A Randomized, Double-blind, Placebo-controlled, Dose Ranging Phase 2 Study to Evaluate the Efficacy and Safety of RIST4721 in Subjects With Palmoplantar Pustulosis
Phase: PHASE2
Conditions: Palmoplantar Pustulosis
Sponsor: Aristea Therapeutics, Inc.

Protocol RIST4721-202 
Version 5.0, Amendment 4.0 
05 April 2022 
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CLINICAL STUDY PROTOCOL 
TITLE PAGE 
Protocol Title:  
A Randomized, Double-blind, Placebo-controlled, Dose 
Ranging Phase 2 Study to Evaluate the Efficacy and Safety of 
RIST4721 in Subjects with Palmoplantar Pustulosis 
Short Title: 
RIST4721 in Subjects with Palmoplantar Pustulosis 
Protocol Number:  
RIST4721-202 
Study Treatment:  
RIST4721 
Study Phase:  
Phase 2 
Sponsor Name: 
Aristea Therapeutics, Inc. 
Legal Registered 
Address: 
 
 
Regulatory Agency 
Identifier Number(s): 
IND: 142756 
EudraCT: 2021-003029-31  
Version: 
5.0, Amendment 4.0 
Approval Date: 
05 April 2022 
 
CONFIDENTIAL 
This protocol is a confidential communication document of Aristea Therapeutics, Inc. The recipient of this 
document agrees not to disclose the information contained herein to others without prior written authorization of 
Aristea Therapeutics, Inc. except that this document may be disclosed to appropriate Institutional Review 
Boards/Independent Ethics Committees or duly authorized representatives of regulatory authorities such as 
European Medicines Agency, or the US Food and Drug Administration under the condition that they maintain 
confidentiality. 

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INVESTIGATOR AGREEMENT 
Protocol Title:  
A Randomized, Double-blind, Placebo-controlled, Dose 
Ranging Phase 2 Study to Evaluate the Efficacy and Safety of 
RIST4721 in Subjects with Palmoplantar Pustulosis 
Protocol Number:  
RIST4721-202 
Version and Date: 
5.0, Amendment 4.0, 05 April 2022 
I have read this protocol and agree to conduct this study in accordance with ethical principles as 
outlined in the International Council for Harmonisation (ICH) guidelines on Good Clinical 
Practice, any applicable laws and requirements and any additional conditions mandated by a 
regulatory authority and/or Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC). 
I acknowledge that I am responsible for the overall study conduct and I agree to personally 
conduct or supervise the described clinical study. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Aristea Therapeutics, Inc. 
 
 
 
 
 
Signature 
 
 
 
Name of Investigator 
 
Date 

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DOCUMENT HISTORY 
DOCUMENT HISTORY 
Document 
Date 
Protocol Amendment 4.0 
05 April 2022 
Protocol Amendment 3.0 
10 November 2021 
Protocol Amendment 2.0 
08 September 2021 
Protocol Amendment 1.0 
09 August 2021 
Original Protocol 
24 May 2021 
Amendment 4.0; 05 April 2022 
Overall Rationale for the Amendment: 
Summary of Changes (in order of appearance) 
Section Number and 
Name 
Description of Change 
Rationale for Change 
1.1 Synopsis 
1.2 Study Scheme 
1.3.1 Table 2, Schedule of 
Activities – Part B (OLE) 
2.1 Study Rationale 
3 Objectives, Endpoints and 
Estimand 
4 Study Design 
5.1.1 Part B Inclusion 
Criteria  
6 Study Treatment and 
Concomitant Therapy 
7 Discontinuation of Study 
Treatment 
8 Study Assessments and 
Procedures 
9 Statistical Considerations 
10 Appendices 
• Incorporate open-label extension 
• To allow long-term evaluation 
of RIST4721 as part of this 
protocol 
2.3.1 Risk Assessments 
• Update number of completed Phase 1 studies 
• To include the most up-to date 
information from clinical 
studies 
5.1 Inclusion Criteria 
• Minor clarification to inclusion criteria 
• For clarity 
5.2 Exclusion Criteria 
6.8 Concomitant 
Medications and Therapies 
• Minor updates to exclusion criteria including 
list of prohibited medications (with 
indication that the list is not exhaustive) 
• To align within the protocol and 
across other protocols 

