Clinical trial NCT03614078
Conditions: Psoriasis Vulgaris Plaque Psoriasis
Sponsor: PRCL Research Inc.
Start date: 2018-09-25; Completion date: 2019-07-08
Enrollment: 92 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The aim of this study is to evaluate safety, tolerability, and efficacy of PRCL-02 in moderate to severe chronic plaque psoriasis

Detailed description:

Arms: arm 1: Loading dose followed by a once daily maintenance dose commencing on Day 2 and continuing for 12 weeks arm 2: Loading dose followed by a once daily maintenance dose commencing on Day 2 and continuing for 12 weeks arm 3: Loading dose followed by a once daily maintenance dose at matching treatment levels, commencing on Day 2 and continuing for 12 weeks
Interventions: intervention 1: PRCL-02 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral tablets intervention 2: Oral tablets

Protocol documents:
Prot_000.pdf: 
PRCL-PoC Protocol (Amendment 1) 
A Phase 2A Study To Evaluate Safety, Tolerability, and Efficacy of PRCL-02 In Patients With 
Moderate To Severe Chronic Plaque Psoriasis 
NCT03614078 
Approved: 20Jul2018 


PROTOCOL PRCL-POC 
A PHASE 2A STUDY TO EVALUATE SAFETY, 
TOLERABILITY, AND EFFICACY OF PRCL-02 IN PATIENTS 
WITH MODERATE TO SEVERE CHRONIC PLAQUE 
PSORIASIS 
 
 
 
Confidential Information 
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of PRCL Research Inc. or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
PRCL-02, unless such persons are bound by a confidentiality agreement with PRCL-02 or 
its subsidiaries.   
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  PRCL 
Research Inc. requests consultation regarding release/redaction prior to any public release.  
In the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of PRCL Research Inc. or its subsidiaries. 
PRCL-02 
Version: Amendment 1 
 Date: 16 Jul 2018 
 
PRCL Research Inc. 
1255 Robert-Bourassa, Suite 1610, 
Montreal, Quebec, H3B 3X3, Canada 
 
 


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PROTOCOL HISTORY 
 
Date 
Version  
Description/summary of changes 
28-Jun-2018 
Final 
Original protocol  
16-Jul-2018 
Amendment I Changes were made following feedback from IRB. 
Text was added to Section 6.3 to indicate that male 
patients should avoid donating sperm while participating 
in this trial and for 4 months after stopping the study 
treatment. 
Text was added to Section 8.2 to indicate that patients 
must withdraw from the study if they become pregnant. 
Text was added to Appendix 2. Follicle Stimulating 
Hormone is now included in the Clinical Laboratory 
Tests, as this test may be used for assessment of patient 
eligibility for the study.  
 
 


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Table of Contents 
Section 
Page 
Table of Contents .............................................................................................................................3 
1. 
Synopsis ...................................................................................................................................9 
2. 
Schedule of Activities ............................................................................................................12 
3. 
Introduction ...........................................................................................................................14 
3.1. 
Study Rationale ................................................................................................................14 
3.2. 
Background.......................................................................................................................14 
3.3. 
Benefit/Risk Assessment ..................................................................................................15 
4. 
Objectives and Endpoints ......................................................................................................16 
5. 
Study Design .........................................................................................................................17 
5.1. 
Overall Design ..................................................................................................................17 
5.2. 
Number of Participants .....................................................................................................17 
5.3. 
End of Study Definition....................................................................................................17 
5.4. 
Scientific Rationale for Study Design ..............................................................................18 
5.5. 
Justification for Dose ........................................................................................................18 
6. 
Study Population ...................................................................................................................19 
6.1. 
Inclusion Criteria ..............................................................................................................19 
6.2. 
Exclusion Criteria .............................................................................................................20 
6.3. 
Lifestyle Restrictions ........................................................................................................21 
6.4. 
Screen Failures .................................................................................................................22 
7. 
Treatments .............................................................................................................................23 
7.1. 
Treatments Administered .................................................................................................23 
7.1.1. 
Packaging and Labelling ..........................................................................................23 
7.2. 
Method of Treatment Assignment ....................................................................................23 
7.2.1. 
Selection and Timing of Doses ................................................................................24 
7.3. 
Blinding ............................................................................................................................24 
7.4. 
Dosage Modification ........................................................................................................25 
7.5. 
Preparation/Handling/Storage/Accountability .................................................................25 
7.6. 
Treatment Compliance .....................................................................................................25 
7.7. 
Concomitant Therapy .......................................................................................................25 
7.8. 
Treatment after the End of the Study ...............................................................................26 
8. 
Discontinuation Criteria ........................................................................................................27 
8.1. 
Discontinuation from Study Treatment ............................................................................27 
8.1.1. 
Discontinuation of Inadvertently Enrolled Patients from 
Study Treatment .......................................................................................................27 


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8.2. 
Discontinuation from the Study........................................................................................28 
8.3. 
Patients Lost to Follow-up ................................................................................................28 
9. 
Study Assessments and Procedures .......................................................................................29 
9.1. 
Efficacy Assessments .......................................................................................................29 
9.1.1. 
Primary Efficacy Assessment - Psoriasis Area and Severity 
Index (PASI) ............................................................................................................29 
9.1.2. 
Exploratory Efficacy Assessments – Static Physicians 
Global Assessment (sPGA) ......................................................................................29 
9.2. 
Adverse Events .................................................................................................................29 
9.2.1. 
Serious Adverse Events ...........................................................................................30 
9.2.1.1. 
Suspected Unexpected Serious Adverse Reactions ...........................................32 
9.2.2. 
Complaint Handling .................................................................................................32 
9.3. 
Treatment of Overdose .....................................................................................................32 
9.4. 
Safety ................................................................................................................................32 
9.4.1. 
Electrocardiograms ..................................................................................................32 
9.4.2. 
Vital Signs ................................................................................................................32 
9.4.3. 
Laboratory Tests ......................................................................................................33 
9.4.4. 
Physical Examination ...............................................................................................33 
9.4.5. 
Safety Monitoring ....................................................................................................33 
9.4.5.1. 
Hepatic Safety Monitoring .................................................................................33 
9.5. 
Pharmacokinetics ..............................................................................................................34 
9.6. 
Sample collection and assay .............................................................................................34 
9.7. 
Bioassay ............................................................................................................................34 
9.8. 
Pharmacodynamics ...........................................................................................................34 
9.8.1. 
Pharmacodynamic Assessments ..............................................................................34 
9.9. 
Pharmacogenomics ...........................................................................................................35 
9.9.1. 
Whole Blood Sample for Pharmacogenetic Research .............................................35 
9.10. Biomarkers .......................................................................................................................35 
9.11. Health Economics or Medical Resource Utilization and Health 
Economics ........................................................................................................................35 
10. Statistical Considerations ......................................................................................................36 
10.1. Sample Size Determination ..............................................................................................36 
10.2. Populations for Analyses ..................................................................................................36 
10.3. Statistical Analyses ...........................................................................................................36 
10.3.1. 
General Statistical Considerations ...........................................................................36 
10.3.2. 
Treatment Group Comparability ..............................................................................37 
10.3.2.1. 
Patient Disposition .............................................................................................37 
10.3.2.2. 
Patient Characteristics ........................................................................................37 


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10.3.2.3. 
Concomitant Therapy .........................................................................................37 
10.3.2.4. 
Treatment Compliance .......................................................................................37 
10.3.3. 
Efficacy Analyses ....................................................................................................37 
10.3.3.1. 
Primary Analyses ...............................................................................................37 
10.3.3.2. 
Secondary Analyses ...........................................................................................37 
10.3.3.3. 
Tertiary/Exploratory Analyses ...........................................................................37 
10.3.4. 
Safety Analyses ........................................................................................................38 
10.3.5. 
Pharmacokinetic/Pharmacodynamic Analyses ........................................................38 
10.3.5.1. 
Pharmacokinetics ...............................................................................................38 
10.3.5.2. 
Pharmacodynamics .............................................................................................38 
10.3.5.3. 
PK/PD .................................................................................................................39 
10.3.6. 
Evaluation of Immunogenicity .................................................................................39 
10.3.7. 
Other Analyses .........................................................................................................39 
10.3.8. 
Interim Analyses ......................................................................................................39 
11. References .............................................................................................................................40 
12. Appendices ............................................................................................................................41 
 
 
 


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List of Tables 
Table 
Page 
Table PRCL 1 
Schedule of Activities .......................................................................................12 
Table PRCL 2 
Objectives and Endpoints ..................................................................................16 
 
 
 


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List of Figures 
Figure 
Page 
Figure PRCL 1 
Illustration of study design for Clinical Protocol PRCL-PoC ...........................17 
 
 
 


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List of Appendices 
Appendix 
Page 
Appendix 1. 
Abbreviations ....................................................................................................42 
Appendix 2. 
Clinical Laboratory Tests ..................................................................................44 
Appendix 3. 
Study Governance Considerations ....................................................................45 
Appendix 4. 
Monitoring Tests for Treatment-Emergent Hepatic Abnormality ....................49 
Appendix 5. 
Classification of Contraceptive Methods ..........................................................50 
 
 
 


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1. Synopsis 
Title of Study: 
A Phase 2a study to evaluate safety, tolerability, and efficacy of PRCL-02 in patients with 
moderate to severe chronic plaque psoriasis. 
Rationale:  
The aim of this study is to evaluate safety, tolerability, and efficacy of PRCL-02 in patients with 
moderate to severe chronic plaque psoriasis.  
Objective(s)/Endpoints: 
Objectives 
Endpoints 
Primary 
• To evaluate the efficacy of PRCL-02 after 
12 weeks of once daily oral dosing in 
patients with moderate to severe chronic 
plaque psoriasis 
• A 75% improvement from baseline to 
Week 12 in the PASI (PASI 75) 
Secondary 
• To evaluate the safety and tolerability of 
PRCL-02 after 12 weeks of once daily oral 
dosing in patients with moderate to severe 
chronic plaque psoriasis 
• Treatment emergent adverse events 
• To characterize the  pharmacokinetics 
(PK) of PRCL-02 after multiple once daily 
oral dosing for 12 weeks, in patients with 
moderate to severe chronic plaque 
psoriasis 
• AUC0-τ, Cmax, tmax at steady state 
Exploratory 
• To evaluate clinical response to PRCL-02 
over time using the PASI and sPGA 
• PASI 
• sPGA  
• To explore the PK/PD exposure-response 
relationships of PRCL-02 
• The relationship between PRCL-02 
exposure and selected PD efficacy and/or 
safety measures may be explored 
Abbreviations: AUC0-τ = area under the concentration versus time curve from time zero to one dosing interval (24 
hrs);  Cmax = maximum observed drug concentration; PASI = Psoriasis Area and Severity Index; PD = 
pharmacodynamics; PK = pharmacokinetics; sPGA = static physician’s global assessment; tmax = time to reach 
maximum observed drug concentration. 
 
 


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Summary of Study Design:   
This will be a multicenter, randomized, double-blinded, placebo-controlled, multiple oral dose 
parallel design study of PRCL-02 in patients with moderate to severe chronic plaque psoriasis. 
Eligble patients will be randomized to one of 3 arms (2 treatment and 1 placebo) within 28 days 
following screening.  Clinical evaluations are at Day 1, weeks 1, 2, 4, 8, 12, 14, 16, 18 and 20 
after randomization. 
Efficacy and safety assessments will be performed at each of the study visits.  Pre-dose blood 
samples will be collected between Week 1 and Week 8 to assess achievement of steady state PK, 
and pre- and post-dose serial samples will be collected  at Week 12, 14, 16, 18 and 20 to evaluate  
steady state PK profile of PRCL-02.  
Treatment Arms and Duration:   
There will be three parallel treatment arms: 2 dose levels of PRCL-02 and a placebo arm.  
Patients will be randomized in 1:1:1 ratio to PRCL-02 Dose 1:PRCL-02 Dose 2:Placebo.  Study 
drug will be administered orally once daily for 12 weeks.  A loading dose will be implemented 
for all treatment arms.  The highest loading and maintenance doses will not exceed the maximum 
loading and maintenance doses administered in Part C of the previous study (SMAD) (300 mg 
amd 54 QD respectively).   
The planned doses are:  
Dose 1: Loading dose of 150 mg followed by a once daily maintenance dose of 25 mg, 
commencing on Day 2 and continuing for 12 weeks.  
Dose 2: Loading dose of 300 mg followed by a once daily maintenance dose of 50 mg, 
commencing on Day 2 and continuing for 12 weeks. 
Doses may be revised upwards or downwards based on new safety information and exposure 
data becoming available during the course of the study. 
Number of Patients:  
Approximately 27 patients will be targeted for enrollment in each of the 3 arms of the study 
(total of approximately 81 patients). 
Statistical Analysis: 
Efficacy: Efficacy analyses will be conducted on the Intent-to-Treat analysis set.  The primary 
analysis will be conducted using a 1-sided, Fisher’s exact test with a 10% type 1 error rate. 
Safety: Safety analyses will be conducted on the Safety analysis set.  Safety parameters that will 
be assessed include: adverse events, clinical laboratory parameters, vital signs, electrocardiogram 
parameters, and physical examination.  The parameters will be listed and summarized using 
standard descriptive statistics. 
Pharmacokinetics/Pharmacodynamics: Plasma PRCL-02 PK parameters after multiple dose 
administration will be calculated using noncompartmental methods.  Pharmacokinetic parameters 


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will be summarized by dose level using descriptive statistics.  Mean and individual PRCL-02 
plasma concentration-time curves will be represented graphically. 
The PK/PD relationship between PRCL-02 exposure and PD efficacy and/or safety measures 
may be explored. 


