be evaluated at every study visit during the Treatment Period. If 
compliance of <80% or >120% is identified at a study visit, the Investigator or designee should 
counsel the subject and ensure steps are taken to improve compliance. 
5. Inclusion/Exclusion Criteria Not Met: If a subject who did not meet one or more of the study 
inclusion or exclusion criteria is identified after randomization, the Investigator, Medical 
Monitor and Sponsor will review that subject profile, including the medical history, prior and 
concomitant medications, physical examination, vital signs, 12-lead ECGs and clinical 
laboratory test results. An exception may be permitted on a case-by-case basis if the subject 
was randomized into the study due to a minor error determined to be of no clinical and/or safety 
risk to the subject.  
6. Protocol Violation: the subject is non-compliant with regard to this protocol (other than the 
withdrawal criteria 4 and 5 listed above), as determined by Sponsor, Medical Monitor or the 
Investigator on a case-by-case basis. 
7. Lost to Follow-up: the subject does not come for a scheduled visit and site staff makes at least 
3 attempts, including a formal letter, to contact the subject over 4 weeks from a scheduled visit 
with no success. 
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 listed above (actual reason must be documented by site). 
11. Other: actual reason must be documented by site. 


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Subjects who are removed from the study or withdraw consent to participate in the study after 
receiving at least one dose of study drug will be requested to complete an Early Termination Visit 
at which time the subject will undergo all the procedures described for Visit 7. Every effort should 
be made to perform the Visit 7 procedures as soon as possible after the last dose of study drug and 
the decision of discontinuation is made and prior to any changes made in the subject’s 
anti-psoriasis therapy. Additionally, at approximately 4 weeks after study drug discontinuation, 
subject should return for a Follow­up Visit, where all procedures described for Visit 8 should be 
performed. 
 
 


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3.5 Study Procedures 
 
Figure 1. Study Schema 
 
JTE-451 200 mg BID (N=50) 
Treatment 
   16 weeks 
Up to 4 weeks 
V = Study Visit 
Rand. = Randomization 
EOT = End of Treatment 
FU = Follow-up   
2 weeks 
2 weeks 
4 weeks 
4 weeks 
Screening 
Up to 4 weeks 
Follow-up 
Approx. 4 weeks 
Approx. 4 weeks 
= Double-blind Treatment Period 
JTE-451 400 mg BID (N=50) 
Placebo BID (N=50) 
4 weeks 
V1 
V2 
(Week 0) 
Rand. 
V3 
(Week 2) 
V4 
(Week 4) 
V5 
(Week 8) 
V6 
(Week 12) 
V7 
(Week 16) 
 
V8 
(Week 20) 
FU 


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Table 1. 
Schedule of Study Procedures 
 
Note: All study procedures should be performed at each study visit prior to study drug administration; 
except for appropriate PK sample collection procedures as discussed below (see Figure 2). When scheduled 
at the same time points, ECG and vital sign parameters collection activities should be performed prior to 
(or at least 15 minutes after) procedures involving venipuncture 
.  
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±4)
Week 12
(Day 84±4)
Week 16
(Day 112±4)
Week 20
(Day 140±4)
Visit
1
2
3
4
5
6
7
8
Informed Consentb
X
Inclusion/ Exclusion Criteria
X
X
Medical History
X
X
Demographic Information
X
Review Prior/ Concomitant Medications
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
Vital Signs including Weight
X
X
X
X
X
X
X
X
Height and Calculate BMI 
X
12-Lead ECG
X
X
X
X
Chest Radiographyc
X
QuantiFERON-TB Gold Plus Test
X
Drugs of Abuse Screen 
X
Viral Serology 
X
FSHd
X
Pregnancy Testd
X
X
X
X
X
X
X
X
HbA1c
X
Serum Biochemistry
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
Psoriasis Body Surface Area
X
X
X
X
X
X
X
X
PASI
X
X
X
X
X
X
X
X
sPGA
X
X
X
X
X
X
X
X
Skindex 16
X
X
X
X
X
X
X
X
Itch NRSe
Digital Photographyf
X
X
PSSI
Randomization using IWRS
X
Access IWRS and Dispense Study Drugi
X
X
X
X
X
Collect Study Drug and Check Compliancej
X
X
X
X
X
Study Drug Administrationk
X
X
X
X
X
JTE-451 PK Blood Samplesl
X
X
X
X
X
Document Adverse Eventsm
X
X
X
X
X
X
X
X
Treatment  Period


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a. 
The target day for each visit after randomization will be calculated relative to the date of Visit 2. Every attempt 
should be made to have the subject attend each visit within the windows specified in the table. The study site is 
encouraged to make a reminder phone call to the subject 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. 
b. Written informed consent must be obtained prior to performing any study-related procedures including washout 
of previous medications prior to or at the Screening Visit to participate in the study.  
c. 
Chest radiography may not be performed if it has been performed within 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 for all female subjects. At Visits 2 through 8 (or Follow-up 
Visit), urine pregnancy tests will be performed only for female subjects of childbearing potential. At Visit 1, 
female subjects with a documented history of lack of menses for ≥12 consecutive months with no other reversible 
medical etiology will be considered post-menopausal. Only for the female with a history of lack of menses but 
onset has been within 12 months prior to Visit 1, an FSH testing is required at Visit 1, then an FSH >40 mIU/mL 
will be considered post-menopausal, otherwise subject is considered of childbearing potential. 
e. 
The Itch NRS during a 24-hour recall period will be recorded in the e-diary by the subject once daily from the 
day of screening through the last visit. Site will dispense the e-diary device at Screening Visit and train the subject 
on how to use the device.  
f. 
If collecting photographs is raised as the reason for not participating in the study, the subject still can be part of 
the study without collecting photographs. Subjects who do not raise this objection will be required to take 
photographs of four half-body views (i.e., upper anterior, lower anterior, upper posterior and lower posterior). 
 
 
i. 
At Visit 2 through Visit 6, randomized subjects will receive sufficient study drug blister cards for the period 
between visits. At Visit 7, study drug will not be dispensed. If a subject discontinues study drug prematurely after 
receiving at least one dose of study drug, the termination should be recorded as soon as possible after the decision 
has been made. 
j. 
Subjects will be instructed to bring all used and unused blister cards to each study visit for accountability purposes. 
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 or returned by the subject. 
k. Oral administration for 16 weeks starting on the day of randomization at Visit 2, BID, at approximately 12-hour 
intervals, 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 
required procedures prior to administration have been performed (except for Visit 7, when no study drug will be 
administered, as the last dose will be taken the day prior to the visit). 
l. 
See Figure 2 for a detailed description of PK sampling time points. 
m. Adverse event information will be collected at the specified time points as well as at any time when a site staff 
member becomes aware of an AE after the subject signs the informed consent for the study. However, stable or 
improving pre-existing conditions detected through the screening procedures at Visit 1 (e.g., abnormalities in 
ECG, physical examination, vital signs and laboratory tests) are considered medical history and should be 
documented accordingly. 


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Figure 2. 
Dosing and Pharmacokinetic Sample Collection Time  
a. Exact date and time of dose at each visit at the site will be collected. 
b. Exact date and time of the last two doses prior to the pre-dose/trough PK sample collection will be 
collected. 
c. The pre-dose PK sample collections (i.e., samples obtained prior to the dosing of the study drug at the 
site) are mandatory in all subjects at all sites. The sample collection date and time will be recorded. 
d. The trough PK sample collections (relative to dosing of the study drug on the day prior to the visit) are 
mandatory in all subjects at all sites. The sample collection date and time will be recorded. 
e. Three post-dose PK samples per subject (relative to the dosing of the study drug at the site) should be 
collected from at least 34 randomized subjects. The samples will consist of one sample from 1 to 2 hours 
window at Week 0 (Visit 2), one sample from 3 to 6 hours window at Week 0 (Visit 2), and one sample 
from 3 to 6 hours window at Week 4 (Visit 4). The relative sampling time of the two samples of 3 to 
6 hours window at Visit 2 and Visit 4 should be separated by at least 1 hour. The sample collection date 
and time will be recorded. 


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3.5.1 Informed Consent 
Written informed consent must be obtained prior to performing any study-related procedures 
including washout of previous medications to participate in the study. A copy of the informed 
consent will be provided to the subject. Washout of previous medications to participate in the study 
will be started once the subject signs the informed consent regardless of the 28-day window of the 
Screening Period. 
3.5.2 Screening Period 
Day -28 (Visit 1) to Day 1 (Visit 2) 
Following signing 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 (fasted at least 10 hours prior to blood and urine sample 
collection), all study procedures except the blood/urine collection activities may be performed; the 
blood/urine collection will be rescheduled on a subsequent day within the visit window and the 
subject will be reminded to fast at least 10 hours.  
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, and viral serology), vital 
sign and ECG assessments is permitted, if considered appropriate by the Investigator, except stated 
otherwise (e.g., up to three-time repeat of blood pressure measurements at the Screening Visit is 
permitted). The repeat test result(s) will 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. 
3.5.3 Double-blind Treatment Period 
Day 1 (Visit 2) to Day 112±4 (Visit 7/Week 16) 
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, including Visit 2 (Randomization Visit), 
should be performed under fasted conditions (fasted at least 10 hours prior to blood and urine 
sample collection). If a subject arrives for a visit not fasted, then all study procedures except the 
blood/urine collection activities may be performed; the blood/urine collection will be rescheduled 
on a subsequent day within the visit window and the subject will be reminded to fast at least 
10 hours. Exception to this would be Visit 2, at which all study procedures should be completed 
within the same session, therefore, if the subject is not fasted at Visit 2, the full visit should be 
rescheduled. Every effort should be made to collect blood/urine samples at similar times 
throughout the study. 
All visits should be performed within the windows specified in Table 1. Every attempt should be 
made to have the subject attend each visit as scheduled. The site is encouraged to 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 


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closely as possible to these windows. A subject should not skip a protocol-specified visit due to 
scheduling difficulties. 
Subjects will be administered the first dose of study drug at the site, upon completion of all 
pre-dosing procedures and randomization at Visit 2; subsequently, they will be instructed to 
self-administer study drug BID, at approximately 12-hour intervals, regardless of meals. However, 
subjects should not take study drug on the day of a study visit until after all study procedures have 
been completed (except for post-dose PK samples collection as shown in Figure 2). On study visit 
days, subjects should take their scheduled study treatment at the site, under the supervision of the 
investigator or designee after all required procedures prior to administration have been performed 
(except for Visit 7, when no study drug will be administered, as the last dose will be taken the day 
prior to the visit). If the subject inadvertently took study drug on the day of the study visit, prior to 
all required procedures, 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. 
Exact date and time of the last two doses prior to the pre-dose/trough PK sample collection at 
Visits 4 through 7 and the dosing time at the site should be documented at each visit during the 
Treatment Period (i.e., Visits 2 through 6).  
Study drug will not be administered and all remaining study drug will be collected from the 
subjects at Visit 7.  
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 Visit 7 should 
be performed, if possible, prior to any changes made in the subject’s anti-psoriasis therapy. 
3.5.4 Follow-up Period 
Day 112±4 (Visit 7/Week 16) to Day 140±2 (Visit 8/Week 20)  
The Follow-up Visit will occur approximately 4 weeks after the last dose of study drug. 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.  
For subjects who discontinue the study prematurely after receiving at least one dose of study drug, 
follow-up procedures, as described for Visit 8 should be performed approximately 4 weeks after 
the last dose of study drug. 
 
 


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3.5.5 Study Restrictions  
3.5.5.1 Previous and Concomitant Medication Restrictions 
3.5.5.1.1 Prohibited Psoriasis Therapy and Immunomodulation Therapy 
Use of the following therapies will NOT be allowed during the Prohibited Period as described in 
Table 2. 
Table 2. 
Psoriasis Therapy and Immunomodulation Therapy Restrictions  
Prohibited Period 
Medication(s) 
24 weeks prior to Visit 2 till 
after the last study visit (Visit 8) 
• IL-12/IL-23p40 inhibitor (e.g., ustekinumab) 
• IL-23p19 inhibitor (e.g., guselkumab, mirikizumab, 
risankizumab, tildrakizumab) 
12 weeks (or 5 times the PK 
half­life, whichever is longer) 
prior to Visit 2 till after the last 
study visit (Visit 8) 
• Biologic agents other than above (including marketed or 
investigational) 
• Investigational systemic therapies 
28 days or 5 times the PK 
half-life (whichever is longer) 
prior to Visit 2 till after the last 
study visit (Visit 8) 
• Acitretin 
• Methotrexate 
• Cyclosporine 
• Apremilast 
• Oral/parental corticosteroids (including intramuscular or 
intraarticular administration) 
• Tofacitinib 
• Fumaric acid ester 
• Other immunomodulating systemic treatment 
• Psoralen plus ultraviolet A (PUVA) therapy 
• Ultraviolet A (UVA) therapy 
• Ultraviolet B (UVB) therapy 
• Investigational topical therapies 
14 days prior to Visit 2 till after 
the last study visit (Visit 8) 
• Topical corticosteroids 
• Topical vitamin A or D analog preparations 
• Anthralin 
• Topical calcineurin inhibitors (e.g., cyclosporine)  
Use of one (1) topical non-medical moisturizer (e.g., Cetaphil®) will be allowed during the study, 
however it will be prohibited within 12 hours prior to the study visit.  
Note: If a subject develops significant clinical exacerbation of their psoriasis at any time during 
the entire duration of the study, study drug may be withdrawn and the subject will be treated 
clinically per existing standard of care. 