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Section Number and 
Name 
Description of Change 
Rationale for Change 
6.6 Continued Access to 
Study Treatment after the 
End of the Study 
• Add section 
• For clarity 
8.5 PK, Biomarkers and PD 
• Re-arrange section 
• For clarity 
10.4 Appendix 4 
Contraceptive Guidance 
• Update language on contraception 
• For clarity 
General 
• Minor administrative changes and 
clarifications made throughout the protocol  
• Eliminate redundancy 
• Correct typographical errors, 
hyperlinks/cross-references, style, and 
formatting (not tracked) 
• Align across protocol sections 
• Update list of abbreviation (not tracked) 
• Update header 
• For consistency and clarity 
• Alignment within protocol and 
across documents 

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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
INVESTIGATOR AGREEMENT...................................................................................................3 
DOCUMENT HISTORY.................................................................................................................4 
1. 
PROTOCOL SUMMARY ..........................................................................................12 
1.1. 
Synopsis ......................................................................................................................12 
1.2. 
Study Scheme .............................................................................................................16 
1.3. 
Schedule of Activities (SoA) ......................................................................................17 
2. 
INTRODUCTION ......................................................................................................22 
2.1. 
Study Rationale ...........................................................................................................22 
2.2. 
Background .................................................................................................................23 
2.2.1. 
Palmoplantar Pustulosis ..............................................................................................23 
2.3. 
Benefit/Risk Assessment ............................................................................................24 
2.3.1. 
Risk Assessments........................................................................................................24 
2.3.1.1. 
Risks of Study Participation .......................................................................................26 
2.3.2. 
Benefit Assessment .....................................................................................................26 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................27 
3. 
OBJECTIVES, ENDPOINTS, AND ESTIMAND ....................................................28 
4. 
STUDY DESIGN .......................................................................................................30 
4.1. 
Overall Study Design ..................................................................................................30 
4.1.1. 
Part A – Double-Blind ................................................................................................30 
4.1.2. 
Part B – OLE ..............................................................................................................31 
4.2. 
Scientific Rationale for Study Design ........................................................................31 
4.3. 
Dose Rationale ............................................................................................................31 
4.4. 
Study Duration ............................................................................................................32 
4.5. 
End of Study Definition ..............................................................................................32 
5. 
STUDY POPULATION .............................................................................................33 
5.1. 
Inclusion Criteria ........................................................................................................33 
5.1.1. 
Part B Inclusion Criteria .............................................................................................34 
5.2. 
Exclusion Criteria (Part A only) .................................................................................34 
5.3. 
Lifestyle Considerations .............................................................................................37 
5.4. 
Screen Failure .............................................................................................................37 

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6. 
STUDY TREATMENT AND CONCOMITANT THERAPY ..................................38 
6.1. 
Study Treatment Administered ...................................................................................38 
6.2. 
Shipping/Handling/Storage/Accountability ................................................................38 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................39 
6.3.1. 
Randomization and Stratification ...............................................................................39 
6.3.2. 
Assignment of Subject Number ..................................................................................39 
6.3.3. 
Assignment of Study Treatment Kit Number .............................................................39 
6.3.4. 
Blinding and Unblinding of an Individual Subject .....................................................39 
6.4. 
Study Treatment Compliance .....................................................................................40 
6.5. 
Stopping Rules and Dose Modifications ....................................................................40 
6.5.1. 
Treatment-related AEs ................................................................................................40 
6.5.2. 
Neutrophil Count Laboratory Abnormality ................................................................41 
6.6. 
Continued Access to Study Treatment After the End of the Study ............................43 
6.7. 
Treatment of Overdose ...............................................................................................43 
6.8. 
Concomitant Medications and Therapies ...................................................................43 
6.8.1. 
Permitted Dermatologic Therapies .............................................................................44 
6.8.2. 
Prohibited Medications ...............................................................................................44 
6.8.3. 
Restricted Medications ...............................................................................................45 
7. 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
WITHDRAWAL FROM STUDY ..............................................................................47 
7.1. 
Discontinuation of Study Treatment and Withdrawal from the Study .......................47 
7.1.1. 
Premature Termination of the Study ...........................................................................48 
7.1.2. 
Pregnancy ...................................................................................................................48 
7.2. 
Lost to Follow-up .......................................................................................................48 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................50 
8.1. 
Key Screening Assessment(s) .....................................................................................50 
8.1.1. 
Psoriasis Area Severity Index (PASI).........................................................................50 
8.2. 
Efficacy Assessments .................................................................................................50 
8.2.1. 
Palmoplantar Pustulosis Psoriasis Area Severity Index (PPPASI).............................50 
8.2.2. 
Palmoplantar Pustulosis Physician Global Assessment (PPPGA) .............................51 
8.2.3. 
Patient Global Assessment (PtGA) .............................................................................51 
8.2.4. 
Numeric Rating Scale (NRS)......................................................................................51 
8.2.5. 
Health-related Quality of Life ....................................................................................51 