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2. Schedule of Activities 
Table PRCL 1 
Schedule of Activities 
Procedure 
Screeninga 
 
 
 
 
 
 
 
 
FU 
EoSb 
Visit # 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Study Days 
-28 to -1 
1 
8 
15 
29 
57 
85 
99 
113 
127 
141 
Window Period (Days) 
 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
Week 
- 
- 
1 
2 
4 
8 
12 
14 
16 
18 
20 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test (♀)c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum FSH (PMP ♀) 
X 
 
 
 
 
 
 
 
 
 
 
QuantiFERON TB Testd 
X 
 
 
 
 
 
 
 
 
 
 
HIV/hepatitis screen 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Study drug dispensinge 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Study drug accountability 
 
 
X 
X 
X 
X 
 X 
 
 
 
X if ET 
Safety Evaluations 
Physical examinationf 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Height/weightg 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Vital signs (pulse and BP)h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGi 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Clinical laboratory testsj 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy and Other Evaluations 
PASI 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
sPGA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK samplingk 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma sample collection for 
PGx assessments 
 
X 
 
 
 
 
 
 
 
 
 


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Abbreviations:  AE = adverse event; BP = blood pressure; ECG = electrocardiogram; EoS = end-of-study; FSH = follicle stimulating hormone; FU = Follow-up; 
HIV = human immunodeficiency virus; PGx = pharmacogenomics; PK = pharmacokinetics; PMP = postmenopausal; S = screening; sPGA = static physician’s 
global assessment; TB = tuberculosis. 
a Randomization will be within 28 days following the screening visit. 
b In the event of early or premature discontinuation, a patient should undergo all activities per the EoS visit. 
c     Serum pregnancy test at Screening and urine pregnancy test at subsequent visits. 
d  If the result of the QuantiFERON®-TB Gold test is positive, the patient will be excluded from the study.  If result is indeterminate, a single re-test will be 
allowed.  If the result of the second test is positive or still indeterminate, the patient will be excluded from the study. Patients who have been vaccinated with 
BCG at any time in the past do NOT need to undergo testing. Documentation of previous vaccination is required. 
e 
On days when there is pre-dose PK sampling (at 1 week, 2 weeks, 4 weeks, 8 weeks and 12 weeks after the first dose), the dosing will be at the site after pre-
dose sampling (patients will be instructed to not dose at home). The patients will be required to bring to the CRU their study treatment kit with all unused 
tablets. On all other days, patients should take their medication at approximately the same time in the morning.  It is recommended (but not required) that the 
dose should be taken with food.  
f 
A full physical examination will be conducted at screening and on Week 4.  Physical examination must include evaluation of the skin and mucus membranes.  
A physical examination may be performed at other visits at the investigator’s discretion. 
g Height at screening visit only. 
h 
Single BP readings and other vital signs (in a seated position) on Day 1 and subsequent visits. 
i 
Singe 12-lead ECG readings (in supine position, for at least 5 minutes prior to the ECG reading).  The screening ECG may be repeated at the investigator’s 
discretion. When scheduled at the same time, the following order of procedures is recommended: ECGs, vital signs, and blood collection (and/or other study 
procedures). 
j 
Clinical laboratory tests will include hematology, serum chemistry, and urinalysis. 
k 
Pre-dose samples are to be obtained at 1 week, 2 weeks, 4 weeks and 8 weeks weeks after the first dose of study drug.  On the last day of dosing (Day 
85/Week 12), the following samples are to be collected: pre-dose and 1, 2, 4, 8 hr post last dose. One sample will also be collected on weeks 2, 4, 6 and 8 
weeks post last dose.   One sample should be taken at the early termination visit, if applicable. Timing of PK sample collection may be adjusted based on 
clinical needs.   Actual sampling dates and times must be accurately recorded. 
 
 
 
 


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3. Introduction 
3.1. Study Rationale 
The aim of this study is to evaluate the safety, tolerability, and efficacy of PRCL-02 in patients 
with moderate to severe chronic plaque psoriasis.  The study will be conducted in compliance 
with the protocol, good clinical practice (GCP), and applicable regulatory requirements.  
3.2. Background 
Psoriasis is one of the most common immune-mediated chronic inflammatory skin diseases, 
affecting about 2- 3% of the world's population.  The most common variant is plaque psoriasis 
(psoriasis vulgaris), which affects most patients with the disease (Nestle et al. 2009; Perera et al. 
2012).  Psoriasis is associated with a high degree of morbidity; patients have a decreased quality 
of life (Rapp et al. 1999; Kimball et al. 2008; Lewis-Beck et al. 2013). 
Activated T lymphocytes and several of the cytokines they produce are key drivers of 
pathogenesis in psoriasis.  This is supported by the efficacy of several non-biologic (e.g. 
cyclosporine, Janus kinase inhibitors) and biologic (IL-12/23, IL-17 and TNFα inhibitors) drugs 
used clinically for treatment of this condition.   Current approved treatment options for psoriasis 
include phototherapy, topical treatments, nonbiologic systemic immune modulators and biologic 
agents that target various functions of T cells and proinflammatory cytokines.  Mild, localized 
psoriasis is typically treated with topical therapy while more extensive, severe disease often 
requires systemic, expensive, and potentially harmful treatments.  There remains a need for 
effective treatment options that have superior long-term safety profiles to the current nonbiologic 
systemic treatments and with a convenient dosing regimen. 
Cytoplasmic calcium (Ca2+) is an important second messenger in mediating fundamental 
biological processes in cells (Tian et al. 2016).  The Ca2+ release-activated Ca2+ (CRAC) channel 
is composed of two key components, STIM (STIM1 and STIM2) (Liou et al. 2005; Zhang et al. 
2015) and ORAI or CRACM (ORAI1, 2 and 3; or CRACM1, 2 and 3) (Mignen 2008), with the 
combination of STIM1/CRACM1 prevailing in most cells and thus best characterized.  Antigen 
stimulation of immune cells triggers Ca2+ entry through CRAC channels, promoting the immune 
response to pathogens by activating the calcineurin-NFAT signaling axis that is targeted by 
traditional calcineurin inhibitors, such as cyclosporine A and tacrolimus. Recent findings 
indicated that therapies specifically targeting CRAC channels may serve as improved 
immunomodulators with high selectivity and low toxicity compared with currently approved 
immunosuppressive agents. 
PRCL-02 is a selective, potent CRACM1 inhibitor which has demonstrated inhibition of T and B 
cell activation, without any demonstrable effect on other immune cells, and with acceptable 
safety and tolerability in rats and cynomolgus monkeys after daily oral dosing up to 3 months.  
Due to the prominent role of T cells in psoriasis, treatment with PRCL-02 in plaque psoriasis is 
expected to provide clinical benefit with convenient dosing and an attractive safety profile. 


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3.3. Benefit/Risk Assessment 
Based on PRCL-02 nonclinical and preliminary clinical data, there are no anticipated risks 
requiring monitoring beyond those included in the protocol.  No clinically significant safety or 
tolerability concerns have been identified in the previous study (PRCL-SMAD) which included 
healthy volunteers given up to 86 mg (single dose) and 54 mg (multiple doses, after a loading 
dose of 300 mg) for 5 days, or in psoriasis patients who received up to 54 mg (multiple doses, 
after a loading dose of 300 mg) for 28 days.  
More information about the known and expected benefits, risks, serious adverse events (SAEs), 
and reasonably anticipated adverse events (AEs) of PRCL-02 can be found in the Investigator’s 
Brochure (IB; PRCL-02 2018).  


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4. Objectives and Endpoints 
Table PRCL 2 shows the objectives and endpoints of the study. 
Table PRCL 2 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• To evaluate the efficacy of PRCL-02 after 
12 weeks of once daily oral dosing in 
patients with moderate to severe chronic 
plaque psoriasis 
• A 75% improvement from baseline to 
Week 12 in the PASI (PASI 75)  
Secondary 
• To evaluate the safety and tolerability of 
PRCL-02 after 12 weeks of once-daily oral 
dosing in patients with moderate to severe 
chronic plaque psoriasis 
• Treatment emergent adverse events 
• To characterize the  pharmacokinetics of 
PRCL-02 after multiple once daily oral 
dosing for 12 weeks, in patients with 
moderate to severe chronic plaque 
psoriasis 
• AUC0-τ, Cmax, tmax at steady state 
Exploratory 
• To evaluate clinical response to PRCL-02 
over time using PASI (Fredriksson and 
Pettersson 1978) and sPGA (Chaudhari et 
al. 2001) 
• PASI 
• sPGA 
• To characterize the PK/PD 
exposure-response relationships of 
PRCL-02 
• The PK/PD relationship of PRCL-02 
exposure and PD efficacy and/or safety 
measures may be explored 
Abbreviations: AUC0-τ = area under the concentration versus time curve from time zero to one dosing interval (24 
hrs); Cmax = maximum observed drug concentration; PASI = Psoriasis Area and Severity Index; PD = 
pharmacodynamics; PK = pharmacokinetic; sPGA = static physician’s global assessment; tmax = time to reach 
maximum observed drug concentration. 


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5. Study Design 
5.1. Overall Design 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel design Phase 2a 
study in patients with moderate to severe chronic plaque psoriasis. 
Screening (up to 28 days prior to first dose of study drug) allows for evaluation of inclusion and 
exclusion criteria.  Following Screening, all eligible patients will be randomly assigned (in 1:1:1 
ratio) to PRCL-02 Dose 1, PRCL-02 Dose 2, or placebo and will receive study drug for 
12 weeks.  Following completion of 12-week treatment, all patients will attend Follow-Up Visits 
at 2, 4, 6 and 8 weeks after the last dose of study drug. 
Efficacy and safety assessments will be performed as defined in the Schedule of Activities 
(Section 2).   
Figure PRCL 1 illustrates the study design.   
Study governance considerations are described in detail in Appendix 3. 
 
 
 
 
Figure PRCL 1 
Illustration of study design for Clinical Protocol PRCL-PoC 
 
5.2. Number of Participants 
Approximately 27 patients will be enrolled in each of the 3 treatment arms; planned total 
enrollment is approximately 81 patients.  
5.3. End of Study Definition 
End of the study is the date for the last patient to complete or discontinue the study. 
End of trial is the date of the last visit or last scheduled procedure for the last patient in the study. 
Study visits - Days
PRCL-Dose 2 arm
PRCL-Dose 1 arm 
Screening
Placebo Arm 
FU
-28 to -1
1
8
15
29
57
85
99
141
12-Weeks Treatment (84 days)
113
127


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5.4. Scientific Rationale for Study Design 
The parallel design is a standard design used to assess efficacy in psoriasis.  The study is patient- 
and investigator-blinded to minimize the potential bias. 
5.5. Justification for Dose 
The planned doses are designed to ensure the evaluation of an exposure range that encompasses 
the anticipated pharmacologically active exposure range, while being safe and tolerable for this 
population.  
The lower dosing regimen: a 150 mg loading dose followed by a maintenance dose of 25 mg QD 
for 12 weeks (starting on Day 2) is intended to achieve an efficacious exposure, based on the 
IC50 for IFNγ in the human whole blood cell assay (40.3 nM or 15.7 ng/mL) (IB Table 4.7).  
The higher dosing regimen: a 300 mg loading dose followed by a maintenance dose of 50 mg 
QD for 12 weeks (starting on Day 2) is anticipated to achieve a maximum efficacious exposure. 
Both doses are within the dosing range that was safe and well tolerated in the SMAD Part C 
study, after once daily dosing of up to 54 mg QD (after a loading dose of 300 mg) for 28 days in 
a psoriasis patient population. 


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6. Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
6.1. Inclusion Criteria 
Patients are eligible to be included in the study only if they meet all of the following criteria.  
The timeframes included in the below criteria are relative to screening unless otherwise noted. 
1. Male and female between 18 to 75 years of age inclusive. 
2. Present with moderate to severe psoriasis vulgaris based on the disease diagnostic criteria 
defined as: 
• Chronic psoriasis vulgaris for at least 6 months prior to randomization.  
• Plaque psoriasis involving at least 10% body surface area (BSA) at both screening 
and baseline (randomization). 
• Psoriasis Area and Severity Index (PASI) total score of at least 12 at both screening 
and baseline (randomization). 
• Static Physician’s Global Assessment (sPGA) score of ≥3 at screening and at 
randomization (randomization). 
3. Are candidates for systemic therapy. 
4. Have a body mass index (BMI) within the range of 18 to 40 kg/m2, inclusive. 
5. Are able and willing to make themselves available for the duration of the study and are 
willing to follow study restrictions/procedures. 
6. Women who are of childbearing potential, who must agree to use 1 highly effective method 
of contraception, or a combination of 2 effective methods of contraception for the entirety of 
the study (Appendix 5). 
Women of non-childbearing potential are defined as women who are: 
• Infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or tubal 
ligation), congenital anomaly such as mullerian agenesis; or 
• Post-menopausal, defined as either: 
o A woman at least 50 years of age with an intact uterus, not on hormone therapy, who 
had had either: 
 Cessation of menses for at least 1 year; or 
 At least 6 months of spontaneous amenorrhea with a follicle-stimulating hormone 
>40 mIU/mL; or 
o A woman 55 years or older not on hormone therapy, who has had at least 6 months of 
spontaneous amenorrhea; or 
• A woman at least 55 years of age with a diagnosis of menopause prior to staring hormone 
replacement therapy. 