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3.5.5.1.3 Permitted Medications to be used with Caution 
Permitted medications (Appendix 1) are based on nonclinical and clinical drug-drug interaction 
data with JTE-451. J
 
 
 
 
 
 
 
 
 


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3.5.5.1.4 General Medication-related Protocol Instructions: 
• Generally, changes in medication dose/route of administration or initiation of new medications 
during the conduct of the study is not recommended unless such actions are considered 
medically necessary; 
• 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), as described in Section 3.5.6.10; 
• Contact the Medical Monitor with questions regarding prior/concomitant therapy.  
3.5.5.2 Dietary Restrictions 
Grapefruit juice and grapefruit are not permitted for at least 3 days prior to Visit 2 and during the 
Treatment Period. 
3.5.5.3 UV-Related Restrictions 
Every effort should be made to minimize/eliminate unnecessary sun exposure during the study. If 
sun exposure is unavoidable, sunscreen with a sun protection factor (SPF) of minimum 30 should 
be utilized. Intentional tanning is prohibited throughout the study. 
3.5.5.4 General Restrictions 
• 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. 
• Subjects should not donate blood or receive any blood or blood products within 4 weeks prior 
to Visit 1 and throughout the study duration. 
• 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. 
 


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3.5.6 Procedure Definitions 
3.5.6.1 Static Physician’s Global Assessment (sPGA) 
The sPGA will be performed on psoriatic lesions overall by the Investigator according to the 
schedule summarized in Table 1. 
The sPGA is used to determine the severity of subject’s psoriatic lesion at a given time point. 
Every effort should be made to perform the sPGA assessments by the same evaluator throughout 
the study. The psoriatic lesion will be graded for induration, erythema and scaling based on the 
scales below. The sum of the 3 scales will be divided by 3 to obtain the final sPGA score. 
Induration (I) 
0 = no evidence of plaque elevation 
1 = barely palpable 
2 = slight but definite elevation, indistinct edge 
3 = elevated with distinct edges 
4 = marked plaque elevation, hard/sharp borders 
Erythema (E) 
0 = no evidence of erythema (post inflammatory hyperpigmentation and/or hypopigmentation may 
be present) 
1 = faint erythema 
2 = light red coloration 
3 = red coloration 
4 = dusky to deep red coloration 
Scaling (S) 
0 = no evidence of scaling 
1 = occasional fine scale 
2 = fine scale predominates 
3 = coarse scale predominates 
4 = thick, coarse scale predominates 
Add I+E+S = _______________/3 = ________ (Total Average) 
Physician’s Static Global Assessment based upon above Total Average 
0 = Cleared, except for residual discoloration 
1 = Minimal – majority of lesions have individual scores for I+E+S/3 that averages 1 
2 = Mild – majority of lesions have individual scores for I+E+S/3 that averages 2 
3 = Moderate – majority of lesions have individual scores for I+E+S/3 that averages 3 
4 = Severe – majority of lesions have individual scores for I+E+S/3 that averages 4 
Note: Scores should be rounded to the nearest whole number (e.g., if the total is ≤1.49, the score 
should be 1; if the total is ≥1.50, the score should be 2) except if the score is >0 and <1, score 
should be treated as 1. 


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3.5.6.2 Psoriasis Body Surface Area (BSA) and Psoriasis Area and Severity Index (PASI) 
The BSA assessment will be performed according to the schedule summarized in Table 1. 
The total BSA affected by plaque-type psoriasis will be estimated from the percentages of areas 
affected, including head, trunk, upper limbs and lower limbs (see below for PASI assessment). 
The following calculations will be done: each reported percentage will be multiplied by its 
respective body region corresponding factor (head = 0.1, trunk = 0.3, upper limbs = 0.2, lower 
limbs = 0.4). The resulting 4 values will be added up to estimate the total BSA affected by 
plaque-type psoriasis. 
Psoriasis area and severity index (PASI), a quantitative rating score to assess the severity of 
psoriatic lesions based on the area coverage and plaque appearance will be performed according 
to the schedule summarized in Table 1.  
Every effort should be made to perform the BSA and PASI assessments by the same evaluator 
throughout the study. 
The PASI score will be derived as indicated in Table 8.  
The head, trunk, upper limbs and lower limbs are assessed separately for erythema, thickening 
(plaque elevation, induration) and scaling (desquamation). The average degree of severity of each 
sign in each of the four body regions is assigned a score of 0 to 4. The area covered by lesions on 
each body region is estimated as a percentage of the total area of that particular body region. Listed 
below are further practical details to help with the assessment: 
1. The neck is assessed as part of the head. 
2. The axillae and groin are assessed as part of the trunk. 
3. The buttocks are assessed as part of the lower limbs. 
4. When scoring the severity of erythema, scales should not be removed. 
Because the head and neck, upper limbs, trunk and lower limbs correspond to approximately 10%, 
20%, 30% and 40% of the body surface area, respectively, the PASI score is calculated using the 
following formula: 
PASI = 0.1(EH+IH+DH)AH + 0.2(EU+IU+DU)AU + 0.3(ET+IT+DT)AT + 0.4(EL+IL+DL)AL 
The PASI scores can range from 0, corresponding to no signs of psoriasis, up to a theoretic 
maximum of 72.0, corresponding to maximal signs of psoriasis. 
 
 


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Table 8. 
The PASI Scoring 
Body 
region 
Erythema (E) Thickening 
(plaque elevation, 
induration, I) 
Scaling 
(desquamation, D) 
Area score (based on true 
area %, A)* 
Head (H)† 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0 = 0% 
1 = 1-9% 
2 = 10-29% 
3 = 30-49% 
4 = 50-69% 
5 = 70-89% 
6 = 90-100% 
Trunk (T)‡ 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0 = 0% 
1 = 1-9% 
2 = 10-29% 
3 = 30-49% 
4 = 50-69% 
5 = 70-89% 
6 = 90-100% 
Upper  
limbs (U) 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0 = 0% 
1 = 1-9% 
2 = 10-29% 
3 = 30-49% 
4 = 50-69% 
5 = 70-89% 
6 = 90-100% 
Lower  
limbs (L)§ 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0 = 0% 
1 = 1-9% 
2 = 10-29% 
3 = 30-49% 
4 = 50-69% 
5 = 70-89% 
6 = 90-100% 
* 
Percentage (not score) of body region (not whole body) affected will be entered in the CRF 
† 
Neck is assessed as part of the Head (H) body region. 
‡ 
Axillae and groin are assessed as part of the Trunk (T) body region. 
§ 
Buttocks are assessed as part of the Lower limbs (L) body region. 
 
 


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3.5.6.3 Skindex-16  
Subjects will complete Skindex-16 questionnaire according to the schedule summarized in Table 1. 
Skindex-16 is a 16-item, skin-related QOL questionnaire (see Appendix 2) and has 3 domain 
scores: symptoms, emotions, and functioning. Each 16-item QOL questionnaire will be reported 
on a scale of 0 to 6. Each raw score will be multiplied by 16.667, thus all responses will be 
transformed to a linear scale of 100 (i.e., from 0 [no effect] to 100 [effect experienced all the time]). 
If more than 25% of the responses missing, the scale is considered missing. An item with multiple 
answers is considered missing. 
3.5.6.5 Itch Numeric Rating Scale (NRS) 
The Itch NRS is a validated, self-reported instrument for measurement of itch intensity. It uses a 
24-hour recall period and asks subjects to rate the worst itch intensity on an 11-point scale ranging 
from 0 (no itch) to 10 (worst itch imaginable). 
The Itch NRS scores will be recorded by the subject using the e-diary once daily (before study 
drug administration once the subject is randomized) preferably at the same time of the day each 


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day from Screening through the last visit. Site will dispense the e-diary device at Screening Visit 
and train the subject on how to use the device.  
3.5.6.7 Physical Examination 
The physical examinations will be performed by a physician or a 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, neurological, psychiatric/emotional, 
lymphatic and musculoskeletal systems.  
3.5.6.8 Height and Weight Measurements and Body Mass Index Calculation 
The height and weight measurements will be performed according to the schedule summarized in 
Table 1. Subjects will remove their shoes and wear light clothing to be consistent between 
measurements of height and/or weight. The BMI will be calculated at Visit 1 using the following 
equation: (weight (kg)/[height (m)2]), 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. 
3.5.6.9 Medical History 
A complete medical history will be performed at Visit 1 and will include evaluations for past or 
present conditions. 
 
Any pre-existing conditions detected at Visit 1 (e.g., abnormalities in ECG, physical examination, 
vital signs and laboratory tests) are considered medical history. 
3.5.6.10 
Prior and Concomitant Medications 
Information pertaining to all medications use (including prescription, over-the-counter, 
supplements, vitamins and minerals) will be collected for the period of at least 30 days prior to 
Visit 1 and throughout the study. 
Information regarding any prior/current psoriasis therapies and/or immunomodulating therapies, 
as listed in Section 3.5.5.1.1 will be collected according to the schedule summarized in Table 1. 
3.5.6.11 
Vital Signs 
Vital sign assessments including blood pressure, heart rate, respiratory rate and body 
temperature (°C) will be performed in 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 
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3.5.6.12 
12-Lead ECG  
12-lead ECG recordings and conduction intervals including RR, PR, QRS, QT and 
Fridericia-corrected QT interval (QTcF) will be obtained according to the schedule summarized in 
Table 1. The Investigator or designee will review and assess each individual ECG report and the 
interpretation of the actual findings, rather than the automatic printout, results on the ECG tracing 
will be documented. Subjects will lay supine without pillows for at least 5 minutes prior to the 
12-lead ECG assessment. 
3.5.6.13 
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. 
3.5.6.14 
Serum Biochemistry 
Blood samples to assess ALP, albumin, ALT, AST, bilirubin, blood urea nitrogen, calcium, carbon 
dioxide, chloride, creatinine phosphokinase, creatinine, gamma-glutamyl transferase, globulin, 
glucose, C-reactive protein, lactate dehydrogenase, low-density lipoprotein cholesterol, phosphate, 
potassium, protein, sodium, total cholesterol, triglyceride, urate will be obtained under fasted 
conditions according to the schedule summarized in Table 1. 
3.5.6.15 
Coagulation 
Blood samples to assess thromboplastin time (PT) and activated partial thromboplastin time 
(aPTT) will be obtained as measures of blood coagulation according to the schedule summarized 
in Table 1. International normalized ratio will also be calculated. 
3.5.6.16 
Viral Serology  
Blood samples to assess HBc antibodies, HBsAg, HCV antibodies and HIV antibodies will be 
obtained at Visit 1. 
3.5.6.17 
Drugs of Abuse and Alcohol Screen 
Urine samples to assess amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine 
metabolites, opiates, ethanol, methadone, methylenedioxymethamphetamine and oxycodone will 
be obtained at Visit 1.  
3.5.6.18 
Urinalysis  
Urine samples to assess bilirubin, occult blood, color, glucose, ketone, leukocyte esterase, nitrite, 
pH, protein, specific gravity, turbidity and urobilinogen, as well as for a microscopic exam (to be 
performed only if the macroscopic exam is abnormal), including bacteria, cast, crystals, epithelial 
cells, mucus threads, erythrocytes, leukocytes and budding yeast will be obtained under fasted 
conditions according to the schedule summarized in Table 1. 
3.5.6.19 
Glycosylated Hemoglobin 
Blood samples to measure glycosylated hemoglobin (HbA1c) will be obtained at Visit 1. 


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3.5.6.20 
Pregnancy Test  
Blood samples from all female subjects will be collected at Visit 1 for a serum pregnancy test to 
assess human chorionic gonadotropin (βHCG) levels. At Visits 2 through 8, urine pregnancy tests 
will be performed only for female subjects of childbearing potential. 
3.5.6.21 
Follicle-stimulating Hormone 
Blood samples to assess the menopausal status will be collected at Visit 1 only from female 
subjects who report a history of for lack of menses but onset within 12 months with no other 
identified biological/surgical cause.  
3.5.6.22 
QuantiFERON®-TB Gold Plus Test 
The QuantiFERON®-TB Gold Plus test (according to the local standard of care) may be used as 
tuberculosis screening tools for the study during the Screening Period. Blood samples will be 
collected, processed and shipped during the Screening Period, according to the laboratory 
instructions. In case of an indeterminate QuantiFERON®-TB Gold Plus test, the test may be 
repeated one time if results can be obtained in time prior to Visit 2. If the retest is also 
indeterminate, subject will not be eligible for the study. 
Subjects with positive QuantiFERON®-TB Gold Plus test and a history of treated latent TB who 
have documented evidence of completed adequate treatment at least 12 months prior to Visit 2 
may participate in the study, if all other study restrictions required by the protocol are met. 
Subjects who have had household contact with a person with active tuberculosis are excluded, 
unless appropriate and documented prophylactic treatment for TB, as recommended by local 
guidelines, was completed at least 30 days prior to Visit 2. 
3.5.6.23 
Chest Radiography 
Chest radiography to include two views (anterior-posterior and lateral) will be obtained during the 
Screening Period in all subjects. If adequate chest radiography has been performed within 
3 months (12 weeks) prior to Visit 1 and documentation (including interpretation of TB status) is 
available, it will be provided to the Investigator for review and documented in the subject’s record. 
This 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.  


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3.5.6.25 
Photography 
If collecting photographs is raised as the reason for not participating in the study, the subject still 
can be part of the study without collecting photographs. Subjects who do not raise this objection 
will be required to take photographs of four half-body views (i.e., upper anterior, lower anterior, 
upper posterior and lower posterior),
 according to the schedule presented in Table 1. In all 
collected photographs, subject identification (e.g., eye, mouth, tattoos) will be blinded. Please refer 
to the photography manual for detailed instructions regarding collection, processing, storage and 
transmission of photographs. 
3.5.6.26 
Blood Samples for Pharmacokinetic Assessments 
Blood samples for quantification of JTE-451 in plasma will be obtained according to the schedule 
summarized in Table 1 and Figure 2. 
At each study visit during the treatment period (i.e., Visit 2 through Visit 7 [except for Visit 3, 
when no PK sample collection will be performed]), the actual dose time, as well as the sample 
collection time will be documented for PK data analysis. Refer to the laboratory manual for 
specific instructions regarding collection and processing of blood samples for PK assessments. 
3.5.6.27 
Analysis of JTE-451 in Plasma 
JTE-451 will be analyzed in plasma using a validated high performance liquid 
chromatography/tandem mass spectrometry (HPLC-MS/MS) method. 
The laboratory performing the JTE-451 assessments will be unblinded to facilitate analysis of only 
the samples from JTE-451-administered subjects. Plasma samples from placebo subjects may be 
analyzed as needed. 