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8.2.6. 
Medical Photography ..................................................................................................52 
8.3. 
Safety Assessments .....................................................................................................52 
8.3.1. 
Physical Examinations ................................................................................................52 
8.3.2. 
Vital Signs ..................................................................................................................53 
8.3.3. 
Electrocardiograms .....................................................................................................53 
8.3.4. 
Clinical Safety Laboratory Assessments ....................................................................54 
8.4. 
Adverse Events and Serious Adverse Events .............................................................54 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................55 
8.4.2. 
Method of Detecting AEs and SAEs ..........................................................................55 
8.4.3. 
Follow-up of AEs and SAEs .......................................................................................55 
8.4.4. 
Regulatory Reporting Requirements for SAEs ...........................................................55 
8.4.5. 
Pregnancy ...................................................................................................................56 
8.4.6. 
Death Events ...............................................................................................................56 
8.5. 
Pharmacokinetics, Biomarkers, and Pharmacodynamics ...........................................56 
8.5.1. 
Pharmacokinetics ........................................................................................................56 
8.5.2. 
Serum Biomarkers ......................................................................................................57 
8.5.3. 
Biomarkers from Skin Tape Strips (Part A only) .......................................................57 
8.5.4. 
Storage and Handling of Blood Samples ....................................................................57 
9. 
STATISTICAL CONSIDERATIONS .......................................................................58 
9.1. 
Sample Size Determination ........................................................................................58 
9.2. 
Population for Analyses ..............................................................................................58 
9.3. 
Statistical Analyses .....................................................................................................59 
9.3.1. 
Study Reporting ..........................................................................................................59 
9.3.2. 
General Considerations ...............................................................................................59 
9.3.3. 
Efficacy Analysis ........................................................................................................59 
9.3.3.1. 
Analysis of Primary Endpoint ....................................................................................59 
9.3.3.2. 
Analyses of Key Secondary Endpoints .......................................................................60 
9.3.3.3. 
Type I Error Control for Primary and Key Secondary Endpoints ..............................60 
9.3.3.4. 
Analyses of Other Efficacy Endpoints .......................................................................60 
9.3.4. 
Safety Analyses ..........................................................................................................60 
9.3.4.1. 
Adverse Events ...........................................................................................................60 
9.3.5. 
Clinical Laboratory Tests ...........................................................................................61 

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9.3.6. 
Electrocardiograms .....................................................................................................61 
9.3.7. 
Vital Signs ..................................................................................................................61 
9.3.8. 
Treatment Exposure and Disposition ..........................................................................61 
9.4. 
Plasma Concentration Analyses .................................................................................61 
9.5. 
Pharmacodynamic Analyses .......................................................................................62 
9.6. 
Planned Interim Analyses ...........................................................................................62 
9.6.1. 
Data Review Committee .............................................................................................62 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................63 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations (Site 
Responsibilities) .........................................................................................................63 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................63 
10.1.2. 
Informed Consent Process ..........................................................................................63 
10.1.3. 
Data Protection ...........................................................................................................64 
10.1.4. 
Dissemination of Clinical Study Data ........................................................................64 
10.1.5. 
Data Quality Assurance ..............................................................................................64 
10.1.6. 
Source Documents ......................................................................................................65 
10.1.7. 
Study and Site Closure................................................................................................65 
10.1.8. 
Publication Policy .......................................................................................................66 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................67 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................69 
10.3.1. 
Definition of AE .........................................................................................................69 
10.3.2. 
Definition of SAE .......................................................................................................70 
10.3.3. 
Definition of Suspected and Unsuspected Adverse Reaction .....................................71 
10.3.4. 
Recording and Follow-Up of Adverse Events and Serious Adverse Events ..............71 
10.3.5. 
Reporting of SAEs ......................................................................................................74 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................75 
10.4.1. 
Definitions ..................................................................................................................75 
10.4.2. 
Contraception Guidance .............................................................................................75 
10.4.3. 
Collection of Pregnancy Information .........................................................................78 
10.5. 
Appendix 5: Palmoplantar Pustulosis Psoriasis Area and Severity Index 
(PPPASI) Scoring .......................................................................................................79 