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6.2. Exclusion Criteria 
Patients will be excluded from study enrollment if they meet any of the following criteria.  The 
timeframes included in the below criteria are relative to screening unless otherwise noted. 
7. Are Eli Lilly and Company, PRCL Research Inc., or Contract Research Organization 
employees, investigator or site personnel directly affiliated with this study and the immediate 
families of either of these.  Immediate family is defined as a spouse, parent, child or sibling, 
whether biological or legally adopted.  
8. Are currently enrolled in any other clinical trial involving a study drug or off label use of a 
drug or device, or any other type of medical research judged not to be scientifically or 
medically compatible with this study.  Patients who participated in the previous PRCL study 
(SMAD) will be allowed to be included in this study, provide that they meet all inclusion and 
none of the exclusion criteria. 
9. Participated in a clinical study within 30 days (defined as the last dose of study drug), prior to 
first dosing in this study. 
10. Present with pustular, erythrodermic psoriasis, generalized pustular psoriasis or acute guttate 
psoriasis. 
11. Have current serious or unstable illnesses including hepatic, renal, gastroenterologic, 
respiratory, cardiovascular (including a history of ischemic or structural heart disease, 
conduction system disease or history of clinically significant arrhythmia), endocrinologic, 
neurologic, psychiatric, immunologic, hematologic, or dermatologic disease and other 
conditions that, in the investigator’s opinion, could interfere with the analyses of safety and 
efficacy in this study. 
12. Have a history of clinically significant severe drug allergies or severe post-treatment 
hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear 
immunoglobulin A (IgA) dermatosis, toxic epidermal necrolysis, or exfoliative dermatitis). 
13. Have received inactivated vaccine within 4 weeks prior to dosing in this study, or a live 
vaccine within 3 months prior to dosing in this study. 
14. Present with a history of clinically significant opportunistic infection (e.g., invasive 
candidiasis or Pneumocystis pneumonia).  
15. Had symptomatic herpes zoster within 3 months of randomization, other recent or ongoing 
infection that, in the opinion of the investigator, poses an unacceptable risk to participate in 
the study. 
16. Present with any of the following laboratory test results; 
• Positive QuantiFERON®-tuberculosis test at screening AND have not been vaccinated for 
tuberculosis.  If result is indeterminate, a single retest will be allowed.  If the result of the 
second test is still indeterminate, the subject will be excluded. Patients who have been 
vaccinated with BCG at any time in the past do NOT need to undergo testing. 
Documentation of previous vaccination is required. 
• For women, positive serum pregnancy test. 
• Evidence of HIV infection or are positive for HIV antibodies based on history or point-
of-care testing (POCT) at screening 


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• Postive test for active hepatitis B as defined as: 
o Positive for hepatitis B surface antigen (HBsAg), or 
o Positive for anti-hepatitis B core antibody (HbcAb) and positive for hepatitis B 
deoxyribonucleic acid (HBV DNA). 
• Positive of anti-hepatitis C antibody with confirmed presence of hepatitis C virus by 
RNA testing, or chronic liver disease with the most recent available aspartate 
transaminase (AST) or alanine transaminase (ALT) > 2X the upper limit of normal 
(ULN). 
• Evidence of clinically significant hepatic or renal impairment, including ALT above 
2 × ULN, AST above 1.5 × ULN, total bilirubin (TBL) above 2 × ULN (TBL accepted 
up to 2 × ULN if direct bilirubin is within normal limits), or estimated glomerular 
filtration rate (eGFR) <60 mL/min/1.73m2 (based on CKD-EPI calculation method). 
17. Clinically significant ECG abnormalities at screening, or clinically significant personal or 
family history (in a first-degree relative) of heart diseases, including: 
o Confirmed corrected QT (QTcF) interval > 450 msec for both men and women. 
o Bundle branch blocks and other conduction abnormalities other than: 
 mild first degree atrioventricular block (≤ 205 msec) or 
 QRS duration shorter than 110 msec without bundle branch block 
morphology. 
o Irregular rhythms other than sinus arrhythmia or occasional, rare supraventricular 
ectopic beats. 
o History of unexplained syncope. 
o Family history of unexplained sudden death or sudden death due to long QT 
syndrome. 
18. Are receiving any of the following therapies for psoriasis: 
• Systemic retinoids within 12 weeks prior to dosing in this study; 
• Systemic psoriasis therapy (such as psoralen and ultraviolet A [PUVA] light therapy, 
cyclosporine, corticosteroids, methotrexate, oral retinoids, mycophenolate mofetil, 
thioguanine, hydroxyurea, sirolimus, azathioprine) or phototherapy (including ultraviolet 
B or self-treatment with tanning beds or therapeutic sunbathing) within 4 weeks prior to 
dosing in this study; 
• Topical psoriasis treatment (other than moisturizing emollients) within 2 weeks prior to 
dosing in this study; or 
• Any biologic agent within the following washout periods: 30 days for anti-TNF inhibitors 
and 90 days for others prior to dosing in this study. 
6.3. Lifestyle Restrictions 
Patients will be instructed to avoid alcohol consumption within 24 hours prior to clinical site 
visit until the last PK blood sample is collected at the respective visits. Patients will also be 


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instructed to restrict sun exposure throughout the study period. Patients are not to apply any 
topical hydrating agent/emollient within 24 hours of a clinic visit. 
Male patients should avoid donating sperm while participating in this trial and for 4 months after 
stopping the study treatment.  
6.4. Screen Failures 
Patients who do not meet the criteria for participation in the study (screen failures) may be 
rescreened (up to 1 time) and the rescreen should be at the discretion of the investigator after 
consultation with sponsor designated medical monitor.  If the rescreening is performed a week or 
longer after the screening visit, the patient must sign a new informed consent form and will be 
assigned a new identification number. Retesting may occur at the discretion of the investigator, 
and after consultation with the sponsor designated medical monitor, within a week of the 
screening visit – in such cases a new identification number will not be assigned. 


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7. Treatments 
7.1. Treatments Administered 
This study involves 3 parallel treatment arms: PRCL-02 Dose 1, PRCL-02 Dose 2, and placebo.  
All patients will receive study drug, to be administered orally once daily, for 12 weeks.   
The planned doses are: 
PRCL-02 Dose 1: Loading dose of 150 mg followed by a once daily maintenance dose of 25 mg, 
commencing on Day 2 and continuing for 12 weeks.  
PRCL-02 Dose 2: Loading dose of 300 mg followed by a once daily maintenance dose of 50 mg, 
commencing Day 2 and continuing for 12 weeks. 
Doses may be revised upwards or downwards based on new safety information and exposure 
data becoming available during the course of the study. 
The drug product is composed of PRCL-02 and inactive ingredients.  Matching placebo will 
consist of only the inactive ingredients.  PRCL-02 or placebo will be provided as tablets of 25 
mg or 50 mg conditioned in blister packs. 
The investigator or his/her designee is responsible for the following: 
• explaining the correct use of study drug to the patient  
• verifying that instructions are followed properly 
• maintaining accurate records of study drug dispensing and collection 
• at the end of the study returning all unused medication to PRCL Research Inc., or its 
designee, unless the sponsor and sites have agreed all unused medication is to be 
destroyed by the site, as allowed by local law 
7.1.1. Packaging and Labelling 
PRCL-02 and placebo will be provided as tablets in blister packs.  The sponsor or its designee 
will provide sufficient quantities of PRCL-02 drug products to allow completion of this study.  
PRCL-02 drug products are manufactured, tested, packaged, and labeled in according with all 
applicable good manufacturing practice requirements, guidelines, and regulations, and will be 
labeled according to the country’s regulatory requirements.  A certificate of release confirming 
that study drugs are to be used “for human use in clinical study” will be supplied.  PRLC-02 drug 
products are for investigational use only and are to be used only within the context of this study. 
7.2. Method of Treatment Assignment 
Patients who meet all criteria for enrollment will be randomized in 1:1:1 to 1 of 3 treatment 
arms: PRCL-02 Dose 1, PRCL-02 Dose 2, or placebo.  Assignment to treatment groups will be 
determined by a computer-generated random sequence using an interactive web-response system 
(IWRS).  The IWRS will be used to assign blister packs containing double-blind drug product to 
each patient. The IWRS system will be programmed to balance the treatment arms according to 


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weight (<95kg and ≥95kg), and prior number of failed therapies (<3 and ≥3). The purpose of the 
algorithm is to maintain approximately the same proportion of patients for these variables in each 
treatment arm. 
During the patient’s dispensing visits, the site will access the IWRS for the correct blister pack 
number to dispense. The drug product will be dispensed in a kit, which will provide amounts of 
treatment consistent with the dispensing plan (Section 7.1) and the allowed window period 
(Table PRCL 1).  The patients will be provided with sufficient treatment to last until the next 
dispensing visit. (Table PRCL 1). 
7.2.1. Selection and Timing of Doses 
Patients should take their medication at approximately the same time in the morning everyday.  It 
is recommended (but not required) that the dose should be taken with food.   
On days when there is pre-dose PK sampling (at 1 week, 2 weeks, 4 weeks, 8 weeks and 
12 weeks after the first dose), the dose must be administered at the site after the pre-dose sample 
has been obtained.  On all other days, patients must take their study drug at approximately the 
same time in the morning.  It is recommended (but not required) that the dose should be taken 
with food.  The study drug (tablet) should be swallowed whole, and should be taken with a glass 
of water. 
7.3. Blinding 
This is a double-blind study; both patients and investigators will be blinded. 
To preserve the blinding of the study, no study personnel will see the randomization table and 
treatment assignments before database lock. 
Emergency unblinding for AEs may be performed through the IWRS, or other means if 
necessary.  Emergency unblinding may be used  ONLY if the patient’s well-being requires 
knowledge of the patient’s treatment assignment. 
If an investigator, site personnel performing assessments, or patient is unblinded, the patient 
must be discontinued from the study, unless there are ethical reasons for the patient to remain in 
the study.  In cases where there are ethical reasons to have the patient remain in the study, the 
investigator must obtain specific approval from the sponsor designated medical monitor for the 
patient to continue in the study. 
In case of an emergency the investigator should contact the sponsor designated medical monitor 
prior to unblinding a patient’s treatment assignment. However, the investigator has the sole 
responsibility for determining if unblinding of a patient’s treatment assignment is warranted for 
medical management of the event.  The patient safety must always be the first consideration in 
making such a determination.  If a patient’s treatment assignment is unblinded, the sponsor must 
be notified immediately.  If the investigator decides that unblinding is warranted, it is the 
responsibility of the investigator to promptly document the decision and rationale and notify the 
sponsor as soon as possible.  


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7.4. Dosage Modification 
Not applicable. 
7.5. Preparation/Handling/Storage/Accountability 
All PRCL-02 drug products will be stored in a secure and locked area with strictly limited access 
and monitored for temperature, and allocated and dispensed by appropriately trained personnel.  
Study drugs will be stored between 2°C to 8°C. 
The investigator or his/her designee is responsible for the following: 
• confirming appropriate temperature conditions have been maintained during transit 
for all study treatment received and any discrepancies are reported and resolved 
before use of the study treatment. 
• ensuring that only participants enrolled in the study may receive study treatment and 
only authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff. 
• the investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (such as receipt, reconciliation and final disposition records). 
7.6. Treatment Compliance 
Patient compliance with study drug will be assessed at each visit.  Compliance will be assessed 
by counting returned tablets.  The patient will be considered significantly noncompliant if he or 
she takes <80% or >120% of dispensed tablets.  Deviations from the prescribed dosage regimen 
should be recorded in the electronic data capture (EDC). 
7.7. Concomitant Therapy 
Refer to the concomitant medications listed in the exclusion criteria (Section 6.2).  Treatment 
with concomitant psoriasis therapies during the study is permitted as outlined below. 
Patients will maintain their usual medication regimen for other concomitant diseases throughout 
the study unless specifically excluded in Section 6.2.  Patients should be on stable doses of 
concomitant medications at baseline, and should remain at a stable dose throughout the study, 
unless changes need to be made for an AE.  Additional systemic drugs are to be avoided during 
the study, unless required to treat an AE.   
Use of non-live seasonal vaccinations and/or emergency vaccination (such as rabies or tetanus 
vaccinations) is allowed. 
The following will be allowed as needed:  
• use of topical antibiotics in the event of secondary infections of lesions;  
• nonprescription shampoos;  
• acetaminophen or aspirin; and 


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• topical moisturizers/ emollients on non-target lesions, bath oils, oatmeal bath preparations, 
and salicylic acid preparations. These topical agents should not be used within approximately 
24 hours prior to visits requiring a PASI assessment. 
 
Use of topical steroids of any potency is prohibited throughout duration of study.  
Other medications may be allowed if approved by the sponsor or its designee.  Patients will be 
instructed to consult the investigator or other appropriate study personnel at the site before taking 
any new medications or supplements. 
7.8. Treatment after the End of the Study 
Not applicable. 