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3.6 Adverse Events 
3.6.1 Safety Definitions 
Akros complies with the following International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use (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 (SAE): An SAE is defined as any untoward medical occurrence at any 
dose that meets any of the following criteria: 
• results in death 
• is life-threatening 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability or incapacity 
• is a congenital anomaly or birth defect 
• other important medical event 
Note: Important medical events that may not immediately result in death, be life-threatening, or 
require hospitalization but may be considered SAEs 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 above. Examples of such 
important 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 Drug 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 drug reaction, the nature (specificity) or 
severity of which is not consistent with the applicable product information (e.g., IB). 
Death: Death represents an outcome, 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. 
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, 


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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 (same diagnosis) would qualify as an SAE. 
Disability: A substantial disruption of a person’s ability to conduct normal life functions. 
Life-threatening: Any AE that places the patient or subject, in the view of the Investigator, at 
immediate risk of death, i.e., it does not include an event 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 parameters that are a result of an AE, which has already 
been reported. 
Pre-existing conditions detected at the Screening Visit (Visit 1), including abnormalities in ECG, 
physical examination, 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. 
Severity of Adverse Event: 
The severity of an AE will be graded as one of the following three grades: mild, moderate or 
severe. To determine the severity of AEs, refer to CTCAE, and translate Grade 1, Grade 2 and 
Grade 3 or higher grades of CTCAE14 into mild, moderate and severe, respectively. The 
investigator should determine the severity taking into account the general status of the subject, 
baseline values, outcomes as well as the severity grade into consideration. An AE of Grade 4 or 
Grade 5 should be assessed whether it should be reported as an SAE according to the SAE 
definition shown in Section 3.6.1. 


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• Mild: The AE is transient and may require only minimal treatment or therapeutic intervention. 
The AE does not generally interfere with usual activities of daily living. 
• Moderate: The AE is alleviated with additional specific therapeutic intervention. The AE 
interferes with usual activities of daily living, causing discomfort but poses no significant or 
permanent risk of harm to the subject. 
• Severe: The AE interrupts usual activities of daily living, or significantly affects clinical status, 
or may require intensive therapeutic intervention. 
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-451, the currently-known safety profile of JTE-451, known class effects 
of similar MOA drugs and any other information that is considered relevant by the Investigator. 
The relationship of an AE to the study drug will be assessed using the following three categories: 
• Not Related: The AE precedes the first administration of the study drug, or sufficient 
information exists to indicate that the etiology is clearly related to a cause other than the study 
drug. 
• Possibly Related: The AE follows a reasonable temporal sequence from the administration of 
the study drug and follows a known or plausible response pattern to the study drug, but could 
readily have been produced by a number of other factors. 
• Related: The AE follows a reasonable temporal sequence from the administration of the study 
drug; follows a known or expected response pattern to the study drug; is confirmed by 
improvement on stopping or reducing the dosage of the study drug (de-challenge) and 
reappearance of the event on repeat exposure (re-challenge); and cannot be reasonably 
explained by the participant’s clinical state. 
Action Taken with Regard to Study Drug: 
The evaluation of the action taken with the study drug will be assessed 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), or if the subject died. 


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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)  
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 appropriate study database. However, pre-existing conditions 
detected as part of the screening procedures should be documented as medical history. 
Worsening of the underlying condition (i.e., plaque psoriasis) or signs/symptoms associated with 
this condition should not be reported as an AE unless they meet at least one SAE criterion. 
Adverse events for the randomized subjects 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 up 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 possibly related or 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). 


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Notes:  
• The investigators should make every effort to assess the causality of the SAE prior to 
transmission of the initial SAE report, even if the investigators have minimal information. The 
SAE report should be amended, if the Investigators change his/her opinion of causality based 
on the follow-up information. 
• Personal information that could potentially identify the patient MUST NOT be included in 
any document that is sent to Sponsor or designee as per ICH GCP Principles 2.11, EU General 
Data Protection Regulation (GDPR) and other applicable laws and legislations. 
The Investigator must continue to follow the subject until the SAE has subsided, the condition 
becomes chronic in nature, the condition stabilizes (in 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 receive all Suspected 
Unexpected Serious Adverse Reaction (SUSAR) reports for onward submission to their local 
IRB/IEC as required. All SUSAR 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, the Sponsor or designee will report all SUSARs 
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 30 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 should 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 as any confirmed use of blinded study drug of more 
than two tablets per dose and/or twice a day. If such situation occurs, 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-451, thus appropriate 
symptomatic and/or supportive care should be provided at the Investigator’s discretion, as needed. 
The subject’s continued eligibility will be left to the judgment of the Investigator. 


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Information on overdose 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 it as soon as possible after he/she first becomes aware of it. If an overdose led to SAE, it 
will be reported to Sponsor or designee according to the Section 3.6.3. 
3.7 Identification of Treatments  
3.7.1 Method of Assigning Subjects to Treatment Groups 
After subject signs the informed consent, each site will assign potential 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-451 and placebo tablets should be stored at room temperature between 20 and 25°C 
(United States Pharmacopeia [USP]) in a secure location with restricted access. Please refer to the 
IMP Handling Directions for detailed instructions. 
3.7.4 Clinical Supplies Packaging 
Each site will receive a supply of double-blind study drug packaged as blister cards corresponding 
to 7 days of BID dosing. Each blister card will contain total 28 tablets.  
Labels will bear appropriate text as required by local regulation. 


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The planned blister card allocation of tablets for each dose, broken down by treatment group, is 
provided below. 
Treatment Group 
Daily Dose 1 
Daily Dose 2 
Tablet 1 
Tablet 2 
Tablet 3 
Tablet 4 
JTE-451 200 mg BID 
(Total daily dose: 400 mg) JTE-451 200 mg Placebo 
JTE-451 200 mg Placebo 
JTE-451 400 mg BID 
(Total daily dose: 800 mg) JTE-451 200 mg JTE-451 200 mg 
JTE-451 200 mg JTE-451 200 mg 
Placebo BID 
Placebo 
Placebo 
Placebo 
Placebo 
3.7.5 Administration of Study Drug 
During the Treatment Period, beginning on the day of Visit 2, subjects will self-administer 
two doses of study drug (2 tablets/dose, twice a day) daily for 16 weeks. Study drug will be taken 
BID, at approximately 12-hour intervals, regardless of meals. On the scheduled study visit days, 
subjects should not take study drug prior to arriving to the site. At the site, study drug will be 
administered from the previously supplied blister card, if available, after all study procedures have 
been completed (except for appropriate PK sample collection procedures as discussed in Figure 2). 
If no tablets from the previously supplied blister cards are available, then the subject should dose 
from the new blister card supplied at that visit. Study drug will not be administered on the day of 
Visit 7. 
At Visit 2, three study drug blister cards will be dispensed to all subjects. From Visit 3 onwards, 
the subjects will be asked to return all study drug blister cards from the former visit for 
accountability and compliance assessment. At each visit, an unused blister card or a partially used 
blister card with the study drug available which was dispensed at the previous visit will be returned 
to the subjects. In addition, new study drug blister cards will be dispensed so that the subjects will 
receive enough study drug for the period between site visits. The subject will be instructed to use 
the blister cards on a first-in/first-out basis. At Visit 7, study drug will not be dispensed. If a subject 
discontinues study drug prematurely, the termination should be recorded as soon as possible after 
the decision has been made. 
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 should also ensure that all study drug will be dispensed only to 
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 the Good Clinical Practices (GCP). 


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3.7.7 Randomization 
Approximately 150 eligible subjects with moderate to severe plaque psoriasis will be randomized 
into this study. Subjects will be randomized in a 1:1:1 ratio (approximately 50 subjects per 
treatment group) to receive JTE-451 200 mg BID (400 mg/day), JTE-451 400 mg BID 
(800 mg/day) or placebo BID. Randomization will be stratified based on prior exposure to biologic 
therapy (i.e., biologic-naïve vs. biologic-experienced subjects) and body weight (i.e., <90 kg vs. 
≥90 kg at Visit 2). 
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). 
JTE-451 200 mg tablets, as well as placebo tablets will be supplied as unbranded tablets, which 
are identical in appearance.  
The laboratory performing JTE-451 plasma concentration assessments will be unblinded to 
facilitate analysis of only the samples from the JTE-451-treated subjects. Plasma samples from 
placebo-treated subjects may be analyzed as needed (see Section 3.5.6.27). 
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 treated without 
knowing the identity of the study drug by using the IWRS. Every effort must be made to contact 
the Medical Monitor prior to breaking the code. If 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 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 sponsor-designated independent member 
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, safety and PK 
evaluations. A formal SAP will be developed before the database lock. Statistical matters not 
addressed in this 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. 


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3.8.1 Subject Population for Analysis 
3.8.1.1 Safety Population 
Safety population consists of the randomized subjects who receive at least one dose of the study 
drug.  
3.8.1.2 Intent-To-Treat (ITT) Population 
The ITT population consists of all subjects who are randomized at Visit 2. 
3.8.1.3 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. 
3.8.1.4 Pharmacokinetic (PK) Population 
The PK population consists of the randomized subjects who receive at least one dose of JTE­451 
and have at least one usable JTE-451 plasma concentration measurement. 
3.8.2 Sample Size 
Approximately 150 eligible subjects (50 subjects in each treatment group) will be randomized into 
the double-blind treatment period. 
The sample size estimation is based on the primary efficacy parameter of the proportion of subjects 
achieving PASI-75 at EOT. 
 
 
 
 
 
Taking into consideration a 15-20% treatment discontinuation rate, about 50 subjects per group 
will be randomized into the double-blind treatment period. 
3.8.3 Interim Analysis 
No interim analysis is planned in this study. 
3.8.4 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 analyses using the PP population may be performed if 
deemed appropriate. 


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3.8.4.1 Efficacy Parameters 
The primary efficacy parameter is the proportion of subjects achieving PASI-75 at EOT. 
The secondary efficacy parameters (for which data will be evaluated at Weeks 2, 4, 8, 12, 16, 20 
and EOT unless otherwise stated) are: 
• Proportions of subjects achieving PASI-50/PASI-75/PASI-90; 
• Percent change from baseline in PASI; 
• Proportion of subjects achieving sPGA score of 0 or 1; 
• Change from baseline in sPGA score; 
• Percent change from baseline in BSA; 
• Change from baseline in Skindex-16; 
• Change from baseline in Itch NRS; 
• Change from baseline in each domain score/questionnaire of Skindex-16. 
3.8.4.2 Efficacy Data Analysis 
The primary efficacy analyses will compare the proportion of subjects achieving PASI-75 response 
in JTE-451 dose groups (200 mg BID and 400 mg BID) with placebo at EOT, respectively. 
Cochran-Mantel-Haenszel test stratified by prior exposure to biologic therapy (biologic-naïve or 
biologic-experienced) and body weight (i.e., <90 kg or ≥90 kg at Visit 2) will be used for the 
primary comparisons. A multiple testing procedure (e.g., step-down procedure) will be considered 
the primary efficacy analyses of PASI-75. For supportive analyses of PASI-75, a logistic 
regression model-based analysis will be performed for the pairwise comparisons between a 
JTE-451 dose group and placebo, and for the evaluation of the dose response relationship. The 
logistic regression models will include the stratifying factors and baseline values of key efficacy 
parameters as covariates. The details will be described in the SAP. 
For dichotomous secondary efficacy parameters, similar analyses as those for the primary efficacy 
parameter above will be performed at EOT or by a defined time point as appropriate.  
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 factor, appropriate baseline and subject as random effect. Appropriate baseline will 
be the parameter from which the efficacy parameter is derived, (e.g., PASI at Week 0 for the 
analysis of percent change from baseline in PASI). The treatment effect of each JTE-451 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. 


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All analyses will be performed two-sided at the 5% significance level. No formal multiple 
comparison adjustment will be made for secondary efficacy parameters. 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.  
Graphical presentations of the treatment profile will be provided for the primary and secondary 
efficacy parameters. 
.  
Descriptive statistics of efficacy parameters over time will be presented by treatment. It will 
include number of subjects (N), arithmetic mean, standard deviation (SD), median, minimum and 
maximum for continuous parameters, and frequency for dichotomous parameters. 
3.8.4.3 Treatment by Center Effect 
The randomization in this study is stratified by prior exposure to biologic therapy 
(i.e., biologic-naïve vs. biologic-experienced subjects) and body weight (i.e., <90 kg vs. ≥90 kg at 
Visit 2). 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. 
3.8.4.4 Treatment by Baseline Covariate Effect 
The treatment-by-baseline effect will be assessed as appropriate. The baseline will be included in 
the respective parametric analysis model of the efficacy parameters where appropriate.  
3.8.4.5 Subgroup Analysis 
Subgroup analyses may be performed if appropriate. 
3.8.4.6 Handling of Dropouts or Missing Data 
There may be missing data intermittently (e.g., a missing visit or subject dropout). For efficacy 
analysis of dichotomous parameters by scheduled 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 which case any value after the 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 efficacy analysis of continuous parameters, missing data will not be imputed. This is because 
the statistical models employed (e.g., mixed effect model) generally provide valid estimates if the 
missing data mechanism is so-called “missing at random,” a common assumption made as the first 
approach for analysis. 
 