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10.6. 
Appendix 6: Guidance to Address the COVID-19 Pandemic and Potential 
Impact on the Clinical Study ......................................................................................80 
10.7. 
Appendix 7: List of Abbreviations .............................................................................83 
10.8. 
Appendix 8: Protocol Amendment History ................................................................85 
11. 
REFERENCES ...........................................................................................................88 
 
 

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LIST OF TABLES 
Table 1: 
Schedule of Activities – Part A (Double-blind) .........................................................17 
Table 2: 
Schedule of Activities - Part B (OLE) ........................................................................20 
Table 3: 
RIST4721 Potential Risks and Risk Mitigation Strategy ...........................................25 
Table 4: 
Study Treatment Description ......................................................................................38 
Table 5:  
Prohibited Therapies or Procedures ............................................................................45 
Table 6:  
PPPGA (Averaged Over all Palmoplantar Lesions) ...................................................51 
Table 7: 
Protocol-Required Safety Laboratory Assessments ...................................................68 
 
LIST OF FIGURES 
Figure 1: 
Study Scheme .............................................................................................................16 
Figure 2: 
Steps for Addressing Neutrophil Counts ....................................................................42 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Randomized, Double-blind, Placebo-controlled, Dose Ranging Phase 2 Study 
to Evaluate the Efficacy and Safety of RIST4721 in Subjects with Palmoplantar Pustulosis 
Short Title: RIST4721 in Subjects with Palmoplantar Pustulosis 
Rationale 
RIST4721 is a small-molecule a high-potency antagonist of human CXC chemokine receptor 
type 2 (CXCR2) that is proposed to have potential as a novel oral treatment for 
neutrophil-mediated inflammatory diseases, including palmoplantar pustulosis (PPP). 
PPP is a rare, recurrent, auto-immune, chronic inflammatory skin condition typically confined to 
the palms and soles. While several factors have been shown to induce PPP, such as infections, 
trauma, stress, and various therapeutic agents, the disease pathophysiology remains poorly 
understood (Benjegerdes, 2016). Recent studies have begun to highlight the importance of the 
innate immune system and cytokines in the development of PPP (Benjegerdes, 2016). In support 
of these hypotheses, neutrophils were found in high numbers in the epidermis of subjects with 
PPP, with focal accumulations observed at the level of pustules (Bissonnette, 2017). In addition, 
high levels of neutrophil-recruiting chemokines, including interleukin (IL)-1 and IL-8, were 
measured in PPP lesions (Kim, 2013; Bissonnette, 2016). 
CXCR2 plays important roles in various acute and chronic inflammatory processes (Jamieson, 
2012; Dyer, 2017). CXCR2 serves as a receptor for a number of cytokines, including IL‑8, and is 
required for neutrophil egress from the bone marrow and recruitment to distant inflammatory 
sites (Eash, 2010; Boppana, 2014). Given the role of neutrophils in inflammation, the blockade 
of CXCR2 may represent a novel therapeutic approach for the treatment of neutrophil‑mediated 
inflammatory disorders, such as PPP (Boppana, 2014). The utility of antagonizing the CXCR2 
receptor was formerly investigated with the use of neutralizing antibodies targeting IL-8, one of 
several CXCR2 ligands (Skov, 2008; Veenstra, 2012). This study revealed that inhibition of the 
IL-8/CXCR2 axis causes clinically relevant reductions in disease activity in PPP subjects (Skov, 
2008). 
RIST4721 antagonism of CXCR2 was demonstrated in vitro by measuring both primary binding 
affinity in human embryo kidney 293 (HEK293) cells transfected with recombinant CXCR2 
(whole cells and membranes) and functional end points in isolated peripheral polymorphonuclear 
cells and human blood neutrophils. In in vitro pharmacology studies covering a number of 
related receptors and targets inhibited by structurally similar molecules, RIST4721 demonstrated 
a CXCR2 selectivity of 134-fold and 47-fold relative to its potency at the human CXC motif 
chemokine receptor 1 (CXCR1) and C-C motif chemokine receptor 2 (CCR2), respectively 
(RIST4721 Investigator’s Brochure [IB]). The in vitro evaluation of RIST4721 as a high-potency 
CXCR2 antagonist translated well in vivo in 4 studies with a rat air pouch model of monosodium 
urate (MSU) crystal-induced inflammation. When rats were previously challenged with MSU 
injection, RIST4721 caused significant, dose-dependent decreases in exudate volume, total white 
blood cell (WBC) count, and neutrophil infiltration at doses 30, 100, and 300 μmol/kg. 