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8. Discontinuation Criteria  
Patients discontinuing from the treatment prematurely for any reason should complete adverse 
event and other follow-up procedures per Section 2 of this protocol. 
Patients discontinuing from the study prematurely for any reason must complete adverse event 
and follow-up procedures per Section 2 of this protocol. 
8.1. Discontinuation from Study Treatment 
Discontinuation due to a hepatic event or liver test abnormality.  Patients who are 
discontinued from using study drug due to a hepatic event or liver test abnormality should have 
additional hepatic safety data collected via EDC.  Discontinuation of the study for abnormal liver 
tests should be considered by the investigator when a patient meets one of the following 
conditions after consultation with the sponsor designated medical monitor: 
• ALT or AST >5X ULN 
• ALT or AST >3X ULN along with one or more of the following criteria: 
o sustained for more than 2 weeks or 
o TBL >2X ULN or 
o prothrombin time >1.5X ULN or 
o the appearance of fatigue, nausea, vomiting, right upper-quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (>5%) 
• alkaline phosphatase (ALP) >3X ULN 
• ALP >2.5X ULN and TBL >2X ULN 
• ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%) 
In addition, patients will be discontinued from the study drug in the following circumstances: 
• White blood cell count ≥1.5X ULN or an increase in white blood cells above ULN and >2X 
ULN from last predose measure 
• Neutrophil or total lymphocyte count of ≥1.5X ULN or an increase in neutrophils or total 
lymphocytes above ULN and >2X ULN from last predose measure 
• Patient received concomitant medication listed in Exclusion Criteria 
• Patient’s failure to comply with protocol requirements or study-related procedures 
• Termination of the study by the sponsor or regulatory authorities 
8.1.1. Discontinuation of Inadvertently Enrolled Patients from Study 
Treatment 
If the Sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the sponsor designate medical monitor 
and the investigator to determine if the patient may continue on investigational product.  If both 
agree it is medically appropriate to continue, the investigator must obtain documented approval 
from the sponsor to allow the inadvertently enrolled patient to continue on investigational 
product. 


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8.2. Discontinuation from the Study 
Patients may be withdrawn from the study if any of the following criteria are observed: 
• Enrollment in any other clinical study involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study. 
• Participation in the study needs to be stopped for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and good clinical practice (GCP) 
• Investigator’s decision: the investigator may decide that the patient should be discontinued 
from the study if, in the investigator’s opinion, continuation in the study would be 
detrimental to the patient’s well-being, in particular in case of an AE 
• Subject decision: the patient requests to be discontinued from the study. 
• Subject becomes pregnant while on study  
Patients who are discontinued from the study may be replaced at the discretion of the Sponsor. 
8.3. Patients Lost to Follow-up 
Every effort must be made to contact patients who do not return for a planned visit and the 
reason for withdrawal should be documented in the EDC. The patient can only be declared as 
‘lost to follow-up’ if the investigator has had no success in contacting the patient.  


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9. Study Assessments and Procedures 
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing). 
Appendix 2 lists the laboratory tests that will be performed for this study. 
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards. 
9.1. Efficacy Assessments 
9.1.1. Primary Efficacy Assessment - Psoriasis Area and Severity 
Index (PASI) 
Primary efficacy assessments will be based on the PASI. 
The PASI is a proven and widely used tool to evaluate the severity of psoriasis  (Hägg et al. 
2017).  The PASI scores the severity of disease on a scale from 0 to 72 (where a score of 72 
indicates extreme disease severity) by combining assessments of extent of body-surface 
involvement in the head, trunk, arms, and legs together with the severity of desquamation, 
erythema, and plaque induration.  
9.1.2. Exploratory Efficacy Assessments – Static Physicians Global 
Assessment (sPGA) 
The static Physicians Global Assessment (sPGA) is a widely used scale in psoriasis clinical trials 
that defines the severity of disease from clear to severe.  
9.2. Adverse Events 
A clinical trial AE is any untoward medical event associated with the use of a drug or drug 
delivery system in humans, whether or not it is considered related to that drug or drug delivery 
system. 
The sponsor has standards for reporting AEs that are to be followed regardless of applicable 
regulatory requirements that may be less stringent. 
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting sponsor or its designee to any event that seems unusual, even if this event may 
be considered an unanticipated benefit to the patient. 
The investigator is responsible for the appropriate medical care of patients during the study. 
Investigators must document their review of each laboratory safety report. 


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The investigator remains responsible for following, through an appropriate healthcare option, 
AEs that are serious or otherwise medically important, considered related to the study drug or the 
study, or that caused them to discontinue the study drug before completing the study.  The 
patient should be followed until the event resolves, stabilizes with appropriate diagnostic 
evaluation, or is reasonably explained.  The frequency of follow-up evaluations of the AE is left 
to the discretion of the investigator. 
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect. 
After the informed consent form (ICF) is signed, study site personnel will record via EDC the 
occurrence and nature of each patient’s preexisting conditions, including clinically significant 
signs and symptoms of the disease under treatment in the study.  In addition, site personnel will 
record any change in the condition(s) and any new conditions as AEs.  Investigators should 
record their assessment of the potential relatedness of each AE to protocol procedure or study 
treatment via EDC. 
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, or a study procedure, taking into account the disease, 
concomitant treatment, or pathologies. 
A “reasonable possibility” means that there is a cause and effect relationship between the study 
drug, study device, and/or study procedure and the AE. 
The investigator answers yes/no when making this assessment. 
Ratings of AEs will be based on the following 3-point severity scale: 
Mild 
Awareness of sign or symptom, but it is easily tolerated; does not interfere with 
daily activities. 
Moderate 
Discomfort enough to slightly disrupt daily activities.  Medical intervention and/or 
close follow-up may be considered. 
Severe 
Incapacitating with complete disruption of daily activities.  Medical intervention 
and/or close follow-up likely. 
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study. 
If a patient’s study drug is discontinued as a result of an AE, study site personnel must report this 
to sponsor or its designee via EDC, clarifying if possible, the circumstances leading to any 
dosage modifications, or discontinuations of treatment. 
9.2.1. Serious Adverse Events 
Study site personnel must alert the sponsor or its designee of any SAE within 24 hours of 
investigator awareness of the event via a sponsor-approved method. Serious adverse event 
reporting to the sponsor begins after the patient has signed Informed Consent. 


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If alerts are issued via telephone, they are to be immediately followed with official notification 
on study-specific SAE forms. This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information. Patients with a serious hepatic AE should have 
additional data collected using the EDC (Section 9.4.5.1). 
An SAE is any AE from this study that results in 1 of the following outcomes: 
• death 
• initial or prolonged inpatient hospitalization 
• a life-threatening experience (that is, immediate risk of dying) 
• persistent or significant disability/incapacity 
• congenital anomaly/birth defect 
• Important medical events that may not be immediately life threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one of 
the other outcomes listed in the definition above.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
Previously planned (prior to the signing of ICF) surgeries should not be reported as SAEs unless 
the underlying medical condition has worsened during the course of the study. 
The following terms will be utilized to assess the relationship of the SAE to administration of 
study treatment: 
• Probably related:  a direct cause and effect relationship between the study treatment and the 
AE is likely. 
• Possibly related:  a cause and effect relationship between the study treatment and the AE has 
not been demonstrated at this time and is not probably, but is also not impossible. 
• Unlikely:  likely to be due to another etiology. 
• Not related:  without questions, the AE is definitely not associated with study drug. 
Although all AEs are recorded in the case report form or EDC after signing informed consent, 
SAE reporting to the Sponsor begins after the subject has signed informed consent and has 
received the study drug.  However, if an SAE occurs after signing informed consent, but prior to 
receiving the study drug, AND is considered Reasonably Possibly Related to a study procedure 
then it MUST be reported. 
Investigators are not obligated to actively seek AEs or SAEs in patients once they have 
discontinued and/or completed the study. Serious adverse events occurring after a patient has 
taken the last dose of study drug will be collected for 30 days after the last dose of the study 
drug. However, if the investigator learns of any SAE, including a death, at any time after a 
patient has been discharged from the study, and he/she considers the event reasonably possibly 
related to the study treatment or study participation, the investigator must promptly notify the 
sponsor and/or its designee. 


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Pregnancy (during maternal or paternal exposure to study treatment) does not meet the definition 
of an AE. However, to fulfill regulatory requirements any pregnancy should be reported 
following the SAE process to collect data on the outcome for both mother and fetus. 
The designated medical monitor of the sponsor will monitor safety data throughout the course of 
the study. The sponsor and/or its designee will review SAEs within appropriate timeframes to 
meet reporting obligations imposed by regulatory authorities. All serious and unexpected AEs 
for this study will be reported to regulatory authorities in accordance with local laws, directives, 
and regulations. 
9.2.1.1. Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB (PRCL-02 2018) and that the investigator identifies as related to study drug.  The 
sponsor has procedures that will be followed for identifying, recording, and expedited reporting 
of SUSARs that are consistent with global regulations and the associated detailed guidance. 
9.2.2. Complaint Handling 
The sponsor collects product complaints on investigational products and drug delivery systems 
used in clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements. 
Patient will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the study drug so that the situation can be assessed. 
9.3. Treatment of Overdose 
Refer to the IB (PRCL-02 2018). 
9.4. Safety 
9.4.1. Electrocardiograms 
For each patient, single 12-lead electrocardiograms (ECGs) should be collected according to the 
Schedule of Activities (Section 2).  Patients should be in a supine position for at least 5 minutes 
prior to recording of an ECG.  The screening ECG may be repeated at the discretion of the 
investigator.  Electrocardiograms should be taken prior to other scheduled study procedures 
taken at similar times, followed by vital signs and then any other study procedures. 
Any clinically significant findings from ECGs and that occur after the patient receives the first 
dose of the study drug should be reported as an AE via EDC. 
9.4.2. Vital Signs 
For each patient, vital signs (sitting pulse and blood pressure) measurements should be 
conducted according to the Schedule of Activities (Section 2).  Vital signs should be recorded in 
sitting position just after the ECG (if the ECG is recorded at the same timepoint) and before any 
other procedures according to the Schedule of Activities (Section 2). 


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Any clinically significant findings from vital signs measurement that that occur after the patient 
receives the first dose of study drug should be reported as an AE via EDC. 
9.4.3. Laboratory Tests 
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).  
With the exception of laboratory test results that may unblind the study, the sponsor or its 
designee will provide the investigator with the results of laboratory tests analyzed by a central 
vendor.  
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of study drug should be reported to the sponsor or its 
designee as an AE via EDC. 
9.4.4. Physical Examination 
A complete physical examination will be conducted at screening and at Week 4.  Physical 
examination at other scheduled visits must include evaluation of the skin and mucus membranes.  
Performance  of other components of a physical examination at these visits will be at the 
investigator’s discretion.  Additinally, a physical examination may be performed at other 
unscheduled visits at the investigator’s discretion, including those visits being made for 
evaluation of an AE. 
9.4.5. Safety Monitoring 
A study level safety review will be conducted quarterly. 
9.4.5.1. Hepatic Safety Monitoring 
If a study patient experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated TBL ≥2X 
ULN, liver testing (Appendix 4) should be repeated within 3 to 5 days including ALT, AST, 
ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator and in 
consultation with the sponsor designated medical monitor.  Monitoring of ALT, AST, TBL, and 
ALP should continue until levels normalize or return to approximate baseline levels.  
Hepatic Safety Data Collection 
Additional safety data should be collected via the EDC if 1 or more of the following conditions 
occur:  
• elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests 
• elevated serum TBL to ≥ 2X ULN (except for cases of known Gilbert’s syndrome)  
• elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests 
• patient discontinued from treatment due to a hepatic event or abnormality of liver tests 
• hepatic event considered to be a SAE 


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9.5. Pharmacokinetics 
9.6. Sample collection and assay 
 
At the visits and times specified in the Schedule of Activities (Section 2), blood samples of 
approximately 3 mL each will be collected to determine the plasma concentrations of PRCL-02. 
Sample times are provided as a guidance and should be adhered to as closely as possible.  Actual 
sampling dates and times must be recorded.  
A maximum of 2 samples may be drawn at additional time points during the study if warranted 
and agreed upon between both the investigator and sponsor.  Instructions for the collection and 
handling of blood samples will be provided by the sponsor.   
9.7. Bioassay 
Plasma samples will be analyzed for PRCL-02 concentrations using a validated HPLC/MS/MS 
method in a bioanalytical laboratory selected by the Sponsor. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. Placebo samples are not planned to 
be assayed.  
Bioanalytical samples collected to measure study drug concentration will be retained for a 
maximum of 1 year following last patient visit for the study. 
9.8. Pharmacodynamics 
9.8.1. Pharmacodynamic Assessments 
Disease activity measures will include the PASI score and sPGA over the period (Refer to 
Section 9.1.1 for details on PASI and Section 9.1.2. for details on sPGA). 
9.8.2. Exploratory Assessments 
Collection of additional samples is also planned for other biomarker research, as indicated in the 
Schedule of Activities. The samples will only be stored for potential future exploratory analyses 
related to psoriasis, the drug and/or its mechanism of action. 
Samples will be identified by the patient number and stored for up to 15 years after the last 
patient visit for the study at a facility selected by the Sponsor. The duration allows the Sponsor to 
respond to regulatory requests related to the study drug. The sample and any data generated can 
only be linked back to the patient by investigator site personnel. 
Samples will be destroyed according to a process consistent with local regulation. 
 