3.8.5 Safety Analyses 
The safety population will be used for the safety data analysis unless otherwise stated. 


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3.8.5.1 Safety Parameters 
The safety parameters are: 
• Adverse events 
• Clinical laboratory safety tests  
• Vital signs 
• ECG parameters 
3.8.5.2 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 current version of 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. 
3.8.6 Pharmacokinetic Analyses 
The PK population will be used for the PK data analysis unless otherwise stated. 
3.8.6.1 Trough Concentration 
Trough (pre-dose) plasma concentrations of JTE-451 at Weeks 2, 4, 8 and 12 will be summarized 
in terms of the number of subjects, arithmetic mean, standard deviation, coefficient of variation 
(CV%), median, minimum and maximum by treatment and visit. The relationship between the 
dose and trough plasma concentrations of JTE-451 will also be assessed. 
3.8.6.2 Exposure-Response Relationship 
3.8.6.3 Population Pharmacokinetic Analysis 
Preliminary population PK analysis will be performed using plasma concentration of JTE­451. 
Population estimates of PK parameters of JTE-451 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 inter-subject variability of these 
parameters will be characterized. The effect of intrinsic/extrinsic factors (e.g., age, body weight, 
gender, race, use of concomitant medications) on the PK of JTE-451 will be evaluated. Other PK 
parameters will be determined and reported as deemed appropriate. The analysis may be carried 
out using the data combined with plasma concentration of JTE-451 obtained in other clinical 
studies. The population PK analysis plan and the report may be prepared separately when 
appropriate. 


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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 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/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 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, if the IRB/IEC 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. 


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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 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 designee should fully inform the subject 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. 
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, IWRS and in all required reports.  
Additionally, data for efficacy parameters, laboratory, photography and information regarding 
screening and randomization may be received by Clinical Data Management from appropriate 
clinical laboratories in electronic format. These data files may be merged with the clinical database. 
4.3.1 Case Report Forms 
Electronic CRFs (including eCOA and e-diary) 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 all subjects who have been randomized for the study and will be 
reviewed by the Clinical Monitor and verified against source documents and must be kept 
up­to-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. 


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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 is provided 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. 
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 filed or if the application is not approved for 
such indication, until two years after the investigation is discontinued and the FDA is notified. 
For sites outside of the US, the Investigator shall retain records required to be maintained under 
this part for a period in accordance with applicable local and national regulations. 
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 prior written permission of the 
Sponsor prior to disposing of or transferring any study records. 
4.8 Confidentiality 
The Investigator, Medical Monitor, 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 


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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/her personal physician or other 
appropriate medical personnel responsible for his/her welfare. 
Data generated in this study must be available for inspection on request by representatives of 
regulatory authorities, Sponsor or designee, and 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 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. 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 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 and/or designee for 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 study monitor 
of the Sponsor or designee as needed regarding study concerns and/or questions. 


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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. 
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 
References 
1. Rachakonda TD, Schupp CW, Armstrong AW. Psoriasis prevalence among adults in the 
United States. J Am Acad Dermatol. 2014 Mar;70(3):512-6. 
2. Huntley C. Psoriasis Epidemiology (Report Reference: DMKC0144470). Datamonitor 
Healthcare. Published on 22/09/2015:1-26. 
3. Kubota K, Kamijima Y, Sato T, Ooba N, Koide D, Iizuka H, et al. Epidemiology of psoriasis 
and palmoplantar pustulosis: a nationwide study using the Japanese national claims database. 
BMJ Open. 2015 Jan 14;5(1):e006450. 
4. Parisi R, Symmons DP, Griffiths CE, Ashcroft DM; Identification and Management of 
Psoriasis and Associated ComorbidiTy (IMPACT) project team. Global epidemiology of 
psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol. 
2013 Feb;133(2):377-85. 
5. Rapp SR, Feldman SR, Exum ML, Fleischer AB Jr, Reboussin DM. Psoriasis causes as much 
disability as other major medical diseases. J Am Acad Dermatol. 1999;41(3 Pt 1):401-7. 
6. Langley RG, Elewski BE, Lebwohl M, Reich K, Griffiths CE, Papp K, et al. Secukinumab in 
plaque psoriasis - Rresults of two phase 3 trials. N Engl J Med. 2014 Jul 24;371(4):326-38. 
7. Leonardi C, Matheson R, Zachariae C, Cameron G, Li L, Edson-Heredia E, et al. 
Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. 
N Engl J Med. 2012 Mar 29;366(13):1190-9. 
8. Krueger JG, Ferris LK, Menter A, Wagner F, White A, Visvanathan S, et al. Anti-IL-23A mAb 
BI 655066 for treatment of moderate-to-severe psoriasis: safety, efficacy, pharmacokinetics, 
and biomarker results of a single-rising-dose, randomized, double­blind, placebo-controlled 
trial. J Allergy Clin Immunol. 2015 Jul;136(1):116-24. 
9. Papp K, Thaçi D, Reich K, Riedl E, Langley RG, Krueger JG, et al. Tildrakizumab (MK­3222), 
an anti-interleukin-23p19 monoclonal antibody, improves psoriasis in a phase IIb randomized 
placebo-controlled trial. Br J Dermatol. 2015 Oct;173(4):930-9. 
10. Heydendael VM, Spuls PI, Opmeer BC, de Borgie CA, Reitsma JB, Goldschmidt WF, et al. 
Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. 
N Engl J Med. 2003;349(7):658-65. 
11. Patel RV, Clark LN, Lebwohl M, Weinberg JM. Treatments for psoriasis and the risk of 
malignancy. J Am Acad Dermatol. 2009;60(6):1001-17. 
12. Hirose T, Smith RJ, Jetten AM. ROR gamma: the third member of ROR/RZR orphan receptor 
subfamily that is highly expressed in skeletal muscle. Biochem Biophys Res Commun. 
1994;205(3):1976-83. 


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13. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. The orphan 
nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T 
helper cells. Cell. 2006;126(6):1121-33. 
14. Common Terminology Criteria for Adverse Events. Quick Reference, Version 5.0, National 
Institutes of Health, National Cancer Institutes. November 27, 2017. 
 
 


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7 
Appendices 
Appendix 1. 
Permitted Medications to be used with Caution 
Appendix 2. 
Skindex-16 Questionnaire 
 
 


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Appendix 1. Permitted Medications to be used with Caution 
Use of the following medications are permitted during the study; however, caution should be used 
when the medications 
 are co-administered with JTE-451. 
Please refer to Section 3.5.5.1.3 for detail of cautions. 
Strong CYP3A4 inhibitor 
Diltiazem 
-- 
-- 
-- 
-- 
Sensitive and/or Narrow Therapeutic Index CYP2C8 substrates 
Montelukast 
Pioglitazone 
Repaglinidea 
Rosiglitazone 
-- 
Sensitive and/or Narrow Therapeutic Index CYP2C9 substrates 
Celecoxib 
Diclophenac 
Glimepiride 
Tolbutamide 
-- 
Sensitive and/or Narrow Therapeutic Index CYP3A4 substrates 
Alfuzosin 
Alprazolam 
Atorvastatinb 
Avanafil 
Buspirone 
Colchicine 
Dihydroergotamine Eletriptan 
Eplerenone 
Ergotamine 
Felodipine 
Lovastatin 
Midazolam 
Nisoldipine 
Tadalafil 
Triazolam 
Sildenafil 
Simvastatinb 
-- 
-- 
Other restricted Medicationsc 
Amlodipine 
Benzonatate 
Bupropion 
Citalopram 
Clotrimazole 
Cyclobenzaprine 
Diazepam 
Escitalopram 
Fluconazole 
Fluoxetine 
Guaifenesin 
Hydroxyzine 
Levothyroxine 
Losartan 
Meloxicam 
Nitrofurantoin 
Pravastatin 
Sertraline 
Tamsulosin 
Trazodone 
OATP1B1/1B3 substrates 
Atorvastatinb 
Bosentan 
Ezetimibe 
Fluvastatin 
Glyburide 
Pitavastatin 
Pravastatin 
Repaglinidea 
Rosuvastatin 
Simvastatinb 
P-gp substrate with Narrow Therapeutic Index 
Apixaban 
Dabigatran etexilate 
Digoxin 
Edoxaban 
a. 
A CYP2C8 and OATP1B1/1B3 substrates. 
b. 
A CYP3A4 and OATP1B1/1B3 substrates. 
c. 
The plasma concentration may decrease due to induction potential of JTE-451 for CYP. 


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Appendix 2. Skindex-16 Questionnaire 
 

SAP_001.pdf: 
 
ClinicalTrials.gov Posted Document Cover Page 
Clinical Study Statistical Analysis Plan (SAP) 
 
PROTOCOL TITLE:  
A Multicenter, Randomized, Double-blind, Placebo-controlled, 
Parallel-group Study to Evaluate the Efficacy and Safety of 
JTE-451 Administered for 16 Weeks in Subjects with Moderate 
to Severe Plaque Psoriasis (IMPACT-PS) 
PROTOCOL NUMBER: AE451-G-18-004 
SAP DATE:  
30 March 2020 
NCT NUMBER: 
NCT03832738 
 


JTE-451 
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Statistical Analysis Plan – Protocol AE451-G-18-004 
Final V1.0 – 30 Mar 2020 
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CONFIDENTIAL 
CONFIDENTIAL 
Akros Pharma Inc. 
Protocol AE451-G-18-004 
A Multicenter, Randomized, Double-blind, Placebo-controlled, 
Parallel-group Study to Evaluate the Efficacy and Safety of JTE-451 
Administered for 16 Weeks in Subjects with Moderate to Severe Plaque 
Psoriasis (IMPACT-PS)
Statistical Analysis Plan 
Final V1.0
30 March 2020




 
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Table of Contents 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................................... 5 
1. 
INTRODUCTION ................................................................................................................................. 7 
2. 
OBJECTIVES ........................................................................................................................................ 7 
3. 
STUDY DESIGN ................................................................................................................................... 7 
 
STUDY PROCEDURES ............................................................................................................................ 8 
 
RANDOMIZATION................................................................................................................................ 11 
4. 
SUBJECT POPULATIONS................................................................................................................ 12 
 
SAFETY POPULATION ......................................................................................................................... 12 
 
INTENT-TO-TREAT (ITT) POPULATION .............................................................................................. 12 
 
PER PROTOCOL (PP) POPULATION ...................................................................................................... 12 
 
PHARMACOKINETIC (PK) POPULATION .............................................................................................. 12 
5. 
ANALYSIS PARAMETERS .............................................................................................................. 12 
 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ............................................................................. 12 
 
EFFICACY PARAMETERS ..................................................................................................................... 13 
5.2.1 
Primary Efficacy Parameter ...................................................................................................... 13 
5.2.2 
Secondary Efficacy Parameters ................................................................................................. 13 
 
5.2.4 
Efficacy Parameters Calculation ............................................................................................... 13 
 
Psoriasis Area and Severity Index (PASI) ............................................................................................. 13 
 
The PASI-50/PASI-75/PASI-90 Response Rate.................................................................................... 15 
 
Static Physician’s Global Assessment (sPGA) ...................................................................................... 15 
 
Psoriasis Body Surface Area (BSA) ...................................................................................................... 16 
 
Skindex-16 ............................................................................................................................................ 16 
 
Itch Numeric Rating Scale (NRS) ......................................................................................................... 16 
 
 
 
SAFETY PARAMETERS ........................................................................................................................ 17 
5.3.1 
Adverse Events (AEs) ................................................................................................................. 17 
5.3.2 
Pre-Treatment Adverse Events .................................................................................................. 17 
5.3.3 
Treatment-Emergent Adverse Events ......................................................................................... 18 
5.3.4 
Medical History ......................................................................................................................... 18 
5.3.5 
Study Medication Compliance ................................................................................................... 18 
5.3.6 
Clinical Laboratory Results ....................................................................................................... 18 
5.3.7 
Vital Signs .................................................................................................................................. 18 
5.3.8 
12-Lead ECG ............................................................................................................................. 19 
5.3.9 
Physical Examination ................................................................................................................ 19 
 
PHARMACOKINETIC (PK) PARAMETERS ............................................................................................. 19 
9 
 
MEDICATIONS/PROCEDURES .............................................................................................................. 19 
5.6.1 
Prior Medications/Procedures................................................................................................... 20 
5.6.2 
Concomitant Medications/Procedures ....................................................................................... 20 
6. 
STATISTICAL METHODOLOGY .................................................................................................. 20 
 
SAMPLE SIZE ...................................................................................................................................... 21 
 
SUBJECT DISPOSITION SUMMARY ....................................................................................................... 21 
 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ........................................................................... 21 


 
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EFFICACY ANALYSIS .......................................................................................................................... 21 
6.4.1 
Analyses of Primary Efficacy Parameter ................................................................................... 22 
6.4.2 
Analyses of Secondary Efficacy Parameters .............................................................................. 23 
 
6.4.4 
Treatment by Center Effect ........................................................................................................ 25 
6.4.5 
Treatment by Baseline Covariate Effect .................................................................................... 25 
6.4.6 
Subgroup Analysis ..................................................................................................................... 25 
6.4.7 
Handling of Dropouts and Missing Data ................................................................................... 25 
 
SAFETY ANALYSIS .............................................................................................................................. 26 
6.5.1 
Adverse Events (AEs) ................................................................................................................. 26 
6.5.2 
Medical History ......................................................................................................................... 27 
6.5.3 
Prior and Concomitant Medications ......................................................................................... 27 
6.5.4 
Clinical Laboratory Tests .......................................................................................................... 27 
6.5.5 
Vital Signs .................................................................................................................................. 28 
6.5.6 
12-Lead ECG ............................................................................................................................. 28 
6.5.7 
Study Medication Exposure and Compliance ............................................................................ 28 
 
PHARMACOKINETIC ANALYSIS ........................................................................................................... 29 
6.6.1 
Method of PK Data Representation ........................................................................................... 29 
6.6.2 
Descriptive Statistics of Plasma Concentrations ....................................................................... 29 
 