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RIST4721 was also evaluated in clinical setting including a Phase 2a, randomized, double-blind, 
placebo-controlled study in subjects with moderate to severe PPP. The primary endpoints of this 
study were related to pustule count assessments as these were hypothesized to be an early 
indicator of efficacy. The primary efficacy endpoints of relative change from baseline in fresh 
and total pustule count at Day 28 did not show statistically significant differences between the 
RIST4721 and placebo groups. The proportion of subjects who achieved a 50% reduction in the 
Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI-50) was numerically higher 
in the RIST4721 group (40.0%) compared to the placebo group (26.3%) at Day 28 (p=0.475). No 
other statistically significant differences were observed between treatment groups. A post-hoc 
subgroup analysis of subjects with an increase in total pustule count between screening and 
baseline was performed (n=20; 13 subjects randomized to placebo and 7 subjects randomized to 
RIST4721); the proportion of subjects with a PPPASI-50 at Day 28 was significantly higher for 
subjects treated with RIST4721 (5 of 7 subjects [71%]) as compared to placebo (2 of 13 subjects 
[15%]; p=0.0223 using Fisher’s exact test). 
The present study will further evaluate the efficacy and safety of RIST4721 at multiple doses 
over 12 weeks (Part A, randomized, double-blind, placebo-controlled) and at 400 mg once daily 
(QD) over 72 weeks (Part B, open-label extension [OLE]) in subjects with moderate to severe 
PPP. 
Objectives, Endpoints, and Estimand (Primary and Secondary) 
Objectives 
Endpoints 
Primary 
 
• To evaluate the efficacy of RIST4721 in 
the treatment of subjects with moderate 
to severe PPP 
• Proportion of subjects achieving a 50% 
reduction in PPPASI score at Week 12 
Primary Estimand 
For the primary objective, the primary estimand is as follows: 
Treatment regimen: RIST4721 400 mg, RIST4721 200 mg, and placebo 
Target population: Subjects with moderate to severe PPP as defined by the inclusion and 
exclusion criteria (Section 5), grouped per randomization assignment 
Variable of interest: responders who achieve a 50% reduction in PPPASI score at Week 12 
Intercurrent events and corresponding strategy: Subjects who withdraw from the study 
prior to Week 12 due to any reason will be imputed as non-responders. Subjects who 
permanently discontinue study treatment but continue in the study will have their response 
statuses derived based on their observed data.  
Population-level summary variable: Difference in proportions of responders 
Key Secondary 
• Key efficacy secondary endpoints 
• Proportion of subjects achieving 
Palmoplantar Pustulosis Physician 

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Objectives 
Endpoints 
Global Assessment (PPPGA) of 0 or 1 at 
Week 12 
• Proportion of subjects achieving 75% 
reduction in PPPASI score at Week 12 
Secondary 
 
• Additional secondary efficacy endpoints 
• Absolute change from baseline in 
PPPGA at Week 12 
• Absolute change from baseline in 
PPPASI at Week 12 
Safety 
• To assess the safety of RIST4721 in this 
population 
• Incidence of treatment-emergent adverse 
events (TEAEs) and serious adverse 
events (SAEs) 
• Change from Baseline in clinical 
laboratory parameters, electrocardiogram 
(ECG) parameters, and vital signs 
Overall Design 
This is a 2-part Phase 2 study in subjects with moderate to severe PPP (defined by a PPPASI ≥12 
and a PPPGA ≥3 at screening ): 
• Part A is a Phase 2, randomized, double‑blind, placebo-controlled, multicenter, 
12‑week study evaluating the efficacy and safety of 2 doses of RIST4721. 
• Part B is an open-label extension, 72 weeks evaluating the safety, tolerability and 
efficacy of RIST4721 400 mg once daily (QD). 
The study will consist of a screening period, a treatment period (12 weeks in Part A and 72 
weeks in Part B), and a follow-up period. All subjects will attend a follow-up visit at the clinic 4 
weeks after last dose of study treatment. Subjects who permanently discontinue study treatment 
will be followed as described in Section 7.1. 
Study schema is shown in Section 1.2. 
Part A: Double-Blind 
After signing an informed consent form, subjects will be screened for study eligibility over 4 
weeks. PPPASI assessments will be performed and recorded to determine eligibility for the 
study. Additionally, medical photographs of the palms of hands and soles of feet from all 
subjects will be collected and centrally read to confirm eligibility for the study. Subjects will be 
required to discontinue any topical medications (with the exception of emollients) used to treat 
PPP at 4 weeks prior to first dose of study treatment (at screening). 
On Day 1 (baseline visit) eligible subjects will be randomized in 1:1:1 ratio to receive study 
treatment orally QD for 12 weeks: 
• RIST4721 400 mg 