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9.9. Pharmacogenomics 
9.9.1. Whole Blood Sample for Pharmacogenetic Research 
A whole blood sample (10 mL) will be collected for pharmacogenetic analysis at baseline 
predose, where local regulations allow.   
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples may be used to investigate variable response to study drug and to 
investigate genetic variants thought to play a role in psoriasis.  Assessment of variable response 
may include evaluation of AEs or differences in efficacy.  
Samples will be identified by the patient number.  These samples and any data generated can be 
linked back to the patient only by the investigator site personnel.   
Samples will be retained at a facility selected by the sponsor or its designee for a maximum of 
15 years after the last patient visit for the study, or for a shorter period if local regulations and/or 
ethical review boards (ERBs)/investigational review boards (IRBs) impose shorter time limits.  
This retention period enables use of new technologies, response to regulatory questions, and 
investigation of variable response that may not be observed until later in the development of the 
study drug. 
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  Regardless of technology utilized genotyping data generated will 
be used only for the specific research scope described in this section.  
9.10. Biomarkers 
Not applicable. 
9.11. Health Economics or Medical Resource Utilization and Health 
Economics 
Not applicable. 


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10. Statistical Considerations 
10.1. Sample Size Determination 
Approximately 27 patients will be randomized to each of the 3 treatment arms. The sample size 
was chosen so that there is at least 80% power to detect an increase in response of 30% or more 
in any PRCL 02 treatment arm relative to placebo using a 1 sided Fisher’s Exact test with a 10% 
type 1 error rate. This assumes a placebo response of 7.5% and PRCL-02 response of 37.5% in 
either PRCL-02 treatment arm for the primary end point, based on available clinical data from 
marketed injectable and oral targeted therapies for psoriasis. The sample size was calculated 
assuming a 10% drop out of patients in each arm and that drop-outs would be analyzed as non-
responders. 
10.2. Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Randomized 
All patients who signed informed consent and are randomized. 
Safety 
All randomized patients who take at least 1 dose of double-blind study 
treatment.  In the event of treatment error, patients will be analyzed according 
to the treatment they actually received. 
Intent-to-Treat (ITT) 
All randomized patients with moderate to severe chronic plaque psoriasis who 
take at least 1 dose of double-blind study treatment and at least the Week 1 
post-baseline PASI assessment.  In the event of a treatment error, patients will 
be analyzed according to the treatment to which were randomized. 
Pharmacokinetic 
All randomized patients who take at least 1 dose of double-blind study 
treatment and provide sufficient data for pharmacokinetic assessments. 
10.3. Statistical Analyses 
10.3.1. General Statistical Considerations 
Statistical analysis of this study will be the responsibility of PRCL Research Inc. or its designee.  
Details of the summarization and analysis of the clinical trial data will be described in the 
Statistical Analysis Plan (SAP), which will be finalized prior to the database lock. 
Efficacy analyses will be conducted on the Intent-to-Treat (ITT) population. 
Data will be presented using summary tables by treatment arms, unless otherwise specified. 
Continuous data will be summarized using the mean, standard deviation, median (for selected 
variables), minimum, and maximum.  Categorical data will be summarized by frequency counts 
and percentages.  Figures may be used to support the presentation of data. 
All tests of treatment effects will be conducted using a 1-sided tests with a 10% type 1 error rate.  
The sample size was calculated assuming a 10% drop-out of patients in each arm, and assuming 
that early withdrawal is not influenced by the treatment effect.  Secondary and any supportive 
analyses may be performed to explore the effect of early withdrawal on the primary endpoint. 


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Baseline values will be defined as the last available value prior to receiving double-blind study 
drug in the Treatment Period. 
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the clinical study report (CSR).   
Additional exploratory analyses of the data will be conducted as deemed appropriate. 
10.3.2. Treatment Group Comparability 
10.3.2.1. Patient Disposition 
All patients who discontinue from the study will be identified, and the extent of their 
participation in the study will be summarized by treatment arm. If known, a reason for their 
discontinuation will be given.  
10.3.2.2. Patient Characteristics 
Patient demographics (age, gender, race, ethnicity, height, weight, and BMI) and other baseline 
characteristics will be summarized by treatment arm using the Safety population. 
10.3.2.3. Concomitant Therapy 
Concomitant therapy will be summarized by treatment arm using the Safety population. 
10.3.2.4. Treatment Compliance 
The proportion of patients who are significantly noncompliant, as noted in Section 7.6 will be 
summarized by treatment arm using the Safety population. 
10.3.3. Efficacy Analyses 
10.3.3.1. Primary Analyses 
Efficacy endpoints will be assessed using the ITT population. 
The primary treatment effect will be measured as the difference between each active treatment 
arm and placebo in the percentage of patients with a ≥75% improvement from baseline in PASI 
(PASI 75) at 12 weeks. 
A one-sided Fisher’s exact test with a 10% type 1 error rate will be used to compare each 
PRCL-02 treatment arm to placebo. 
10.3.3.2. Secondary Analyses 
Safety/tolerability and PK analyses are described in Sections 10.3.4 and 10.3.5.  
10.3.3.3. Tertiary/Exploratory Analyses 
The percentage of patients with a ≥90% improvement from baseline in PASI (PASI 90) at 
12 weeks will be analyzed similarly to PASI 75.  PASI 75, PASI 90, and sPGA will be 
summarized at each scheduled visit.  Observed values of the PASI score and subscores, sPGA, 
and the change and percent change from baseline to each scheduled visit will be summarized 


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using descriptive statistics and the treatment groups compared using analysis of variance 
methods. 
10.3.4. Safety Analyses 
The safety analysis will be conducted using the safety population.  
The safety and tolerability of treatment will be assessed by evaluating the following: 
• Treatment-emergent AEs (TEAEs) by Preferred Term and maximum severity 
• SAEs 
• AEs leading to discontinuation 
• Vital signs 
• ECGs 
• Laboratory measurements 
• Physical examination 
Treatment-emergent adverse events are defined as the reported AEs that first occurred or 
worsened during the double-blind treatment phase and follow-up compared with baseline.  The 
most recent version of Medical Dictionary for Regulatory Activities Preferred Term will be used. 
Treatment-emergent adverse events will be summarized by the number and percentage of 
patients with the event. 
Other safety parameters that will be assessed include physical examinations, safety clinical 
laboratory parameters, vital signs, and ECG parameters.  The parameters will be listed and 
summarized using standard descriptive statistics.  Additional analysis will be performed if 
warranted upon review of the data. 
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses 
10.3.5.1. Pharmacokinetics 
Pharmacokinetic analysis will be performed on the PK analysis set; patients dosed with 
PRCL-02 active that have evaluable concentrations will be included. Individual plasma PRCL-02 
PK parameters will be calculated using non-compartmental analysis (NCA). Actual sampling 
times will be used for parameter derivations. 
PRCL-02 steady state PK parameters such as the maximum concentration (Cmax,ss), time of 
maximum concentration (tmax,ss),  are under the concentration versus time curve within a dosing 
interval (AUC0-τ,ss), the first-order terminal elimination rate constant (λz), the terminal elimination 
half-life (t1/2), apparent clearance (CL/F)  and apparent volume of distribution (Vd/F) will be 
reported.  
Other parameters may be calculated as deemed appropriate.  
Pharmacokinetic parameters will be summarized by dose level using descriptive statistics.  Mean 
and individual PRCL-02 plasma concentration-time curves will be represented graphically.  
10.3.5.2. Pharmacodynamics 
Pharmacodynamic analysis will be performed on the PD analysis set.  


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PASI and sPGA scores will be individually listed.  
These parameters will be summarized, on observed values and on changes from baseline 
(pre-dose) values by treatment arms. 
10.3.5.3. PK/PD 
The PK/PD relationship of PRCL-02 with PD, efficacy, and/or safety measures may be explored. 
10.3.6. Evaluation of Immunogenicity 
Not applicable. 
10.3.7. Other Analyses 
Not applicable 
10.3.8. Interim Analyses 
No interim analyses are planned for this study.  
 


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11. References 
[PRCL-02] PRCL Research Inc. June 2018. Investigator’s Brochure for PRCL-02. 
Bonifati C, Berardesca E. Clinical outcome measures of psoriasis. Reumatismo. 2007;59(S1):64-7. 
Fowler JF Jr, Hebert AA, Sugarman J.Fowler JF Jr, Hebert AA, Sugarman J. DFD-01, a Novel 
Medium Potency Betamethasone Dipropionate 0.05% Emollient Spray, Demonstrates Similar 
Efficacy to Augmented Betamethasone Dipropionate 0.05% Lotion for the Treatment of 
Moderate Plaque Psoriasis. J Drugs Dermatol. 2016;15(2):154-62 
Hägg D, Sundström A, Eriksson M, Schmitt-Egenolf M. Severity of Psoriasis Differs Between 
Men and Women: A Study of the Clinical Outcome Measure Psoriasis Area and Severity 
Index (PASI) in 5438 Swedish Register Patients. Am J Clin Dermatol. 2017 Aug;18(4):583-
590. 
Kimball AB, Gladman D, Gelfand JM, Gordon K, Horn EJ, Korman NJ, Korver G,Krueger GG, 
Strober BE, Lebwohl MG; National Psoriasis Foundation. National Psoriasis Foundation 
clinical consensus on psoriasis comorbidities and recommendations for screening. J Am Acad 
Dermatol. 2008;58(6):1031-42. 
Lewis-Beck C, Abouzaid S, Xie L, Baser O, Kim E. Analysis of the relationship between 
psoriasis symptom severity and quality of life, work productivity, and activity impairment 
among patients with moderate-to-severe psoriasis using structural equation modeling. Patient 
Prefer Adherence. 2013;7:199-205. 
Liou J, Kim ML, Heo WD, Jones JT, Myers JW, Ferrel JE, Meyer T. STIM is a Ca2+ sensor 
essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr Biol. 2005;15(13):1234-41. 
Mignen O, Thompson JL, Shuttleworth TJ. Both Orai1 and Orai3 are essential components of 
the arachidonate-regulated Ca2+-selective (ARC) channels. J Physiol. 2008;586:185-95. 
Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009;361(5):496-509. 
Perera GK, Di Meglio P, Nestle FO. Psoriasis. Annu Rev Pathol. 2012;7:385–422.  
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. 
Tian C, Du L, Zhou Y, Li M. Store-operated CRAC channel inhibitors: opportunities and 
challenges. Future Med Chem. 2016;8(7):817-32.  
Zhang H, WU L, Pchitskaya E, Zakharova O, Saito T, Saido T, Bezprozvanny I. Neuronal store-
operated calcium entry and mushroom spine loss in amyloid precursor protein knock-in mouse 
model of alzheimer's disease. J Neurosci. 2015;35(39):13275-86. 


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12. Appendices 


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Appendix 1. 
Abbreviations 
Term 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC0-τ 
area under the concentration versus time curve throughout a dosing interval 
BSA 
body surface area 
Ca2+ 
cytoplasmic calcium 
Cmax 
maximum observed drug concentration 
CRAC 
cytoplasmic calcium release-activated cytoplasmic calcium 
ECG 
Electrocardiogram 
EDC 
electronic data capture 
EoS 
End-of-Study 
FU 
Follow-up 
GCP 
good clinical practice 
IB 
Investigator’s Brochure 
Ig 
immunoglobulin 
ICF 
informed consent form 
ITT 
Intent-to-Treat 
IWRS 
interactive web-response system 
PASI 
Psoriasis Area and Severity Index 
PASI 75 
A 75% improvement from baseline to Week 12 in the Psoriasis Area and 
Severity Index 
PK/PD 
pharmacokinetics/pharmacodynamics 
QD 
once daily 


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QTc 
corrected QT interval 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sPGA 
statis physician global assessment 
SUSARs 
suspected unexpected serious adverse reactions 
TBL 
total bilirubin 
tmax 
time to reach maximum observed drug concentratoin 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 


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Appendix 2. 
Clinical Laboratory Tests 
Clinical Laboratory Tests 
Hematology 
Clinical Chemistry 
Hemoglobin 
Serum Concentrations of: 
Hematocrit 
Sodium 
Erythrocyte count (RBC) 
Potassium 
Mean cell volume (MCV) 
Chloride 
Mean cell hemoglobin concentration (MCHC) 
Bicarbonate 
Leukocytes (WBC) 
Total bilirubin 
Neutrophils, segmented and banded 
Direct bilirubin 
Lymphocytes 
Alkaline phosphatase 
Monocytes 
Alanine aminotransferase (ALT/SGPT) 
Eosinophils 
Aspartate aminotransferase (AST/SGOT) 
Basophils 
Blood urea nitrogen (BUN) 
Platelets 
Creatinine 
 
Uric acid 
 
Calcium 
Urinalysis 
Magnesium 
Color 
Glucose, random 
Specific gravity 
Albumin, total protein 
pH 
Lactate dehydrogenase (LDH) 
Protein 
Creatine kinase (CK) 
Glucose 
Phosphorus 
Ketones 
eGFR 
Blood 
 
Urine microalbumin 
Pregnancy Test (females only)
 
Follicle-stimulating Hormone (FSH) 
 
 
 