6.6.4 
Population Pharmacokinetic Analysis ....................................................................................... 29 
 
7. 
SUBJECT DATA LISTING ............................................................................................................... 29 
8. 
SOFTWARE AND QUALITY CONTROL ...................................................................................... 29 
9. 
REFERENCES .................................................................................................................................... 30 
10. 
APPENDICES .................................................................................................................................. 31 
 
GENERAL CLINICALLY-SIGNIFICANT CRITERIA FOR SAFETY PARAMETERS ....................................... 31 
 
MOCK SUMMARY TABLES .................................................................................................................. 34 
 
MOCK DATA LISTINGS ....................................................................................................................... 34 
 
MOCK FIGURES .................................................................................................................................. 34 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ATC 
Anatomical therapeutic chemical 
BLQ 
Below the lower limit of quantification 
BID 
Twice a day 
BMI 
Body mass index 
BSA 
Body surface area 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case report form 
CTCAE 
Common terminology criteria for adverse events 
CV% 
Coefficient of variation 
DB 
Double-blind 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
EOT 
End of treatment 
FSH 
Follicle-stimulating hormone 
GEE 
Generalized estimating equation 
ITT 
Intent to treat 
IWRS 
Interactive web response system 
LOCF 
Last observation carried forward 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical dictionary for regulatory activities 
MMRM 
Mixed effect model with repeated measures 
NA 
Not applicable 
NCS 
Not clinically significant 
NRS 
Numerical rating scale 
OR 
Odds Ratio 
PASI 
Psoriasis Area and Severity Index 
PBSA 
Psoriasis body surface area 
PCS 
Potentially clinically significant 
PD 
Pharmacodynamic 
PK 
Pharmacokinetics 
PP 
Per protocol 
PPK 
Population PK 
PR 
Interval from beginning of the P wave to the beginning of the QRS complex in the frontal 
plane 
 
PT 
Preferred term 


 
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Abbreviation 
Definition 
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 
RR 
Interval from beginning of the QRS complex in the frontal plane to the next QRS complex 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOC 
System organ class 
SOP 
Standard operating procedure 
sPGA 
Static Physician’s Global Assessment 
TEAE 
Treatment-emergent adverse event 
WHO 
World health organization 


 
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1. INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the statistical methods that will be used during the 
analysis and reporting of data collected for a Phase 2 double-blind (DB), placebo-controlled, 
parallel-group study evaluating efficacy, safety and pharmacokinetic (PK) of JTE-451 in subjects 
with moderate to severe plaque psoriasis. This SAP should be read in conjunction with the study 
protocol. This version of the SAP has been developed using protocol version 3.0 dated 
24 June 2019.  
2. OBJECTIVES 
Primary Objective 
To evaluate the efficacy of JTE-451 administered for 16 weeks in subjects with moderate to severe 
plaque psoriasis compared with placebo. 
Secondary Objectives 
• To evaluate the safety and tolerability of JTE-451 administered for 16 weeks in subjects with 
moderate to severe plaque psoriasis. 
• To evaluate the pharmacokinetics (PK) of JTE-451 administered for 16 weeks in subjects with 
moderate to severe plaque psoriasis. 
3. STUDY DESIGN 
This is a 16-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study 
in subjects with moderate to severe plaque psoriasis.  
Eligible subjects will be randomized at Visit 2 to receive JTE-451 200 mg twice a day (BID) 
(400 mg/day), 400 mg BID (800 mg/day) or placebo BID for 16 weeks. Approximately 
150 subjects are planned to be randomized into 3 treatment groups. Randomized subjects will visit 
the site at Weeks 2, 4, 8, 12 and 16 during the treatment period. A follow-up visit will take place 
approximately 4 weeks after the last dose of study drug. Randomization will be stratified based on 
prior exposure of subjects to biologic therapy (i.e., biologic-naïve vs. biologic-experienced 
subjects) and body weight (i.e., <90 kg vs. ≥90 kg at Visit 2). 


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The study duration will be of approximately 24 weeks per subject: 
•
Up to 28-day Screening Period
•
16-week double-blind Treatment Period
•
4-week Follow-up Period
 Study Procedures 
The study schema and schedule of study procedures are described in Figure 1 and Table 1, 
respectively. 
Figure 1. 
Study Schema 
JTE-451 200 mg BID (N=50) 
Treatment 
  16 weeks
Up to 4 weeks 
V = Study Visit 
Rand. = Randomization 
EOT = End of Treatment 
FU = Follow-up   
2 weeks 
2 weeks 
4 weeks 
4 weeks 
Screening 
Up to 4 weeks
Follow-up 
Approx. 4 weeks 
Approx. 4 weeks 
= Double-blind Treatment Period 
JTE-451 400 mg BID (N=50) 
Placebo BID (N=50) 
4 weeks 
V1 
V2 
(Week 0) 
Rand. 
V3 
(Week 2) 
V4 
(Week 4) 
V5 
(Week 8) 
V6 
(Week 12) 
V7 
(Week 16) 
V8 
(Week 20) 
FU 


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Table 1. 
Schedule of Study Procedures 
Note: All study procedures should be performed at each study visit prior to study drug administration; 
except for appropriate PK sample collection procedures as discussed below (see Figure 2). When scheduled 
at the same time points, ECG and vital sign parameters collection activities should be performed prior to 
(or at least 15 minutes after) procedures involving venipuncture 
   
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±4)
Week 12
(Day 84±4)
Week 16
(Day 112±4)
Week 20
(Day 140±4)
Visit
1
2
3
4
5
6
7
8
Informed Consentb
X
Inclusion/ Exclusion Criteria
X
X
Medical History
X
X
Demographic Information
X
Review Prior/ Concomitant Medications
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
Vital Signs including Weight
X
X
X
X
X
X
X
X
Height and Calculate BMI 
X
12-Lead ECG
X
X
X
X
Chest Radiographyc
X
QuantiFERON-TB Gold-In-Tube
X
Drugs of Abuse Screen 
X
Viral Serology 
X
FSHd
X
Pregnancy Testd
X
X
X
X
X
X
X
X
HbA1c
X
Serum Biochemistry
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
Psoriasis Body Surface Area
X
X
X
X
X
X
X
X
PASI
X
X
X
X
X
X
X
X
sPGA
X
X
X
X
X
X
X
X
Skindex 16
X
X
X
X
X
X
X
X
Itch NRSe
Digital Photographyf
X
X
Randomization using IWRS
X
Access IWRS and Dispense Study Drugi
X
X
X
X
X
Collect Study Drug and Check Compliancej
X
X
X
X
X
Study Drug Administrationk
X
X
X
X
X
JTE-451 PK Blood Samplesl
X
X
X
X
X
Document Adverse Eventsm
X
X
X
X
X
X
X
X
Treatment  Period


 
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a. 
The target day for each visit after randomization will be calculated relative to the date of Visit 2. Every attempt 
should be made to have the subject attend each visit within the windows specified in the table. The study site is 
encouraged to make a reminder phone call to the subject 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. 
b. Written informed consent must be obtained prior to performing any study-related procedures including washout 
of previous medications prior to or at the Screening Visit to participate in the study.  
c. 
Chest radiography may not be performed if it has been performed within 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 for all female subjects. At Visits 2 through 8 (or Follow-up 
Visit), urine pregnancy tests will be performed only for female subjects of childbearing potential. At Visit 1, 
female subjects with a documented history of lack of menses for ≥12 consecutive months with no other reversible 
medical etiology will be considered post-menopausal. Only for the female with a history of lack of menses but 
onset has been within 12 months prior to Visit 1, an FSH testing is required at Visit 1, then an FSH >40 mIU/mL 
will be considered post-menopausal, otherwise subject is considered of childbearing potential. 
e. 
The Itch NRS during a 24-hour recall period will be recorded in the e-diary by the subject once daily from the 
day of screening through the last visit. Site will dispense the e-diary device at Screening Visit and train the subject 
on how to use the device.  
f. 
If collecting photographs is raised as the reason for not participating in the study, the subject still can be part of 
the study without collecting photographs. Subjects who do not raise this objection will be required to take 
photographs of four half-body views (i.e., upper anterior, lower anterior, upper posterior and lower posterior). 
 
 
 
 
i. 
At Visit 2 through Visit 6, randomized subjects will receive sufficient study drug blister cards for the period 
between visits. At Visit 7, study drug will not be dispensed. If a subject discontinues study drug prematurely after 
receiving at least one dose of study drug, the termination should be recorded as soon as possible after the decision 
has been made. 
j. 
Subjects will be instructed to bring all used and unused blister cards to each study visit for accountability purposes. 
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 or returned by the subject. 
k. Oral administration for 16 weeks starting on the day of randomization at Visit 2, BID, at approximately 12-hour 
intervals, 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 
required procedures prior to administration have been performed (except for Visit 7, when no study drug will be 
administered, as the last dose will be taken the day prior to the visit). 
l. 
See Figure 2 for a detailed description of PK sampling time points. 
m. Adverse event information will be collected at the specified time points as well as at any time when a site staff 
member becomes aware of an AE after the subject signs the informed consent for the study. However, stable or 
improving pre-existing conditions detected through the screening procedures at Visit 1 (e.g., abnormalities in 
ECG, physical examination, vital signs and laboratory tests) are considered medical history and should be 
documented accordingly. 
 
 
 
 
 
 
 
 


 
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Figure 2. 
Dosing and Pharmacokinetic Sample Collection Time  
 
a. 
Exact date and time of dose at each visit at the site will be collected. 
b. Exact date and time of the last two doses prior to the pre-dose/trough PK sample collection will be collected. 
c. 
The pre-dose PK sample collections (i.e., samples obtained prior to the dosing of the study drug at the site) are 
mandatory in all subjects at all sites. The sample collection date and time will be recorded. 
d. The trough PK sample collections (relative to dosing of the study drug on the day prior to the visit) are mandatory 
in all subjects at all sites. The sample collection date and time will be recorded. 
e. 
Three post-dose PK samples per subject (relative to the dosing of the study drug at the site) should be collected 
from at least 34 randomized subjects. The samples will consist of one sample from 1 to 2 hours window at Week 0 
(Visit 2), one sample from 3 to 6 hours window at Week 0 (Visit 2), and one sample from 3 to 6 hours window at 
Week 4 (Visit 4). The relative sampling time of the two samples of 3 to 6 hours window at Visit 2 and Visit 4 
should be separated by at least 1 hour. The sample collection date and time will be recorded. 
 
 Randomization 
Approximately 150 eligible subjects with moderate to severe plaque psoriasis will be randomized 
into this study. Subjects will be randomized in a 1:1:1 ratio (approximately 50 subjects per 
treatment group) to receive JTE-451 200 mg BID (400 mg/day), JTE-451 400 mg BID 
(800 mg/day) or placebo BID. Randomization will be stratified based on prior exposure to biologic 
therapy (i.e., biologic-naïve vs. biologic-experienced subjects) and body weight (i.e., <90 kg vs. 
≥90 kg at Visit 2). 
An Interactive Web Response System (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 Protocol Section 3.7.8). 
 


 
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4. SUBJECT POPULATIONS 
 Safety Population 
The safety population consists of the randomized subjects who receive at least one dose of the 
study drug.  
 Intent-To-Treat (ITT) Population  
The ITT population consists of all subjects who are randomized at Visit 2. Subjects will be 
analyzed according to the treatment to which they were assigned, even if subjects do not take the 
assigned treatment, do not receive the correct treatment, or otherwise do not follow the protocol.  
 Per Protocol (PP) Population 
The PP population is a subset of the ITT population in which subjects do not have any major 
protocol deviations as listed below:  
1. Dosing compliance not in 80%-120% (based on actual dosing period) 
2. Subject’s last dose not between Days 90-134 
3. Subject did not take 360-536 tablets in total 
4. >4 days between last dose and last non-follow-up efficacy assessment 
5. Not meeting Inclusion Criterion #2, #3 or #4 
6. Meeting Exclusion Criterion #1, #2, #3, #4, #5 (details shown below) or #10  
7. Subject took “key” prohibited concomitant medications or had unstable background 
therapy that could potentially affect efficacy results/interpretation 
• Use of restricted medications listed in Table 2 of the protocol in the prohibited period 
• Use of prohibited medications listed in Table 4 and Table 5 of the protocol in the 
prohibited period. The exclusion decision will be made based on the review of the 
individual case and will be documented 
8. Subject took incorrect study medication, e.g. due to incorrect drug dispense  
9. Significant procedural deviations/non-compliance that could potentially affect efficacy 
results/interpretation 
A pre­analysis 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. 
 Pharmacokinetic (PK) Population 
The PK population consists of the randomized subjects who receive at least one dose of JTE­451 
and have at least one usable JTE-451 plasma concentration measurement. 
5. ANALYSIS PARAMETERS 
 Demographic and Baseline Characteristics 
Demographic variables include age, gender, ethnic group, country, race, body weight, height and 
body mass index (BMI) at Screening Visit. 


 
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Baseline (last non-missing value prior to first dose) subject characteristics include but not limited 
to the following parameters: prior biologic therapy use (naïve or experienced), weight category 
(<90 kg or ≥90 kg), age category (<65 years or ≥65 years), prior exposure to oral systemic 
non-biologic therapies (yes or no), number of prior anti-psoriasis systemic treatment (biologic or 
non-biologic; 0, 1 or ≥2), time from diagnosis, itch numeric rating scale (NRS, week average at 
one week prior to Day 1 dosing, i.e., Day -6 to Day 1), psoriasis body surface area (BSA), psoriasis 
area and severity index (PASI) score, static physician’s globa  
sessmen  ( PGA) score, 
Skindex-16 questionnaire scale scores and overall score,
 
.  
Summary tables for demographic and baseline characteristics will be generated for the safety, ITT 
and PP populations, respectively.  
 Efficacy Parameters 
 
The primary efficacy parameter is the proportion of subjects achieving PASI-75 at end of 
treatment (EOT).  
 