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• RIST4721 200 mg 
• Placebo 
Randomization will be stratified by smoking status (current smoker vs. former or non-smoker). 
After initiation of study treatment on Day 1, subjects will return to the clinic and be evaluated as 
specified in the Schedule of Activities (SoA; Table 1 – Part A). 
All subjects who remain on study treatment through and including Week 12 will be eligible to 
enter Part B (OLE) as specified below.  
Part B: OLE 
Subject may participate in Part B if they have completed Part A, been compliant with study 
procedures, are currently receiving study treatment (RIST4721 or placebo), and meet eligibility 
criteria for Part B (refer to Section 5.1.1). 
Subjects who consent to participate in Part B will commence with the extension enrollment visit, 
which will occur on the same day as Part A End of Treatment (EOT) visit; these subjects will not 
complete Part A follow-up visit. Subjects must enroll into Part B portion of the study within 7 
days of Part A EOT visit. 
After signing Part B informed consent, eligible subjects will receive RIST4721 400 mg QD for 
72 weeks of treatment. Subjects who received lower doses of RIST4721 or placebo will be 
switched to RIST4721 400 mg QD. Throughout the study, subjects will be evaluated as specified 
in the SoA (Table 2 - Part B). 
Treatment Groups and Number of Subjects: 
The study will randomize approximately 156 evaluable subjects, with 52 subjects per treatment 
group (RIST4721 400 mg, RIST4721 200 mg, and placebo). 
Duration 
For each subject, the total study duration is expected to be as follows:  
Study Period 
Part A 
Part B 
Screening/observation period:  
4 weeks 
Not applicable 
Treatment period:  
12 weeks 
72 weeks 
Follow-up period 
4 weeks after last dose of study treatment 
 
Data Review Committee 
A non-independent, internal Data Review Committee (DRC) comprised of Sponsor 
representatives not directly involved in the conduct of the study, and/or external expert 
physician(s), will regularly monitor overall safety and emerging efficacy results on an unblinded 
basis, as well as general aspects of study conduct, to ensure that the benefits and risks of study 
participation remain acceptable (refer to Section 9.6.1). 
 

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1.2. 
Study Scheme 
Figure 1: 
Study Scheme 
 
Abbreviations: EOT, end of treatment; OLE, open-label extension; QD, once daily, R, randomization.