Serology Tests 
Coagulations Studies 
Human immunodeficienty virus (HIV) 
Prothrombin time/International normalized ratio 
(PT/INR) 
Hepatitis B surface antigen (HBsAg) 
Activated partial thromboplastin time (APTT) 
Anti-hepatitis B core antibody (HBcAb) 
 
Hepatitis B deoxyribonucleic acid (HBV DNA) 
 
Hepatitis C antibody (HCV Ab) 
Hepatitis C virus ribonucleic acid (HCV RNA) 
 


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Appendix 3. 
Study Governance Considerations 
 
 
 
 


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Appendix 3.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
Appendix 3.1.1. 
Informed Consent 
The investigator is responsible for: 
• ensuring that the patient understands the nature of the study, the potential risks and benefits 
of participating in the study, and that their participation is voluntary. 
• ensuring that informed consent is given by each patient.  This includes obtaining the 
appropriate signatures and dates on the informed consent form (ICF) prior to the performance 
of any protocol procedures and prior to the administration of investigational product. 
• answering any questions the patient may have throughout the study and sharing in a timely 
manner any new information that may be relevant to the patient’s willingness to continue his 
or her participation in the study. 
• ensuring that a copy of the ICF is provided to the participant or the participant’s legal 
representative and is kept on file. 
• ensuring that the medical record includes a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the ICF.  
Appendix 3.1.2. 
Recruitment 
PRCL Research Inc. or its designee is responsible for the central recruitment strategy for 
patients.  Individual investigators may have additional local requirements or processes. 
Investigators will be responsible for patient recruitment through local requirements or processes.   
Appendix 3.1.3. 
Ethical Review 
The investigator must give assurance that the ethical review board (ERB) was properly 
constituted and convened as required by International Council for Harmonisation (ICH) 
guidelines and other applicable laws and regulations. 
Documentation of ERB approval of the protocol and the ICF  must be provided to PRCL 
Research Inc. before the study may begin at the investigative sites.  PRCL Research Inc. or its 
representatives must approve the ICF, including any changes made by the ERBs, before it is used 
at the investigative sites.  All ICFs must be compliant with the ICH guideline on Good Clinical 
Practice (GCP). 
The study site’s ERB(s) should be provided with the following: 
• the protocol and related amendments and addenda, current Investigator Brochure (IB) and 
updates during the course of the study 
• informed consent form 
• other relevant documents (for example, curricula vitae, advertisements) 
 
 


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Appendix 3.1.4. 
Regulatory Considerations 
This study will be conducted in accordance with the protocol and with the: 
• consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• applicable ICH GCP Guidelines 
• applicable laws and regulations 
Some of the obligations of the sponsor will be assigned to a third party. 
Appendix 3.1.5. 
Investigator Information 
Licensed physicians with a specialty in Dermatology will participate as investigators in this 
clinical trial. 
Appendix 3.1.6. 
Protocol Signatures 
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study. 
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a PRLC Research Inc. representative. 
Appendix 3.1.7. 
Final Report Signature 
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study. 
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study. 
Appendix 3.2. 
Data Quality Assurance 
To ensure accurate, complete, and reliable data, PRCL Research Inc. or its representatives will 
do the following: 
• provide instructional material to the study sites, as appropriate 
• sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the CRFs, and study 
procedures. 
• make periodic visits to the study site 
• be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax 


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• review and evaluate CRF data and use standard computer edits to detect errors in data 
collection 
• conduct a quality review of the database 
In addition, PRCL Research Inc. or its representatives will periodically check a sample of the 
patient data recorded against source documents at the study site.  The study may be audited by 
PRCL Research Inc. or its representatives, and/or regulatory agencies at any time.  Investigators 
will be given notice before an audit occurs. 
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents. 
Appendix 3.2.1. 
Data Capture System 
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system. 
Data managed by a central vendor, such as laboratory test data or ECG data, will be stored 
electronically in the central vendor’s database system.  Data will subsequently be transferred 
from the central vendor to the PRCL Research Inc. data warehouse.  
Appendix 3.3. 
Study and Site Closure 
Appendix 3.3.1. 
Discontinuation of Study Sites 
Study site participation may be discontinued if PRCL Research Inc., the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP. 
Appendix 3.3.2. 
Discontinuation of the Study 
The study will be discontinued if  PRCL Research Inc. judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP. 
 


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Appendix 4. 
Monitoring Tests for Treatment-Emergent 
Hepatic Abnormality 
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the PRCL Research Inc., or its 
designated medical monitor. 
Hepatic Monitoring Tests 
Hematology 
Haptoglobin 
Hemoglobin 
 
Hematocrit 
Coagulation 
RBC 
Prothrombin Time 
WBC 
Prothrombin Time, INR 
Neutrophils, segmented 
 
Lymphocytes 
Hepatic Serologies 
Monocytes 
Hepatitis A antibody, total 
Eosinophils 
Hepatitis A antibody, IgM 
Basophils 
Hepatitis B surface antigen 
Platelets 
Hepatitis B surface antibody 
 
Hepatitis B Core antibody 
Chemistry 
Hepatitis C antibody 
Total bilirubin 
Hepatitis E antibody, IgG 
Direct bilirubin 
Hepatitis E antibody, IgM 
Alkaline phosphatase 
 
ALT 
Anti-nuclear antibody 
AST 
 
GGT 
Alkaline Phosphatase Isoenzymes 
CPK 
 
 
 
Anti-smooth muscle antibody (or anti-actin 
antibody) 
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalised ratio; 
RBC = red blood cells; WBC = white blood cells. 
 
 
 


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Appendix 5. 
Classification of Contraceptive Methods 
Highly Effective Methods of Contraception: 
• Combined oral contraceptive pill and mini-pill 
• NuvaRing 
• Implantable contraceptives 
• Injectable contraceptives (such as Depo-Provera®) 
• Intrauterine device (such as Mirena® and ParaGard®) 
• Contraceptive patch – ONLY women <198 pounds or 90 kg 
• Total Abstinence 
• Vasectomy – for men in clinical trials 
Effective Methods of Contraception (must use combination of 2 methods): 
• Male condom with spermicide 
• Female condom with spermicide 
• Diaphragm with spermicide 
• Cervical sponge 
• Cervical cap with spermicide 
Ineffective Forms of Contraception – not acceptable as a method for clinical trials 
• Spermicide alone (please note spermicide alone is not considered a barrier method) 
• Immunocontraceptives 
• Periodic abstinence 
• Fertility awareness (calendar method, temperature method, combination of above 2, 
cervical mucus, symptothermal) 
• Withdrawal 
• Post coital douche 
• Lactational amenorrhea 

SAP_001.pdf: 
 
 PRCL-PoC Statistical Analysis Plan 
 A Phase 2A Study To Evaluate Safety, Tolerability, and Efficacy of PRCL-02 In Patients With 
Moderate To Severe Chronic Plaque Psoriasis (Version 1 Final) 
NCT03614078  
Approved: December 3, 2018 


 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 draft 1 
Page 1 of 18 
20NOV2018 
Please use 11pt Calibri (black) text. 
 
 
Statistical Analysis Plan 
PRCL-POC 
A Phase 2a Study to Evaluate Safety, Tolerability, and Efficacy 
of PRCL-02 in Patients with Moderate to Severe Chronic Plaque 
Psoriasis 
 
Version 1 Final 
Effective Date: 20 NOV 2018 
 
Prepared for 
PRCL Research Inc. 
1255 Robert Bourassa, Suite 1610, 
Montreal, Quebec, H3B 3X3, Canada 
 
 
 
 
 
 
 
 
 
Prepared by 
EMB Statistical Solutions, LLC 
55 Corporate Woods 
9300 West 110th Street, Suite 550 
Overland Park, Kansas 66210 


PRCL Research, Inc.  
Compound: PRCL-02 
 
Protocol: PRCL-POC 
 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 draft 1 
Page 2 of 18 
20NOV2018 
Table of Contents 
Description 
Page 
ABBREVIATIONS/DEFINITIONS .............................................................................. 4 
1. 
Introduction and Objectives ................................................................................ 5 
1.1. 
Introduction .......................................................................................................... 5 
1.2. 
Study Objectives and Endpoints ......................................................................... 5 
1.3. 
Sample Size Determination .................................................................................. 6 
2. 
General Statistical Methodology and Conventions ........................................... 6 
2.1. 
General Considerations........................................................................................ 6 
2.2. 
Randomization and Unblinding Plan ................................................................. 7 
2.3. 
Analysis Populations ............................................................................................ 7 
2.4. 
Treatment Groups ................................................................................................ 8 
2.5. 
Definition of Baseline Assessments ..................................................................... 8 
2.6. 
Definition of Study Visit ....................................................................................... 8 
2.7. 
Handling of Dropouts and Missing Data ............................................................ 8 
2.8. 
Adjustment for Multiplicity ................................................................................ 9 
2.9. 
Adjustment for Multiple Centers ........................................................................ 9 
2.10. Adjustment for Covariates .................................................................................. 9 
2.11. Subgroup Analyses ............................................................................................... 9 
2.12. Coding of Concomitant Medications and Adverse Events ............................... 9 
2.13. Computation of Questionnaire Scores ................................................................ 9 
3. 
Interim Analyses ................................................................................................. 10 
4. 
Patient Characteristics ....................................................................................... 10 
4.1. 
Patient Disposition .............................................................................................. 10 
4.2. 
Protocol Violations ............................................................................................. 10 
4.3. 
Demographics and Baseline Assessments......................................................... 11 
4.4. 
Concomitant Medications .................................................................................. 11 


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5. 
Efficacy Analyses ................................................................................................ 11 
5.1. 
Primary Analysis ................................................................................................ 11 
5.2. 
Secondary Analyses ............................................................................................ 12 
5.3. 
Exploratory Analyses ......................................................................................... 12 
6. 
Safety Analyses ................................................................................................... 12 
6.1. 
Study Medication Exposure and Treatment Compliance .............................. 13 
6.2. 
Adverse Events .................................................................................................... 13 
6.3. 
Clinical Laboratory Analyses ............................................................................ 14 
6.3.1. Clinical laboratory assessments over time ....................................................... 15 
6.3.2. Clinical laboratory shift tables .......................................................................... 15 
6.4. 
Vital Signs and Weight ....................................................................................... 15 
6.5. 
Electrocardiograms ............................................................................................ 15 
6.6. 
Other Safety Analyses ........................................................................................ 16 
7. 
Pharmacokinetic/Pharmacodynamic Analyses ............................................... 16 
8. 
Reporting Conventions ...................................................................................... 16 
9. 
Schedule of Assessments .................................................................................... 18 
 


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ABBREVIATIONS/DEFINITIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EoS 
End-of-Study 
FU 
Follow-up 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web-Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
PASI 
Psoriasis Area and Severity Index 
PASI 75 
A 75% improvement from baseline in the Psoriasis Area and Severity Index 
PASI 90 
A 90% improvement from baseline in the Psoriasis Area and Severity Index 
PK 
Pharmacokinetics 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDTM 
Standard Data Tabulation Model 
SOC 
System Organ Class 
sPGA 
static Physician Global Assessment 
TEAE 
Treatment Emergent Adverse Event 
WHODD 
World Health Organization Drug Dictionary 
 
 
 


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1. 
INTRODUCTION AND OBJECTIVES 
1.1. 
Introduction 
Study PRCL-POC is a multicenter, randomized, double-blinded, placebo controlled, multiple oral dose 
parallel design study of PRCL-02 in patients with moderate to severe chronic plaque psoriasis. Clinical 
evaluations are at pre-treatment, and at Day 1, Weeks 1, 2, 4, 8, 12, 14, 16, 18, and 20 after 
randomization. 
The purpose of this statistical analysis plan (SAP) is to describe the analysis variables and statistical 
procedures that will be used to analyze and report the results from PRCL-POC: “A Phase 2a Study to 
Evaluate Safety, Tolerability, and Efficacy of PRCL-02 in Patients with Moderate to Severe Chronic 
Plaque Psoriasis.”  
This SAP is based on the protocol PRCL-POC, which was approved on 16 July 2018.  
Some of the analyses detailed here may be more explicit or in some aspects different from those stated in 
the protocol. In case of differences, this SAP supersedes the statistical sections in the protocol. 
Changes to the protocol that impact the design, the data collected, or the statistical methods and that occur 
after the finalization of this SAP may require amendment of the approved SAP. Similarly, changes to the 
planned analysis variables and/or statistical methods described in the approved SAP may also require 
amendment of the SAP.  
The formats for the tables, listings, and figures described in this SAP are provided in a companion 
document. Changes to the formats of these reports that are decided after the finalization of the SAP will 
not require an amendment. In addition, any additional supportive or exploratory analyses requested after 
SAP approval will not require amendment of the SAP. These additional analyses will be described in the 
clinical study report (CSR).  
See the study protocol for details about the study design, procedures, and schedule of assessments and see 
the electronic case report form (eCRF) for details about variables collected and their possible values. 
The time and events schedule for this study is provided in Section 10. 
EMB Statistical Solutions, LLC will have responsibility for performing these analyses. 
1.2. 
Study Objectives and Endpoints 
The aim of this study is to evaluate safety, tolerability, and efficacy of PRCL-02 in patients with moderate 
to severe chronic plaque psoriasis. There will be three parallel treatment arms: 2 dose levels of PRCL-02 
and a placebo arm. Patients will be randomized in 1:1:1 ratio to PRCL-02 Dose 1:PRCL-02 
Dose 2:Placebo.  
Table 1 shows the objectives and endpoints of the study.   