The secondary efficacy parameters (for which data will be evaluated at Weeks 2, 4, 8, 12, 16, 20 
and EOT unless otherwise stated) are: 
• Proportions of subjects achieving PASI-50/PASI-75/PASI-90; 
• Percent change from baseline in PASI; 
• Proportion of subjects achieving sPGA score of 0 or 1; 
• Change from baseline in sPGA score; 
• Percent change from baseline in BSA; 
• Change from baseline in Skindex-16; 
• Change from baseline in Itch NRS; 
• Change from baseline in each domain score/questionnaire of Skindex-16. 
 
 Psoriasis Area and Severity Index (PASI) 
The PASI is a quantitative rating score to assess the severity of psoriatic lesions based on the area 
coverage and plaque appearance. The PASI score will be derived as indicated in Table 2 below 
(refer to protocol Section 3.5.6.2 for further details). 


 
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Table 2. 
The PASI Scoring 
Body 
region 
Erythema (E) 
Thickening (plaque 
elevation, 
induration, I) 
Scaling 
(desquamation, D) 
Area score (based on true 
area %, A)* 
Head (H)† 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0 = 0% 
1 = 1-9% 
2 = 10-29% 
3 = 30-49% 
4 = 50-69% 
5 = 70-89% 
6 = 90-100% 
Trunk (T)‡ 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0 = 0% 
1 = 1-9% 
2 = 10-29% 
3 = 30-49% 
4 = 50-69% 
5 = 70-89% 
6 = 90-100% 
Upper  
limbs (U) 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0 = 0% 
1 = 1-9% 
2 = 10-29% 
3 = 30-49% 
4 = 50-69% 
5 = 70-89% 
6 = 90-100% 
Lower  
limbs (L)§ 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0 = 0% 
1 = 1-9% 
2 = 10-29% 
3 = 30-49% 
4 = 50-69% 
5 = 70-89% 
6 = 90-100% 
Percentage (not score) of body region (not whole body) affected will be entered in the CRF 
† 
Neck is assessed as part of the Head (H) body region. 
‡ 
Axillae and groin are assessed as part of the Trunk (T) body region. 
§ 
Buttocks are assessed as part of the Lower limbs (L) body region. 
The PASI score is calculated using the following formula: 
PASI = 0.1(EH+IH+DH)AH + 0.2(EU+IU+DU)AU + 0.3(ET+IT+DT)AT + 0.4(EL+IL+DL)AL 
The PASI scores can range from 0, corresponding to no signs of psoriasis, up to a theoretic 
maximum of 72.0, corresponding to maximal signs of psoriasis. The calculated composite PASI 
score will be directly available in the corresponding database. 


 
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 The PASI-50/PASI-75/PASI-90 Response Rate 
The PASI-50/PASI-75/PASI-90 response rate will be calculated for Visits 3 through EOT 
respectively based on the PASI score collected by the Investigator.  
The PASI-50/PASI-75/PASI-90 response is a dichotomous variable with a positive (= responder) 
or negative (= non-responder) outcome.  
• PASI-50 is ≥50% improvement from baseline 
• PASI-75 is ≥75% improvement from baseline 
• PASI-90 is ≥90% improvement from baseline 
 Static Physician’s Global Assessment (sPGA) 
The sPGA is used to determine the severity of subject’s psoriatic lesion at a given time point. The 
psoriatic lesion will be graded for induration, erythema and scaling based on the scales below. The 
sPGA will be derived by the sponsor for all study visits. 
The sum of the 3 scales will be divided by 3 to obtain the final sPGA score. 
Induration (I) 
0 = no evidence of plaque elevation 
1 = barely palpable 
2 = slight but definite elevation, indistinct edge 
3 = elevated with distinct edges 
4 = marked plaque elevation, hard/sharp borders 
Erythema (E) 
0 = no evidence of erythema (post inflammatory hyperpigmentation and/or hypopigmentation may 
be present) 
1 = faint erythema 
2 = light red coloration 
3 = red coloration 
4 = dusky to deep red coloration 
Scaling (S) 
0 = no evidence of scaling 
1 = occasional fine scale 
2 = fine scale predominates 
3 = coarse scale predominates 
4 = thick, coarse scale predominates 
Add I+E+S = _______________/3 = ________ (Total Average) 
Physician’s Static Global Assessment based upon above Total Average 
0 = Cleared, except for residual discoloration 
1 = Minimal – majority of lesions have individual scores for I+E+S/3 that averages 1 
2 = Mild – majority of lesions have individual scores for I+E+S/3 that averages 2 
3 = Moderate – majority of lesions have individual scores for I+E+S/3 that averages 3 
4 = Severe – majority of lesions have individual scores for I+E+S/3 that averages 4 


 
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Note: Scores should be rounded to the nearest whole number (e.g., if the total is <1.50, the score 
should be 1; if the total is ≥1.50, the score should be 2) except if the score is >0 and <1, score 
should be treated as 1. 
 Psoriasis Body Surface Area (BSA) 
The total BSA affected by plaque-type psoriasis will be estimated from the percentages of areas 
affected, including head, trunk, upper limbs and lower limbs. The psoriasis BSA will be derived 
by the Sponsor for all study visits.  
The following calculations will be done: each reported percentage will be multiplied by its 
respective body region corresponding factor (head = 0.1, trunk = 0.3, upper limbs = 0.2, lower 
limbs = 0.4). The resulting 4 values will be added up to estimate the total BSA affected by 
plaque-type psoriasis. 
 Skindex-16 
Skindex-16 is a 16-item, skin-related quality of life (QOL) questionnaire (refer to Appendix 2 of 
the protocol) and has three domain scores: symptoms, emotions, and functioning. Each 16-item 
QOL questionnaire will be reported on a scale of 0 to 6. Each raw score will be multiplied by 
16.667, thus all responses will be transformed to a linear scale of 100 (i.e., from 0 [no effect] to 
100 [effect experienced all the time]). A scale score is the average of non-missing items in a given 
scale as follows.  
• Symptom scale score: average of items 1-4 
• Emotions scale score: average of items 5-11 
• Functioning scale score: average of items 12-16 
• Overall score: average of 16 items 
 Itch Numeric Rating Scale (NRS) 
The Itch NRS is a validated, self-reported instrument for measurement of itch intensity. It uses a 
24-hour recall period and asks subjects to rate the worst itch intensity on an 11-point scale ranging 
from 0 (no itch) to 10 (worst itch imaginable). 
The Itch NRS scores will be recorded by the subject using the e-diary once daily (before study 
drug administration once the subject is randomized) preferably at the same time of the day each 
day from Screening through the last visit. 


 
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 Safety Parameters 
 
An adverse event (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.  
Serious AE (SAE) is the AE that meets a criterion of the SAE definition per protocol. The severity 
of an AE is graded by Investigators referring to Common Terminology Criteria for Adverse Events 
(CTCAE) and translated into mild, moderate and severe and causality of AE is assessed in three 
categories “not related”, “possibly related” or “related”. 
The Medical Dictionary for Regulatory Activities (MedDRA) Version 23.0 will be used to map 
verbatim AEs to preferred terms and their respective system organ classes. Adverse events will be 
characterized as either pre-treatment or treatment-emergent according to the criteria described in 
the following sections. 
 
A pre-treatment AE is the AE with an onset time that is prior to the treatment period, but after the 
informed consent is obtained. 


 
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The treatment-emergent AE (TEAE) is defined as one of the following; 
• An AE that occurred during the treatment period or the follow-up period. In the process of 
collecting the onset dates of AEs, an AE that occurs after the initiation of trial medication on 
Day 1 (the first day of the treatment period) should be treated as a TEAE. All AEs occurring 
on the day of first dose will be considered as TEAE if the time of AE occurrence relative to 
the dosing is unknown. 
• An AE present prior to the treatment period that worsened in severity during the treatment 
period or the follow-up period. 
• Any events that are present prior to the treatment period and have recovered, but recurred 
during the treatment period or the follow-up period should be considered as new TEAEs. 
 
A complete medical history will be obtained at the Screening Visit (Visit 1) and will include 
evaluations for past or present conditions. Specifically, any known history of psoriatic arthritis and 
scalp psoriasis will be documented at Visit 2. 
Any pre-existing conditions detected at Visit 1 (e.g., abnormalities in ECG, physical examination, 
vital signs and laboratory tests) are considered medical history. 
 
Total number of tablets taken will be recorded in the eCRF for the corresponding intervals as 
scheduled in Table 1. Compliance of the study medication will be calculated as follows: 
Compliance (%) = 
Total tablets taken
Treatment duration × 4 x 100% 
Compliance will be calculated for the treatment duration by visits, and the entire treatment period.  
 
Hematology, coagulation, serum biochemistry and urinalysis are collected as scheduled in Table 1. 
The following information will be derived for each of the hematology, coagulation, serum 
biochemistry, urinalysis and other parameters: 
• Change from baseline at all post-baseline visits 
• Classification relative to the normal range (‘Low’, ‘Normal’ or ‘High’) 
• Treatment-Emergent potentially clinically significant (PCS) abnormalities, if applicable 
In addition, viral serology, drugs of abuse and alcohol screen, glycosylated hemoglobin (HbA1c), 
pregnancy test, Follicle-stimulating Hormone (FSH), QuantiFERON®-TB Gold-In-Tube test and 
chest radiography will also be obtained at the corresponding scheduled visit, respectively. 
 
Vital signs and body weight are collected as scheduled in Table 1. Vital signs include 
systolic/diastolic blood pressure, heart rate, respiratory rate and body temperature (°C). Subjects 
must rest in a sitting position for at least 5 minutes in preparation for blood pressure and heart rate 
assessments. The following information will be derived for all vital signs and body weight: 


 
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• Change from baseline at all post-baseline visits 
• Treatment-emergent PCS abnormalities, if applicable 
 
Twelve-lead ECG recordings and conduction intervals including RR, PR, QRS, QT and 
Fridericia-corrected QT interval (QTcF) are obtained according to the schedules summarized in 
Table 1. The QTcF (Fridericia’s formula, QTcF = QT/RR1/3) will be derived and reported in the 
database.  
The following information will be calculated for each of the 12-lead ECG measurements: 
• Change from baseline to all post-baseline visits 
• Treatment-emergent PCS abnormalities, if applicable 
The overall clinical interpretation of an ECG is assessed as follows: normal, abnormal not 
clinically significant or abnormal clinically significant.  
 
The physical examinations will be performed by a physician or a 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, neurological, psychiatric/emotional, 
lymphatic and musculoskeletal systems.  
Clinically significant abnormal physical examination findings will be recorded as medical history 
or AE where appropriate.  
 Pharmacokinetic (PK) Parameters 
The pharmacokinetic parameters are: 
• Trough plasma levels of JTE-451; 
 Medications/Procedures 
At each study visit, investigators will review concomitant medications and procedures with the 
patients. The World Health Organization (WHO) Drug Dictionary version Global B3 March 2020 
or later will be used to classify medications by preferred term, chemical ingredient names and 
WHO Level 3 Anatomical Therapeutic Chemical (ATC) classification of trade name. Medication 


 
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records will be characterized as prior medication and/or concomitant medication based on the 
subjects’ start and end date of the study drug. 
 
Prior medications/procedures are defined as any medications/procedures started and ended before 
the first dose of the study drug. 
 
Any medications/procedures that begin before the start of the first dose of study drug and continue 
past that, or that begins on or after the first dose of study drug and up to 28 days after last dose of 
the study drug will be considered as concomitant medications/procedures. 
6. STATISTICAL METHODOLOGY 
Titles and headers of all statistical analysis tables will indicate the corresponding study population; 
the number of subjects for the population and for each treatment will be presented in the tables. 
Summary statistics for continuous parameters will include the number of subjects with 
non-missing data (n), mean, standard deviation (SD), median, minimum and maximum. For 
plasma concentrations, summary statistics will also include the coefficient of variation (CV%). 
Summary statistics for discrete parameters will include frequency count and percentage of which 
the denominator will be clearly indicated in the analysis table.  
For efficacy and safety summaries, mean and median will be presented to 1 more decimal than the 
source data; SD will be presented to 2 more decimals than the source data; minimum and maximum 
will be presented in the same precision as the source data. Percentages including response rate will 
be presented to 1 decimal, e.g., xx.x%. P-values will be presented to 3 decimals. P-values greater 
than 0.999 will be presented as >0.999; p-values less than 0.001 will be presented as <0.001.  
For figures, the corresponding study population will be displayed in the titles. All collected 
observations will be included in the related listings. 
Baseline value is defined as the last non-missing value prior to the first dose. If the scheduled 
Day 1 value (i.e., not unscheduled or repeat measurement on Day 1) is available, the scheduled 
Day 1 value will be the baseline, as all procedures are to be performed before dosing at each visit. 
The determination of baselines and EOT values for both efficacy and safety variables will be based 
on available scheduled assessments and unscheduled assessments. Only assessments from 
scheduled visits will be used for the by-visit summary tables, however, data collected from both 
scheduled and unscheduled visits will appear in the subject listings.  
When calculating percent change from baseline in efficacy analyses, if the baseline value is 0 and 
the post-baseline value is also 0, then the percent change from baseline is set to 0. If the baseline 
value is 0 or missing and the post-baseline value is non-zero or missing, then the percent change 
from baseline is set to missing. 