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2. 
INTRODUCTION 
RIST4721 is a small-molecule a high-potency antagonist of human CXC chemokine receptor 
type 2 (CXCR2) that is proposed to have potential as a novel oral treatment for neutrophil 
mediated inflammatory diseases, including palmoplantar pustulosis (PPP). PPP is a rare, 
recurrent, auto-immune, chronic inflammatory skin condition typically confined to the palms 
and soles. 
2.1. 
Study Rationale 
While several factors have been shown to induce PPP, such as infections, trauma, stress, and 
various therapeutic agents, the disease pathophysiology remains poorly understood 
(Benjegerdes, 2016). Recent studies have begun to highlight the importance of the innate 
immune system and cytokines in the development of PPP (Benjegerdes, 2016). In support of 
these hypotheses, neutrophils were found in high numbers in the epidermis of subjects with PPP, 
with focal accumulations observed at the level of pustules (Bissonnette, 2017). In addition, high 
levels of neutrophil-recruiting chemokines, including interleukin (IL)-1 and IL-8, were measured 
in PPP lesions (Kim, 2013; Bissonnette, 2016). 
The CXCR2 plays important roles in various acute and chronic inflammatory processes 
(Jamieson, 2012; Dyer, 2017). CXCR2 serves as a receptor for a number of cytokines, including 
IL‑8, and is required for neutrophil egress from the bone marrow and recruitment to distant 
inflammatory sites (Eash, 2010; Boppana, 2014). Given the role of neutrophils in inflammation, 
the blockade of CXCR2 may represent a novel therapeutic approach for the treatment of 
neutrophil‑mediated inflammatory disorders, such as PPP (Boppana, 2014). The utility of 
antagonizing the CXCR2 receptor was formerly investigated with the use of neutralizing 
antibodies targeting IL-8, one of several CXCR2 ligands (Skov, 2008; Veenstra, 2012). This 
study revealed that inhibition of the IL-8/CXCR2 axis causes clinically relevant reductions in 
disease activity in PPP subjects (Skov, 2008). 
RIST4721 antagonism of CXCR2 was demonstrated in vitro by measuring both primary binding 
affinity in human embryo kidney 293 (HEK293) cells transfected with recombinant CXCR2 
(whole cells and membranes) and functional end points in isolated peripheral 
polymorphonuclear cells and human blood neutrophils. In in vitro pharmacology studies 
covering a number of related receptors and targets inhibited by structurally similar molecules, 
RIST4721 demonstrated a CXCR2 selectivity of 134-fold and 47-fold relative to its potency at 
the human CXC motif chemokine receptor 1 (CXCR1) and C-C motif chemokine receptor 2 
(CCR2), respectively (RIST4721 Investigator’s Brochure [IB]). The in vitro evaluation of 
RIST4721 as a high-potency CXCR2 antagonist translated well in vivo in 4 studies with a rat air 
pouch model of monosodium urate (MSU) crystal-induced inflammation. When rats were 
previously challenged with MSU injection, RIST4721 caused significant, dose-dependent 
decreases in exudate volume, total white blood cell (WBC) count, and neutrophil infiltration at 
doses 30, 100, and 300 μmol/kg. 
RIST4721 was also evaluated in clinical setting including a Phase 2a, randomized, double-blind, 
placebo-controlled study in subjects with moderate to severe PPP. The primary endpoints of this 
study were related to pustule count assessments as these were hypothesized to be an early 
indicator of efficacy. The primary efficacy endpoints of relative change from baseline in fresh 

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and total pustule count at Day 28 did not show statistically significant differences between the 
RIST4721 and placebo groups. The proportion of subjects who achieved at 50% reduction in the 
Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI-50) was numerically higher 
in the RIST4721 group (40.0%) compared to the placebo group (26.3%) at Day 28 (p=0.475). 
No other statistically significant differences were observed between treatment groups. A post-
hoc subgroup analysis of subjects with an increase in total pustule count between screening and 
baseline was performed (n=20; 13 subjects randomized to placebo and 7 subjects randomized to 
RIST4721); the proportion of subjects with a PPPASI-50 at Day 28 was significantly higher for 
subjects treated with RIST4721 (5 of 7 subjects [71%]) as compared to placebo (2 of 13 subjects 
[15%]; p=0.0223 using Fisher’s exact test). 
The present study will further evaluate the efficacy and safety of RIST4721 at multiple doses 
over 12 weeks (Part A, randomized, double-blind, placebo-controlled) and at 400 mg once daily 
(QD) over 72 weeks (Part B, open-label extension [OLE]) in subjects with moderate to severe 
PPP.  
2.2. 
Background 
2.2.1. 
Palmoplantar Pustulosis 
PPP is a chronic inflammatory skin condition characterized by sterile pustules with erythema, 
hyperkeratosis, and scaling on the palms and soles (Benjegerdes, 2016; Dermatologists, 2018). It 
is considered a rare disease with an estimated prevalence of 0.01 to 0.05% (Lomholt, 1964; 
Hellgren, 1971; Mrowietz, 2011; Brunasso, 2013)  and reported as high as 0.12% in a Japanese 
study, suggesting higher rate in Japan (Kubota, 2015). PPP is more commonly diagnosed in 
females (estimated prevalence range of 65.3% to 94%) than males, and in smokers 
(Michaëlsson, 2007; Kubota, 2015; Wilsmann-Theis, 2017). The mean age at disease onset 
ranges from 40 to 58 (Eriksson, 1998; Adişen, 2009; Brunasso, 2013; Wilsmann-Theis, 2017; 
Misiak-Galazka, 2018). Triggering factors include smoking, infections and stress, metal allergy, 
certain drugs, and co-morbid diseases such as thyroid disease, metabolic syndrome, atopy, 
arthritis, and celiac disease (Misiak-Galazka, 2020). There is a high prevalence of thyroid 
dysfunction in patients with PPP, often times underdiagnosed (Benjegerdes, 2016; Bissonnette, 
2016; Wilsmann-Theis, 2017). 
A number of reports suggest that PPP represents a distinct entity because of its unique genetic 
and molecular features (Benjegerdes, 2016; Bissonnette, 2016; Wilsmann-Theis, 2017). The 
disease tends to affect more frequently the thenar, hypothenar, and central areas of the palms, as 
well as the corresponding areas of the soles, although pustular lesions may also extend to the 
subject’s wrists and heels (Benjegerdes, 2016). Erythema develops at the periphery of the 
lesions. Itching may be present. The clinical manifestations of PPP make it a debilitating 
condition that puts the afflicted subjects at risk of social stigmatism and reduced quality of life 
(Stanford, 2014). 
Off-label topical therapy typically consists of corticosteroid treatment with or without occlusion. 
Other topical agents used for the treatment of PPP include calcipotriene, photochemotherapy 
(i.e., psoralen and long-wave ultraviolet radiation [PUVA]), and tacrolimus (Benjegerdes, 2016). 
Topical agents are generally known to have limited efficacy in PPP, in part due to the lower 
relative absorptive capacity of the palms and soles compared to other body areas (Greaves, 1989; 
Kumar, 2004). 