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Table 1. Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the efficacy of PRCL-02 after 12 weeks 
of once daily oral dosing in patients with moderate 
to severe chronic plaque psoriasis 
A 75% improvement from baseline to Week 12 
in the PASI (PASI 75) 
Secondary 
To evaluate the safety and tolerability of PRCL-02 
after 12 weeks of once daily oral dosing in patients 
with moderate to severe chronic plaque psoriasis 
Treatment emergent adverse events 
To characterize the pharmacokinetics (PK) of 
PRCL-02 after multiple once daily oral dosing for 
12 weeks, in patients with moderate to severe 
chronic plaque psoriasis 
AUC0-τ, Cmax, tmax at steady state 
Exploratory 
To evaluate clinical response to PRCL-02 over time 
using the PASI and sPGA 
• PASI 
• sPGA 
To explore the PK/PD exposure-response 
relationships of PRCL-02 
The relationship between PRCL-02 exposure 
and selected PD efficacy and/or safety measures 
1.3. 
Sample Size Determination 
Approximately 27 patients will be randomized to each of the 3 treatment arms for a total of 81 patients. 
The sample size was chosen so that there is at least 80% power to detect an increase in response of 30% 
or more for the primary objective (percentage of patients reaching a PASI 75 at week 12) in any PRCL-02 
treatment arm relative to placebo using a one-sided Fisher’s Exact test with a 10% type 1 error rate. This 
assumes a placebo response of 7.5% and PRCL-02 response of 37.5% in either PRCL-02 treatment arm 
for the primary end point, based on available clinical data from marketed injectable and oral targeted 
therapies for psoriasis. The sample size was calculated assuming a 10% drop out of patients in each arm 
and that drop-outs would be analyzed as non-responders. 
2. 
GENERAL STATISTICAL METHODOLOGY AND CONVENTIONS 
2.1. 
General Considerations 
All computations for statistical analyses will be performed using SAS® software, Version 9.4 or later. All 
SAS programs used in the production of statistical summary outputs will be validated with independent 
programming prior to finalization. In addition, all program outputs will be independently reviewed. The 
validation process will be used to confirm that all data manipulations and calculations were accurately 
done. Once validation is complete, a senior statistical reviewer will perform a final review of the 
documents to ensure the accuracy and consistency with this plan and consistency within tables. Upon 


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completion of validation and quality review procedures, all documentation will be collected and filed by 
the project statistician or designee. 
Before implementation of parametric methods of analysis, the distribution of analysis variables will be 
examined to determine if model assumptions are satisfied. Transformations or nonparametric methods of 
analysis may be used if warranted. However, in some cases, nonparametric analysis may be the initially 
proposed method due to the expected distribution of response. Whenever alternative methods of analysis 
are required, the description of the new method along with the rationale for its use will be documented in 
the CSR. 
The eCRF data for all patients will be provided in Standard Data Tabulation Model (SDTM) datasets. 
Data listings supplied as part of the CSR will be sorted by investigative site and patient identification 
number, and patients will be identified in the listings by the investigator number concatenated with the 
patient number. 
2.2. 
Randomization and Unblinding Plan 
This is a double-blind study; both patients and investigators will be blinded. Eligible patients will be 1:1:1 
randomized to one of 3 arms (2 treatment and 1 placebo) within 28 days following screening. Assignment 
to treatment groups will be determined by a computer-generated random sequence using an interactive 
web-response system (IWRS). The IWRS will be used to assign blister packs containing double-blind 
drug product to each patient. The IWRS system will be programmed using an adaptive allocation scheme 
to balance the treatment arms according to the following baseline measurements: 
• 
weight (< 95kg and ≥ 95kg), and  
• 
prior number of failed therapies (< 3 and ≥ 3). 
To preserve the blinding of the study, no study personnel will see the randomization table and treatment 
assignments before database lock. 
Emergency unblinding for AEs may be performed through the IWRS, or other means if necessary. 
Emergency unblinding may be used ONLY if the patient’s well-being requires knowledge of the patient’s 
treatment assignment. 
Unblinding will occur after the last patient completes the study and all data management activities have 
been completed (i.e. data entered, coding completed, and all queries resolved). 
2.3. 
Analysis Populations 
The analysis populations are described in Table 2. 
Table 2. Analysis Populations 
Population 
Description 
Randomized 
All patients who sign informed consent and were randomized. 
Safety 
All randomized patients who take at least 1 dose of double-blind study treatment. In 
the event of a treatment error, patients will be analyzed according to the treatment 
they actually received. 


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Population 
Description 
Intent-to-Treat 
(ITT) 
All randomized patients with moderate to severe chronic plaque psoriasis who take 
at least 1 dose of double blind study treatment and have at least the Week 1 post-
baseline PASI assessment. In the event of a treatment error, patients will be 
analyzed according to the treatment to which they were randomized. 
Pharmacokinetic All randomized patients who take at least 1 dose of double blind study treatment 
and provide sufficient data for pharmacokinetic assessments. 
2.4. 
Treatment Groups 
This study involves 3 parallel treatment arms: PRCL-02 Dose 1, PRCL-02 Dose 2, and placebo. All 
patients will receive study drug, to be administered orally once daily, for 12 weeks. The planned active 
doses are:  
Dose 1: Loading dose of 150 mg followed by a once daily maintenance dose of 25 mg, commencing on 
Day 2 and continuing for 12 weeks.  
Dose 2: Loading dose of 300 mg followed by a once daily maintenance dose of 50 mg, commencing on 
Day 2 and continuing for 12 weeks. 
Doses may be revised upwards or downwards based on new safety information and exposure data 
becoming available during the course of the study. 
2.5. 
Definition of Baseline Assessments 
Day 1 is defined in the protocol as the first day of Visit 2. The last assessment made on or before this date 
will be defined as the Baseline assessment. Adverse events that occurred on Day 1 will be assumed to be 
treatment-emergent, unless there is evidence to the contrary. 
2.6. 
Definition of Study Visit 
Patient data will be analyzed according to the nominal visit collected in the eCRF. Unscheduled visits at 
which safety data is collected (e.g. labs and ECGs) may result in clinically significant findings or 
withdrawal, which will be included in adverse event and/or disposition summaries. 
2.7. 
Handling of Dropouts and Missing Data 
Dates 
Imputation of missing or partial dates is not expected, but if a complete date is required for calculations, 
the following algorithms will be applied:  
• 
For the start date:  
- If year, month, and day are missing then use the minimum of the patient's first visit date or the 
consent date.  
- If either only month or month and day are missing then use January 1.  
- If only day is missing, impute the first day of the month.  


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• 
For the end date:  
- If year, month, and day are missing then use the patient's last visit date.  
- If either only month or month and day are missing then use December 31.  
- If only day is missing then use the last day of the month.  
- Do not expand the record past the patient's last visit.  
The original missing or partial date, the imputed complete date, and the indicator variable that indicates 
which dates were imputed will be retained in the database. 
PASI and sPGA Response 
Patients whose response to treatment cannot be determined due to missing data (including early 
withdrawal) will be considered non-responders in the analyses. 
2.8. 
Adjustment for Multiplicity 
There are no planned adjustments for multiple efficacy endpoints or analyses. 
2.9. 
Adjustment for Multiple Centers 
Differences between study centers will be not be incorporated into the statistical analyses for this study. 
There are no plans to analyze data within centers. 
2.10. Adjustment for Covariates 
Efficacy analyses will adjust for the baseline value of the endpoint where possible. Exploratory analyses 
may be performed that adjust for the strata used in the randomization. 
2.11. Subgroup Analyses 
There are no planned subgroup analyses. 
2.12. Coding of Concomitant Medications and Adverse Events 
Adverse events (AEs) and conditions/procedures from the patients’ medical histories will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA), and concomitant medications will be coded 
using the World Health Organization Drug Dictionary (WHODD). The versions of the dictionaries used 
for reporting will be provided in the CSR. 
2.13. Computation of Questionnaire Scores 
Psoriasis Area and Severity Index (PASI) 
The PASI scores the severity of disease on a scale from 0 to 72 (where a score of 72 indicates extreme 
disease severity) by combining assessments of the extent of body surface involvement (A) in the head, 
trunk, arms, and legs together with the severity of desquamation (D), erythema (E), and plaque 
induration (I). Values for the extent of body surface involvement and severity are classified according to 
Table 3. 


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Table 3. PASI Scoring 
Degree of Severity 
Value 
None 
Slight 
Moderate 
Marked 
Very Marked 
0 
1 
2 
3 
4 
Surface area involved 
Value 
None 
< 10% 
10-29% 
30-49% 
50-69% 
70-89% 
90-100% 
0 
1 
2 
3 
4 
5 
6 
The PASI subscore for each region is calculated as (D+E+I)*A. The Total PASI score is then calculated 
as 0.1*(Head Score) + 0.3*(Trunk Score) + 0.2*(Arms Score) + 0.4*(Legs Score). 
The PASI subscores will not be computed if any element of the equation is missing. The total score will 
not be computed if any subscore is missing. 
Static Physicians Global Assessment (sPGA) 
The sPGA defines the severity of disease (an average of the investigator’s perception of induration, 
erythema, and scaling) from clear (score=0) to severe (score=5). Patients were to enter the trial with at 
least a score of 3 at screening and at randomization; therefore, patients with a post-baseline score less than 
3 will be considered responders. 
3. 
INTERIM ANALYSES 
No interim analyses are planned for this study. 
4. 
PATIENT CHARACTERISTICS 
4.1. 
Patient Disposition 
The disposition of all randomized patients will be presented. The number of patients in each Analysis 
Population will be presented overall and by treatment group. In addition, the reason for treatment 
discontinuation and study discontinuation will be tabulated for the overall population and by treatment 
group using the list of reasons provided in the eCRF.  
4.2. 
Protocol Violations 
A list of protocol violations that could potentially impact the analysis of the study will be determined 
during the conduct of the study by study team members who are blinded to study treatment being 
received. The number and percentage of patients with each violation will be tabulated overall and by 
randomized treatment assignment.  


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4.3. 
Demographics and Baseline Assessments 
Patient’s baseline age, sex, race, height, body weight, body mass index, number of previously failed 
therapies, and baseline efficacy measures will be summarized using descriptive statistics by treatment arm 
and overall. These summaries will be based on the Safety population. Patients who are missing 
measurements of the baseline variable being analyzed will not be included in the summary for that 
variable. 
For the purposes of the Clinical Trial Registry, a summary will be made by age categorized as 49 or 
younger, 50-64, 65-84, and 85 or older. 
Patient height and weight will be collected prior to randomization. Both variables will be reported in 
metric units (height in cm and weight in kg) and will be summarized as continuous variables along with 
Body Mass Index (BMI; in kg/m2). 
No statistical testing will be performed for comparisons of baseline characteristics. 
4.4. 
Concomitant Medications 
Concomitant medications will be defined as medications taken on or after the date of first dose of 
randomly assigned study treatment. This includes all medications initially taken prior to the date of first 
dose of randomly assigned study medication but with a stop date that is either missing or after the date of 
first dose of randomly assigned study medication. Those medications where the stop date is documented 
as prior to the date of first dose of randomly assigned study medication will be classified as prior 
medications. The prior medications will not be included in any summary reports. 
The number (percent) of patients who receive each concomitant medication, based on the WHODD 
preferred drug name, will be tabulated. By-patient listings of all concomitant medications, including 
WHODD preferred drug name, will be prepared. 
5. 
EFFICACY ANALYSES 
5.1. 
Primary Analysis 
Efficacy endpoints will be assessed using the ITT population. 
The primary treatment effect will be measured as the difference between each active treatment arm and 
placebo in the percentage of patients with a ≥ 75% improvement from baseline in PASI (PASI 75) at 12 
weeks. 
A one-sided Fisher’s exact test with a 10% type 1 error rate will be used to compare each PRCL-02 
treatment arm to placebo. Point estimates for the treatment differences (PRCL minus placebo) will be 
calculated using a lower 90% exact unconditional confidence interval. 
Supporting Analysis of the Primary Endpoint 
The primary treatment difference may be analyzed using only those patients with a Week 12 PASI 
assessment; that is, no imputation made for early withdrawal. 
The primary treatment differences may be analyzed using a Cochran-Mantel-Haenszel test, adjusting for 
the four strata used in the randomization [weight (< 95kg and ≥ 95kg), and prior number of failed 
therapies (< 3 and ≥ 3)] if there are a sufficient number of patients in each cell. 