 
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 Sample Size 
Approximately 150 eligible subjects (50 subjects in each treatment group) will be randomized into 
the double-blind treatment period. 
The sample size estimation is based on the primary efficacy parameter of the proportion of subjects 
achieving PASI-75 at EOT. 
Taking into consideration a 15-20% treatment discontinuation rate, about 50 subjects per group 
will be randomized into the double-blind treatment period. 
 Subject Disposition Summary 
Subject disposition will be summarized and tabulated by treatment group and in total. The number 
and percentage of subjects in the safety, ITT, PP and PK populations will be tabulated. 
Discontinued patients and the reasons for discontinuation will be summarized. The number of 
subjects at each scheduled visit will be tabulated for the ITT population by treatment group and in 
total. 
 Demographics and Baseline Characteristics 
Demographics and baseline characteristics as defined in Section 5.1 will be presented by treatment 
group with descriptive statistics for the safety, ITT and PP populations. 
 Efficacy Analysis 
Analyses of primary and secondary efficacy parameters will be performed for both the ITT and 
PP populations, respectively. A
 
y. 
For efficacy analyses, the JTE-451 treatment period is defined as the time period from the first 
dose of study drug to the last dose of study drug plus 4 days. The EOT value is defined as the last 
value taken during the JTE-451 treatment period. For PASI-50/75/90 and sPGA response analyses 
at EOT, if 10% or more subjects take any other psoriasis treatment that is listed in the protocol 
Section 3.5.5.1.1, a sensitivity analysis will be conducted using an alternative EOT value. The data 
used for the alternative EOT value determination will be up to and excluding the start of the other 
psoriasis treatment. The alternative EOT value will be the last value within 4 days after the last 
dose of JTE-451 in this data cutoff.  
All analyses will be performed two-sided at the 5% significance level. No formal multiple 
comparison adjustment will be made for secondary efficacy parameters. The estimated treatment 


 
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effect (relative to placebo) from the model, along with a two-sided 95% confidence interval (CI) 
and p-value, will be tabulated where appropriate. 
Graphical presentations of the treatment profile will be provided for the primary and secondary 
efficacy parameters. Sensitivity analysis and model fit assessment may be conducted, and data 
transformation may be employed if appropriate. 
 
The primary efficacy parameter (PASI-75 response rate at EOT) will be compared for each 
JTE­451 dose group with placebo using the Cochran-Mantel-Haenszel (CMH) test, stratified by 
prior exposure to biologic therapy (Yes or No) and body weight (<90 kg or ≥90 kg at Visit 2). The 
adjusted odds ratio for each active treatment group to the placebo group along with 95% CIs and 
p-value will be reported. 
A sample SAS code as below: 
 Cochran-Mantel-Haenszel test (Run by K=2, 3 separately): 
           PROC FREQ DATA=<input>; 
                  TABLES   <biologic therapy> * <body weight > * <TRTn> *<PASI75> / CMH;  
                  WHERE <TRTn> IN (1, K); 
           RUN; 
Note: 
o 
<biologic therapy>=0 represents ‘Biologic-naïve’;  
<biologic therapy> =1 represents ‘Biologic-experienced’; 
o 
<body weight >=0 represents ‘Body weight < 90 kg’; 
<body weight >=1 represents ‘Body weight >= 90 kg’; 
o 
<TRTn>=1 for placebo, <TRTn>=2 for JTE-451 200 mg, <TRTn>=3 for JTE-451 400 mg,  
o 
<PASI75> =0 represents a non-responder,  <PASI75> =1 represents a responder;  
In addition, logistic regression model-based supportive analyses will be performed for the pairwise 
comparisons between JTE-451 and placebo groups (as shown in Model 1 below) and for the 
evaluation of dose response relationship (as shown in Model 2 below). The logistic regression 
models will include baseline PASI value and two stratification factors (prior biologic therapy and 
body weight) as covariates. 
Sample SAS codes as below: 
 Model 1 (pairwise treatment vs placebo comparison) 
PROC LOGISTIC DATA=<input> DESCENDING; 
     CLASS <biologic therapy> <body weight >; 
     MODEL <PASI75> = <Dose_200>  < Dose_400>  <Baseline X> 
                                         <biologic therapy>  <body weight > ; 
RUN;   
 
 Model 2 (dose-response analysis)   
PROC LOGISTIC DATA=<input> DESCENDING; 
     CLASS <biologic therapy> <body weight >; 


 
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     MODEL <PASI75> = <Dose> <Baseline X>  
                                          <biologic therapy> <body weight >; 
     ODDSRATIO <Dose>; 
RUN; 
Note:  
o 
In Model 1, <Dose_x> = 1 if dose=x; otherwise. <Dose_x>=0; i.e., <Dose_x> is a dummy variable.  
o 
In Model 2, <Dose> = 0, 200, 400 for placebo and each JTE-451 dose level, respectively. 
o 
<Baseline X> denotes baseline PASI value. 
o 
<PASI75> =1 represents a responder; <PASI75> =0 represents a non-responder.  
o 
<biologic therapy> =0 represents ‘Biologic-naïve’;  
<biologic therapy> =1 represents ‘Biologic-experienced’; 
o 
<body weight>=0 represents ‘Body weight < 90 kg’; 
<body weight>=1 represents ‘Body weight >= 90 kg’; 
From the model fitting, one obtains adjusted odds ratios and corresponding p-values for the respective 
pairwise treatment comparison versus placebo. 
 
For dichotomous secondary efficacy parameters at defined single time point, similar analyses used 
for the primary efficacy parameter above will be performed as appropriate. For assessing 
dichotomous efficacy parameter measured at multiple time points, a generalized estimating 
equation (GEE) method on the logit scale will be used. The model includes effects for treatment, 
time, treatment by time interaction, stratification factors, appropriate baseline and subject as the 
repeated factor. The odds ratio (OR) of each JTE-451 dose group relative to placebo at the same 
time point will be estimated.  
A sample SAS code as below: 
 Model: (Generalized estimating equation (GEE) method on the logit scale) 
PROC GENMOD DATA=<input>; 
                      CLASS <usubjid> <visit>(REF=”Week 0”) <TRTn>(REF=1) 
                                   <biologic therapy>(REF =0)  < body weight >(REF =0); 
                      MODEL <SAPE> = <TRTn> <visit> <TRTn>*<visit> <Baseline> <biologic therapy> < body weight > 
                                                        /DIST=BINOMIAL LINK=LOGIT; 
                      REPEATED SUBJECT=<usubjid>(<TRTn>) / TYPE=UN CORRW; 
                RUN; 
Note:   
o 
<usubjid> denotes subject ID; 
o 
<SAPE> denotes any dichotomous efficacy parameter; 
o 
<TRTn>=1 for placebo, <TRTn>=2 for JTE-451 200 mg, <TRTn>=3 for JTE-451 400 mg;   
o 
<Baseline> denotes appropriate baseline corresponding to the efficacy parameter; 
o 
<biologic therapy> =0 represents ‘Biologic-naïve’;  
<biologic therapy> =1 represents ‘Biologic-experienced’; 
o 
<body weight>=0 represents ‘Body weight < 90 kg’; 
<body weight>=1 represents ‘Body weight >= 90 kg’; 
For assessing the continuous efficacy parameter measured at multiple time points, a mixed effect 
model with repeated measures (MMRM) will be used. The model includes fixed effects for 
treatment, time, treatment by time interaction, stratification factors, appropriate baseline and 


 
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measurements within each subject as repeated measures. The treatment difference of each JTE-451 
dose group relative to placebo at the same time point will be estimated as well as the corresponding 
95% CI.  
A sample SAS code is displayed below: 
 Model: (Mixed-effect model with repeated measures (MMRM)) 
PROC MIXED DATA=<input>; 
                      CLASS <usubjid> <visit> <TRTn>(REF=1)  <biologic therapy>(REF =0)  < body weight >(REF =0); 
                      MODEL <PCHG> = <Baseline>  <TRTn>  < visit > <TRTn>*<visit>  
                                                        <biologic therapy> < body weight >; 
                      REPEATED/SUBJECT=<usubjid>(<TRTn>)  TYPE=UN; 
                      LSMEANS < TRTn >/PDIFF CL; 
                RUN; 
Note:   
o 
<PCHG> denotes change from baseline or percent change from baseline in any continuous efficacy 
parameter; 
o 
<TRTn>=1 for placebo; <TRTn>=2 for JTE-451 200 mg; <TRTn>=3 for JTE-451 400 mg;   
o 
<Baseline> denotes appropriate baseline corresponding to the efficacy parameter; 
o 
<biologic therapy> =0 represents ‘Biologic-naïve’;  
<biologic therapy> =1 represents ‘Biologic-experienced’; 
o 
<body weight>=0 represents ‘Body weight < 90 kg’; 
<body weight>=1 represents ‘Body weight >= 90 kg’; 
 
The assessments from the follow-up visit and derived EOT will not be included in the GEE or 
MMRM models. 
 
The Itch NRS scores will be summarized descriptively by each JTE-451 dose group and placebo 
group, and analyzed in an MMRM for weekly averages (by-visit only) as described above.   
Observed values and changes from the weekly average at one week prior to Week 0 to the weekly 
average at one week prior to each scheduled visit which includes the day of scheduled visit and a 
6-day collection before the scheduled visit will be derived and analyzed by each study visit from 
Week 0 to the Follow-up visit (including EOT) using both the ITT and PP populations, respectively. 
The data used for by-visit average score derivation in the treatment period (not including the 
Follow-up visit) will be up to the day of last dose plus 4 days. For the Follow-up visit, the weekly 
average will use the collection at the day of Follow-up visit and the 6-day collection before the 
Follow-up visit.  
In addition, the Itch NRS scores will be derived and analyzed by each JTE-451 dose group and 
placebo as following: 
• Observed values and changes from baseline (one week prior to Week 0) in weekly average 
score will be analyzed by each week from Week 0 to Week 20 using the ITT population only. 
For early-terminated subjects, the data used for weekly average score derivation will be up to 
the day of last dose plus 4 days.  


 
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• Descriptive statistics of observed values and changes from Day 1 in daily score will be 
presented by each day from Day -6 to Day 28 using the ITT population only. For 
early-terminated subjects, the data used for daily score summary will be up to the day of last 
dose plus 4 days. 
 
 
 
The randomization in this study is stratified by prior exposure to biologic therapy 
(i.e., biologic-naïve vs. biologic-experienced subjects) and body weight (i.e., <90 kg vs. ≥90 kg at 
Visit 2). 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 treatment-by-baseline effect will be assessed as appropriate. The baseline will be included in 
the respective parametric analysis model of the efficacy parameters where appropriate.  
 
As exploratory analyses, further subgroup analyses may be conducted for selected parameters. The 
subgroups that may be examined include, but are not limited to, the following: 
• Prior biologic therapy (naïve vs. experienced) 
• Body weight (<90 kg vs. ≥90kg at Visit 2)   
 
There may be missing data intermittently (e.g., a missing visit or subject dropout). For 
PASI-50/-75/-90 and sPGA (achieving score of 0 or 1) responses, subjects with missing EOT data 
will be imputed as non-responders at EOT; for analyses by scheduled time points, missing data 
will not be imputed. For analysis with multiple time points, any missing data will be imputed using 
the last observation carried forward (LOCF) method. For parameters analyzed both by time point 
and with multiple time points, these two approaches would strengthen the findings when they are 
similar. 
For efficacy analysis of continuous parameters, missing data will not be imputed. This is because 
the statistical models employed (e.g., mixed effect model) generally provide valid estimates if the 
missing data mechanism is so-called “missing at random,” a common assumption made as the first 
approach for analysis. 
For the Itch NRS, 4 completed days are necessary to derive a weekly score (1-3 missed days, 
consecutive or non-consecutive, are allowed). Any missing individual items are treated as missing 
data. When a weekly score in post-dose time point cannot be calculated (less than 4 completed 
days), the time point will not be included in the analysis. If a baseline weekly score cannot be 
derived (i.e., less than 4 completed days from Day -6 to Day 1), the Itch NRS score of the subject 
will not be included in the analysis. 


 
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For the Skindex-16, if more than 25% of the responses are missing, the scale is considered missing. 
An item with multiple answers is considered missing. The skindex-16 score will be derived for all 
study visits.  
Additional sensitivity analyses of the primary efficacy parameter, i.e., PASI-75 at EOT, may be 
performed using other missing data handling procedures or approaches. 
 Safety Analysis 
All safety analyses will be summarized based on the Safety population. 
Potentially clinically significant (PCS) abnormalities will be defined according to the Akros Safety 
Reporting Standards as of 18 Oct, 2004. The PCS values for vital signs, ECG and laboratory data 
will be flagged in data listings. 
Treatment-emergent PCS abnormalities are values that meet the specified criteria after the 
initiation of study drug (see Section 10.1 for detailed clinically significant criteria). 
Treatment-emergent PCS values will be summarized, presenting the number and percentage of 
subjects who had at least one PCS value on or after the first dose of study drug (JTE-451 or 
placebo). The denominator is always the number of subjects in the safety population, regardless of 
whether the subject had any post-baseline measurements. The numerator is the number of subjects 
in the safety population with any PCS value in the treatment-emergent period. Note that for the 
purpose of determining PCS abnormalities, baseline is always the last non-missing value before 
the first dose of study drug. As all procedures will be performed before dosing at each scheduled 
visit, the values of the scheduled Day 1 collection will be baseline and will not be 
treatment-emergent PCS. 
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. 
 
AEs will be summarized by MedDRA system organ class (SOC) and preferred term (PT) in 
descending order unless otherwise specified. For the summary of number of subjects, if a subject 
reports more than one AE that was coded to the same SOC or PT, the subject will be counted only 
once for that specific system organ class or preferred term. For the summary of number of AEs, 
all AEs will be counted. 
The number and percentage of subjects experiencing TEAEs will be tabulated by treatment 
according to the following categories: 
• Overall summary of TEAEs. 
• TEAEs by system organ class and preferred term. 
• TEAEs by system organ class, preferred term and maximum severity. 
• TEAEs by system organ class, preferred term and causality. 
• TEAEs by preferred term (in order of descending frequency in the total JTE-451 group). 
• TEAEs leading to study discontinuation by system organ class and preferred term. 
• Serious AEs (SAEs) by system organ class and preferred term. 