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5.2. 
Secondary Analyses 
Safety/tolerability and PK analyses are described in Section 6 and Section 7, respectively. 
5.3. 
Exploratory Analyses 
The percentage of patients with a ≥ 90% improvement from baseline in PASI (PASI 90) at 12 weeks will 
be analyzed similarly to PASI 75. PASI 75 and PASI 90 will be summarized at each scheduled visit.  
Observed values of the PASI score and subscores, the sPGA score, and the change and percent change 
from baseline to each scheduled visit will be summarized using descriptive statistics and the treatment 
groups compared using analysis of variance methods.  
The quantitative secondary efficacy endpoints will be assessed by analyzing the change from baseline to 
the 12-week time point using PROC MIXED to model the difference in the Week 12 change from 
baseline score between treatment groups and to handle missing assessments. The change from baseline to 
each scheduled post-baseline visit will be estimated using repeated measures mixed models assuming data 
are missing at random, with covariates for baseline and visit. The lower 95% confidence limit of the 
difference in mean scores at Week 12 (PRCL minus Placebo) will be estimated from the mixed model. 
The effects of baseline scores and treatment will be allowed to vary across visits. The following example 
SAS code will be used, for assessments at Weeks 1, 2, 4, 8, and 12. For patients who withdraw prior to 
Week 12, data from the early termination visit will be used as the next visit’s assessment; for example, if 
a patient’s last scheduled assessment is at Week 4, the early termination data will be included in the 
analysis as Week 8. 
proc mixed; 
  class visit treatment patient; 
  model endpoint=week*baseline week*treatment; 
  repeated week / type=vc subject=patient; 
  random patient; 
run; 
In addition, plots of each least squares mean (± standard error) for the scores by scheduled visit will be 
created  
If the data appear non-Normal or if a reasonable variance-covariance structure cannot be fit to the data, 
the treatment comparisons will be made using Wilcoxon Rank-Sum tests at each visit using the observed 
data. 
6. 
SAFETY ANALYSES 
All analyses of safety including the extent of exposure to study medication will be performed using the 
Safety population. 
No statistical testing will be performed for comparisons of safety endpoints. 


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6.1. 
Study Medication Exposure and Treatment Compliance 
Extent of Exposure 
Time on study will be derived for each patient as: 
• 
Time on study = Date of last visit – Date of randomization + 1. 
The extent of exposure to study drug will be derived for each patient as: 
• 
Extent of exposure = Date of last dose of study drug – Date of 1st dose of study drug + 1. 
Time on study and extent of exposure will be descriptively summarized for each treatment sequence and 
treatment arm. 
Treatment Compliance 
Patient compliance with study drug will be assessed at each visit. Compliance will be assessed by 
counting returned tablets. The patient will be considered significantly noncompliant if he or she takes 
< 80% or > 120% of the dispensed tablets. Deviations from the prescribed dosage regimen should be 
recorded. 
Treatment compliance will be calculated for each treatment phase using the formula: 
• 
Treatment Compliance =100 ((number of capsules received)/(number of capsules intended)). 
The total number of tablets intended is equal to the number of days the patient spent in the treatment 
phase.  
Treatment compliance will be descriptively summarized for each treatment arm. 
6.2. 
Adverse Events 
Summaries of AEs will include the number of patients with at least one AE for each treatment group. 
When reporting by system organ class (SOC) and preferred term (PT), the reports will present the SOC in 
alphabetical order; while PTs within the SOC will be presented in order of overall decreasing frequency 
of occurrence overall. A patient with multiple AEs (different PTs) coded to the same SOC will be counted 
only once for that SOC, but will be counted each time for different PTs within that SOC. A patient with 
separate events of the same PT (different start/stop dates) will be counted only once in the frequency 
tables for that PT. 
Summaries of AEs will include the number of patients with at least one AE for each treatment group. 
When reporting by system organ class (SOC) and preferred term (PT), the reports will present the SOC in 
alphabetical order; while PTs within the SOC will be presented in order of overall decreasing frequency 
of occurrence overall. A patient with multiple AEs (different PTs) coded to the same SOC will be counted 
only once for that SOC, but will be counted each time for different PTs within that SOC. A patient with 
separate events of the same PT (different start/stop dates) will be counted only once in the frequency 
tables for that PT. 


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Treatment-Emergent Adverse Events 
Treatment-emergent adverse events (TEAE) include all adverse events that emerge or worsen after taking 
the first dose of study drug. TEAEs will be summarized for each treatment group by SOC and PT, and by 
PT in order of decreasing frequency of preferred term. 
Serious Adverse Events 
Treatment-Emergent SAEs will be summarized for each treatment arm by SOC and PT. These reports 
will also include the total number of SAE for each SOC and PT.  
Treatment-Emergent Adverse Events Resulting in Death 
If there are any TEAEs that result in death, a listing of all deaths will be provided. In addition, a summary 
table may also be created by PT in order of decreasing frequency of preferred term. 
Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation 
TEAEs for which the action taken with medication is ‘Drug Withdrawal’ will be identified as TEAEs that 
lead to study drug discontinuation. The TEAEs that lead to study drug discontinuation will be 
summarized for each treatment group by SOC and PT for the Safety population. A by-patient listing of 
the TEAEs that lead to study drug discontinuation will also be provided. 
Treatment-Related Treatment-Emergent Adverse Events 
Every AE will be assessed by the investigator for its relationship to the randomly assigned study 
medication. The subset of TEAEs considered by the investigator as either possibly, probably, or definitely 
related to study treatment will be summarized as drug-related TEAEs by SOC and PT. 
Treatment-Emergent Adverse Events by Maximal Severity 
Every AE will be graded by the investigator as mild, moderate, or severe, so for each patient the greatest 
severity observed can be obtained by comparing the severity of all of a patient’s TEAEs that share the 
same SOC or PT. A table of TEAEs by maximal severity will be prepared for each treatment arm by SOC 
and PT.  
Treatment-Emergent (Not Including Serious) Adverse Events 
The most common non-serious TEAEs will be summarized. All PT that occur in at least 5% of the Safety 
Population patients in any treatment group, when not counting the serious TEAEs, will be tabulated by 
SOC and PT for each treatment group. These reports will also present the total number of TEAEs for each 
SOC and PT. 
6.3. 
Clinical Laboratory Analyses 
Blood samples for hematology and clinical chemistry and urine samples for urinalysis will be collected. 
Profiles for the hematology, clinical chemistry and the numeric urinalysis parameters will be summarized, 
and extreme values for select parameters during the on-treatment period during the study will be 
summarized.  


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6.3.1. Clinical laboratory assessments over time 
Change from baseline for each of the hematology, clinical chemistry and the numeric urinalysis 
parameters will be derived for each of the post-dose time points using the pre-dose measurement as the 
baseline. Descriptive statistics for the measurement at baseline and the measurement and change from 
baseline at each post-dose time point will be tabulated.  
6.3.2. Clinical laboratory shift tables 
Each laboratory parameter will be classified as low, normal or high relative to the central laboratory’s 
normal range. For each treatment group shift tables will be generated from the pre-dose category to the 
category post-dose for each laboratory parameter. The shift tables will present the number (percent) of 
patients who started in a category (low, normal, high) at baseline and ended in a category at the end of the 
study. A missing category will be included for both pre-dose and post-dose, so that all patients in the 
Safety population will be represented in the table. The percentages will be calculated using number of 
patients in the Safety population who have measurements at pre-dose and post-dose.  
Shift tables comparing pre-dose to the other time points in the study may be generated if warranted after 
data review. 
Similar shift tables for the categorical urinalysis parameter will also be produced using all categories 
reported for a parameter during the study.  
6.4. 
Vital Signs and Weight 
Extreme vital signs will be determined using the following criteria:  
• 
Pulse rate either < 50 bpm or > 100 bpm, 
• 
Systolic blood pressure either ≤ 90 mmHg or ≥ 160 mmHg,  
• 
Diastolic blood pressure either ≤ 50 mmHg or ≥ 100 mmHg. 
The number (percent) of patients having extreme vital signs will be tabulated by treatment group at each 
scheduled visit. The percentage will be calculated using the number of patients in the Safety population 
with data at each visit as the denominator. The number (percent) of patients having extreme vital signs 
post-baseline (including unscheduled assessments) will be calculated. 
Change from baseline statistics will also be defined for the measurements of blood pressure, pulse rate 
and temperature using the pre-dose values as baseline. Descriptive statistics for the measurement of 
temperature will also be provided by treatment group. 
All patients who have an extreme vital sign value will be documented in a by-patient listing. The listing 
will include all of the vital sign measurements from the study for the patient, and the noteworthy values 
will be flagged. 
6.5. 
Electrocardiograms 
At each time point, the change from baseline will be derived for each numeric parameter using the pre-
dose value as baseline. Descriptive statistics for the value of each parameter at each time point and the 
change from baseline for each parameter at each post-dose time point will be provided by treatment 
group. 


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The number (percent) of patients who either had an abnormal ECG (regardless whether clinically 
significant or not) or had an extreme QTc value at any time while on-treatment will be tabulated by 
treatment group. Extreme QTc values will be determined using the following criteria:  
• 
QTc ≥ 500 msec 
• 
QTc ≥ 550 msec 
• 
Change from baseline in QTc ≥ 30 msec 
• 
Change from baseline in QTc ≥ 60 msec. 
All on-treatment values, including unscheduled assessments, will be considered. 
6.6. 
Other Safety Analyses 
Results of physical exams will be included in listings but not summarized. 
7. 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES 
Pre-dose samples are to be obtained at 1 week, 2 weeks, 4 weeks and 8 weeks after the first dose of study 
drug. On the last day of dosing (Day 85/Week 12), the following samples are to be collected: pre-dose 
and 1, 2, 4, 8, 24 (Day 86), 72 hr (Day 88), and 168 hr (1 week; Day 92) post dose. One sample should be 
taken at the EOS visit (at least 6 weeks after the last dose [Week 18]). One sample should be taken at the 
early termination visit, if applicable. 
Pharmacokinetic parameters will be summarized by dose level using descriptive statistics. PK parameters 
such as the maximum concentration (Cmax,ss), time of maximum concentration (Tmax,ss), area under the 
concentration versus time curve within a dosing interval (AUC0-τ,ss), the first-order terminal elimination 
rate constant (λz), the terminal elimination half-life (t1/2), apparent clearance (CL/F), and apparent 
volume of distribution (Vd/F) will be reported. Other parameters may be calculated as deemed 
appropriate. Mean and individual PRCL-02 plasma concentration-time curves will be represented 
graphically. 
Note that for all PK parameters but Tmax, summary statistics will include geometric mean and geometric 
CV%. Tmax will be reported as median and range (minimum to maximum).  
The PK/PD relationship of PRCL-02 with PD, efficacy, and/or safety measures may be explored. 
8. 
REPORTING CONVENTIONS 
This section details the general conventions to be used for the statistical analyses. Departures from these 
general conventions will be provided in the specific detailed sections of this analysis plan. The following 
conventions will be applied to all data presentations and analyses:   
• 
Quantitative variables will generally be summarized by the number of patients, mean, standard 
deviation, median, minimum, and maximum.  
• 
Categorical variables will be summarized by the number and percentage of patients within each 
category. 
• 
All mean and median values will be formatted to one more decimal place than the measured value. 


PRCL Research, Inc.  
Compound: PRCL-02 
 
Protocol: PRCL-POC 
 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 draft 1 
Page 17 of 18 
20NOV2018 
• 
Standard deviation values will be formatted to two more decimal places than the measured value. 
• 
Minimum and maximum values will be presented with the same number of decimal places as the 
measured value. 
• 
The number and percent of responses will be presented in the form XX (XX %), where the percentage 
is in parentheses. Percentages will be rounded to the nearest percent. In the case of a frequency of 
zero, the frequency and percentage will be presented as 0 rather than 0 (0%). 
• 
All summary tables will include the analysis population sample size (i.e. number of patients) in each 
treatment group. 
• 
Date variables will be formatted as ddMMMYYYY for presentation. 
For PK data, the geometric coefficient of variation will be calculated assuming the data follow a log-
Normal distribution. That is, let X = concentration.  
If Y = log[X] has a Normal distribution with  
E[Y] = μ and Var[Y] = σ2,  
then X has a log-Normal distribution with  
E[X] = exp[μ + .5*σ2] = exp[μ]*exp[.5*σ2]  
and  
Var[X] = exp[2μ + 2*σ2] – exp[2μ + σ2] = exp[2μ]*exp[σ2]*(exp[σ2] – 1) 
so 
SD[X] =exp[μ]*exp[.5*σ2]*sqrt(exp[σ2] – 1) 
Therefore, CV[X] = SD[X]/E[X] = sqrt(exp[σ2] – 1). The log-transformed concentration values will be 
computed and the coefficient of variation calculated using the sample variance.  
 
 


PRCL Research, Inc.  
Compound: PRCL-02 
 
Protocol: PRCL-POC 
 
 
 
EMB Statistical Solutions, LLC 
Confidential and Proprietary 
Effective Date 
Statistical Analysis Plan v1 draft 1 
Page 18 of 18 
20NOV2018 
9. 
SCHEDULE OF ASSESSMENTS 
Procedure 
Screening 
 
 
 
 
 
 
 
 
FU 
EoS 
Visit # 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Study Days 
-28 to -1 
1 
8 
15 
29 
57 
85 
99 
113 
127 
141 
Window Period 
(Days) 
 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
Week 
- 
- 
1 
2 
4 
8 
12 
14 
16 
18 
20 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test (♀) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum FSH (PMP ♀) 
X 
 
 
 
 
 
 
 
 
 
 
QuantiFERON TB 
Test 
X 
 
 
 
 
 
 
 
 
 
 
HIV/hepatitis screen 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Study drug dispensing 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Study drug 
accountability 
 
 
X 
X 
X 
X 
X 
 
 
 
X if 
ET 
Safety Evaluations 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Height/weight 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Vital signs (pulse and 
BP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Clinical laboratory 
tests 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy and Other Evaluations 
PASI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
sPGA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK sampling 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma sample 
collection for PGx 
assessments 
 
X 
 
 
 
 
 
 
 
 
 
See protocol for footnotes.