 
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• SAEs leading to study discontinuation by system organ class and preferred term. 
In addition, adverse drug reactions (ADRs) will be summarized. Per ICH E2A guidance, all 
noxious and unintended responses to a medicinal product related to any dose should be considered 
ADRs. The phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility, i.e., the relationship cannot be 
ruled out. For the purpose of analysis, all TEAEs that are related, possibly related or has missing 
relationship to the study drug will be considered as ADRs. The following summaries of ADRs will 
be presented: 
• Number of ADRs by system organ class, preferred term and maximum severity. 
• Number of subjects with ADRs by preferred term (in order of descending frequency in the total 
JTE-451 group) 
Listings will be provided for AEs, SAEs and AEs leading to study discontinuation.  
 
Subjects with significant medical history conditions and/or surgeries, the corresponding system 
organ class and preferred term coded from the MedDRA (Version 23.0) will be presented in the 
data listing. 
 
Prior medications and concomitant medications will be listed in the data listings. Concomitant 
medications will be summarized by ATC Level 3 term, drug preferred term and treatment group. 
 
Descriptive statistics of observed results and change from baseline for hematology, serum 
biochemistry, coagulation and continuous urinalysis will be presented by time point and treatment 
group. Frequency and percentage of the distribution of discrete urinalysis tests will be presented 
by time point. Number and percentage of subjects with treatment-emergent PCS abnormal values 
will be summarized by treatment group.  
The number and percentage of subjects with post-baseline abnormalities in liver tests will be 
summarized by treatment group according to Table 3.  
 
 


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Table 3. 
Criteria for Categorical Analysis in Liver Tests 
Parameter 
Specified Value 
ALT 
ALT ≥ULN×3 
ALT ≥ULN×5 
ALT ≥ULN×10 
ALT ≥ULN×20 
AST 
AST ≥ULN×3 
AST ≥ULN×5 
AST ≥ULN×10 
AST ≥ULN×20 
ALT and AST 
ALT and AST ≥ULN×3 ALT and AST ≥ULN×5 ALT and AST 
≥ULN×10 
ALT and AST 
≥ULN×20 
ALT or AST 
ALT or AST ≥ULN×3 
ALT or AST ≥ULN×5 
ALT or AST ≥ULN×10  ALT or AST ≥ULN×20 
T-Bil 
T-Bil >ULNx1.5 
T-Bil >ULN×2 
ALP 
ALP > ULN×1.5 
ALT and T-Bil 
ALT ≥ULN×3 and T-Bil ≥ULN×1.5 
ALT ≥ULN×3 and T-Bil ≥ ULN×2 
AST and T-Bil 
AST ≥ULN×3 and T-Bil ≥ULN×1.5 
AST ≥ULN×3 and T-Bil ≥ ULN×2 
ALT, AST, ALP and 
T-Bil 
ALT ≥ULNx3, AST ≥ULNx3, ALP ≥ULN×2 and T-Bil ≥ULN×2 
ALT and AST 
ALT or AST > ULN×3 at any treatment visit and any of the following AEs: Nausea, Vomiting, Anorexia, 
Abdominal pain or Fatigue, reported within +/- 14 days of the abnormal AT values.  
Other clinical laboratory tests (e.g., drug abuse, alcohol screen, viral serology, pregnancy) will be 
listed in the data listings. 
Qualitative urine parameters are generally reported by a descriptive score, which may differ 
between laboratories. For pooling the data, the qualitative results will be mapped to a four-point 
scale. A clinical review will be performed on the mapping of the descriptive scores to the 
four-point scale; and the descriptive scores will be remapped where appropriate. The four-point 
scale will be used in the determination of the PCS abnormalities. 
The mean profile may be presented for selected laboratory parameters. 
Descriptive statistics of observed results and change from baseline for vital signs and body weight 
will be presented by time point and treatment group. Number and percentage of subjects with 
treatment-emergent PCS abnormal values will be presented by treatment group. 
Descriptive statistics of observed results and change from baseline will be presented by time point 
and treatment group for RR, PR, QRS, QT and QTcF intervals. The number and percentage of 
subjects with treatment-emergent PCS abnormal values will be presented by treatment group. 
Clinical interpretation of overall ECG findings will be summarized by time point and treatment 
group.  
A summary of total duration of study medication exposure, which is calculated as (last dose date 
of study drug – first dose date of study drug + 1), will be presented by treatment group. Average 
daily dose will also be summarized by treatment group, which is calculated as (total dose of study 
drug taken/total duration of study medication exposure), where the total dose is calculated as 
[(total number of tablets/4) × daily dose level in the treatment group (0, 400 mg or 800 mg)].  


 
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Study drug compliance will be summarized between visits and overall for each treatment group. 
Study drug compliance will also be presented as categories <80%, 80%-120% and >120%. 
 Pharmacokinetic Analysis 
All PK data will be summarized or analyzed based on the PK population. 
 
The PK data including individual data and descriptive statistics for plasma drug concentrations 
will be represented with 3 significant values except for CV% which will be represented to 
1 decimal place. The ratio values (see Section 6.6.2) will be displayed to 2 decimal places. 
 
Descriptive statistics of plasma concentration data for JTE-451 will be presented by treatment and 
visit (nominal time point) with n, arithmetic mean, geometric mean, SD, CV%, median, minimum 
and maximum. The mean ratio of trough concentration relative to the lowest dose will be calculated. 
Mean plasma concentration-time profiles will be plotted by treatment on linear scales. Below the 
limit of quantification (BLQ) concentrations will be treated as zero for descriptive statistics. 
 
Population PK (PPK) analyses may be performed. Population PK analysis plan will be specified 
in a separate analysis document and the results of PPK analyses will be presented in a standalone 
report separately from the Clinical Study Report.  
 
7. SUBJECT DATA LISTING 
Subject listings of all the data collected in the study database, including eCRF data and any external 
data transfers (such as clinical laboratory results), will be presented by treatment group and subject 
number. 
If a subject prematurely discontinues the study, additional subjects may be enrolled at the 
discretion of the Sponsor, as appropriate. 
8. SOFTWARE AND QUALITY CONTROL 
All analysis will be performed using SAS® Version 9.4 or higher. The SOPs of 
 will be 
followed in the creation and quality control of all tables, listings and analysis. 


 
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9. REFERENCES 
Please see the references in protocol.  


 
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10. 
APPENDICES 
  General Clinically-Significant Criteria for Safety Parameters  
 
Parameter 
(Full Names) 
 
Reporting 
Unit 
 
Clinically Significant Criteria 1 
 
Low 
High 
Hematology 
 
 
 
Hematocrit 
% 
Male   ≤37% 
Female ≤32% 
NA 
Hemoglobin 
g/dl 
Male   ≤11.5 
Female ≤9.5 
NA 
White blood cell 
E3/mm3 
≤2.8 
≥16.0 
Platelets 
E3/mm3 
≤75 
≥700 
Mean corpuscular hemoglobin 
pg/cell 
-- 
-- 
Mean corpuscular hemoglobin 
concentration 
g/dl 
-- 
-- 
Mean corpuscular volume 
fl 
-- 
-- 
Red blood cell 
E6/mm3 
≤3.5 
NA 
Differential  
 
 
 
Bands or (Band neutrophil 
(stab)) 
% 
NA 
≥10% 
Basophil (absolute) 
E3/mm3 
NA 
≥0.4 
Basophil (%) 
% 
NA 
≥5% 
Lymphocytes (absolute) 
E3/mm3 
≤0.5 
≥4.5 
Lymphocytes (%) 
% 
≤10% 
≥80% 
Monocytes (absolute) 
E3/mm3 
NA 
≥1.5 
Monocytes (%) 
% 
NA 
≥ 20% 
Neutrophils (absolute) 
E3/mm3 
≤1.0 
  
Neutrophils (%) 
% 
≤15% 
≥90% 
Eosinophils (absolute) 
E3/mm3 
NA 
≥0.7 
Eosinophils (%) 
% 
NA 
≥10% 
Coagulation 
 
 
 
Prothrombin time 
seconds 
NA 
≥16 
International Normalized 
Ratio 
ratio 
NA 
≥2.00 
Partial thromboplastin time  
Seconds 
NA 
≥50 
                                                          
 
1 Can be revised as appropriate, but should be consistent within the project. 


 
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Parameter 
(Full Names) 
 
Reporting 
Unit 
 
Clinically Significant Criteria 1 
 
Low 
High 
Heart Function 
 
 
 
Aspartate transaminase 
IU/l 
NA 
≥3 x UNL 
Lactic dehydrogenase  
U/L 
NA 
≥3 x UNL 
CPK (MB Fraction) 
μg/L 
-- 
-- 
Liver Function  
 
 
 
Alkaline Phosphatase 
IU/l 
NA 
≥3 x UNL 
Alanine transaminase 
IU/l 
NA 
≥3 x UNL 
Total Bilirubin 
mg/dl 
NA 
≥2.0 
Gamma-glutamyltransferase 
IU/l 
NA 
≥3 x UNL 
Total Protein 
g/dl 
≤4.5 
≥9.0 
Albumin 
g/dl 
≤2.5 
≥6.5 
Renal Function 
 
 
 
Blood urea nitrogen 
mg/dl 
NA 
≥30 
Creatinine 
mg/dl 
NA 
≥2.0 
Thyroid Function 
 
 
 
 T3 Uptake, total 
nmol/L 
-- 
-- 
Reverse T3 
nmol/L 
-- 
-- 
Thyroxine (T4) 
nmol/L 
-- 
-- 
Human chorioic gonadotropin 
IU/L 
-- 
-- 
Free T4 
pmol/L 
-- 
-- 
Thyroid- stimulating hormone 
mU/L 
-- 
-- 
Follicle- stimulating hormone 
-- 
-- 
-- 
Lipid Chemistry 
 
 
 
Total cholesterol 
mg/dl 
NA 
≥300 
 
LDL cholesterol 
mg/dl 
-- 
-- 
 
HDL cholesterol 
mg/dl 
-- 
-- 
Ratio (LDL/HDL) 
Fraction 
-- 
-- 
Triglycerides 
mg/dl 
NA 
≥300 
 
 


 
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Parameter 
(Full Names) 
 
 
Reporting Unit 
 
Clinically Significant Criteria 1 
 
Low 
High 
Electrolytes 
 
 
 
       Chloride 
MEq/l 
≤90 
≥112 
Potassium 
MEq/l 
≤3.0 
≥5.8 
Sodium 
MEq/l 
≤130 
≥150 
Bicarbonate 
MEq/L 
-- 
-- 
Metabolic 
 
 
 
Calcium 
mg/dl 
≤7.0 
≥15.5 
Phosphate 
mg/dl 
≤1.5 
≥6.0 
Blood Glucose  
mg/dl 
≤50 
(fasting) 
≥180 
(fasting) 
Uric Acid  
mg/dl 
NA 
Male    ≥10.5 
Female ≥8.5 
Cancer 
 
 
 
Prostate-specific antigen 
-- 
-- 
-- 
Alpha-fetoprotein 
-- 
-- 
-- 
Viral tests 
 
 
 
HIV 
-- 
-- 
-- 
HIV2 
-- 
-- 
-- 
Hepatitis A virus 
-- 
-- 
-- 
Hepatitis A antibody 
-- 
-- 
-- 
Hepatitis B virus 
-- 
-- 
-- 
  Hepatitis B surface Antigen 
-- 
-- 
-- 
Hepatitis B core antigen 
-- 
-- 
-- 
Hepatitis C virus 
-- 
-- 
-- 
Urinalysis 
 
 
 
(Urine) protein  
 
NA 
Increase≥2 
(Urine) glucose 
 
NA 
Increase≥2 
(Urine) bilirubin 
 
NA 
Increase≥2 
Occult blood 
 
NA 
Increase≥2 
Color 
 
NA 
Increase≥2 
Ketone 
 
NA 
Increase≥2 
Leukocyte esterase 
 
NA 
Increase≥2 
pH 
 
Decrease≥2 
Increase≥2 
Turbidity 
 
NA 
Increase≥2 
Urobilinogen 
 
NA 
Increase≥2 
Specific gravity 
 
≤1.005 
NA 
 
 
 
 
 
                                                          
 
1 Can be revised as appropriate, but should be consistent within the project. 


 
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Parameter 
(Full Names) 
 
 
Reporting Unit 
 
Clinically Significant Criteria 1 
 
Low 
High 
Vital Sign 
Systolic blood pressure 
mmHg 
≤90 and 
≥20 decrease 
≥180 and 
≥20 increase 
Diastolic blood pressure  
mmHg 
≤50 and 
≥15 decrease 
≥105 and 
≥15 increase 
Pulse rate 
bpm 
≤50 and 
≥15 decrease 
≥120 and 
≥15 increase 
Body Temperature 
C° 
NA 
≥1.11 C° Increase 
Respiration rate 
#/min 
≤ 10 
-- 
Height 
cm 
-- 
-- 
Weight 
kg 
≥7% decrease 
≥7% increase 
Body mass index 
kg/m2 
 
 
Hip Circumference 
cm 
 
 
Waist Circumference 
cm 
 
 
ECG 
 
 
 
Heart rate 
bpm 
<50 
>100 
R-R interval 
msec 
-- 
-- 
PR interval 
msec 
NA 
>200 msec and >Baseline 
QRS interval 
msec 
NA 
>120 msec and >Baseline 
QT interval 
msec 
NA 
>450 and 
>30 increase 
QTc interval 
msec 
<=350 and 
Baseline<375 
>450 or >480 or 
>500 with Baseline <450 
QTc interval1 
msec 
NA 
>30 increase or 
>60 increase 
 
 Mock Summary Tables 
The mock summary tables will be created in a separate document. 
 Mock Data Listings 
The mock summary listings will be created in a separate document. 
 Mock Figures 
The mock summary figures will be created in a separate document. 
                                                          
 
1 Can be revised as appropriate, but should be consistent within the project.