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Off-label systemic treatments, including methotrexate and cyclosporin, have been used to treat 
PPP, although little controlled data exist on administration of these drugs to PPP patients 
(Thomsen, 1971; Reitamo, 1993; Erkko, 1998; Jin, 2019). Retinoids, such as acitretin, have been 
shown to be effective in some PPP cases. However, significant safety concerns, such as 
extensive dryness of mouth and lips, sicca symptoms of the eyes, hair loss, and increased blood 
lipid values, were associated with the use of these agents (Lassus, 1988). Side effects associated 
with the use of cyclosporin and methotrexate can include headache, nausea, mouth ulcers, 
hypertension, frequent urination, gastrointestinal reactions, inflammation of the liver or lung, 
hypertrichosis, and increased creatinine laboratory values (Reitamo, 1993; Erkko, 1998; Jin, 
2019; AOCD, 2021) . Additional off-label systemic treatments that have been investigated 
include colchicine, dapsone, and biologic agents, such as tumor necrosis factor alpha (TNF-α) 
inhibitors (e.g., etanercept, infliximab, adalimumab) or IL inhibitors (e.g., guselkumab, 
ustekinumab, secukinumab, spesolimab) (Bissonnette, 2008; Bissonnette, 2011; Mrowietz, 2019; 
Terui, 2019; Mrowietz, 2021). These treatments have modest efficacy at best in PPP and can be 
associated with side effects, such as higher rates of infections, in addition to nasopharyngitis, 
headache, urticaria, and cellulitis (Bissonnette, 2011; Terui, 2018). More serious adverse events 
(SAEs) included infusion reactions and hepatitis (Bissonnette, 2011; Sanchez, 2017). 
In a German cohort of 172 PPP patients, the most common systemic agents used were 
corticosteroids (40.1%), acitretin (37.8%), and methotrexate (27.9%). Despite treatment with 
these therapies, patients continued to experience a high burden of disease defined by PPPASI 
scores and there was no improvement in quality of life measured by the Dermatology Life 
Quality Index (DLQI) (Wilsmann-Theis, 2017). 
The lack of targeted systemic treatments for PPP warrants development of a more effective and 
well-tolerated option. 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and potential benefits and potential risks of 
RIST4721 may be found in the IB. 
2.3.1. 
Risk Assessments 
The safety of RIST4721 has been assessed in 6 Phase 1 clinical studies in healthy subjects (161 
subjects received single or multiple doses of RIST4721 ranging from 19 to 730 mg) and 1 Phase 
2a study in subjects with moderate to severe PPP (15 subjects with moderate to severe PPP 
received RIST4721 300 mg QD for 28 days in the Phase 2a study RIST4721-201). RIST4721 
was generally well tolerated. In the Phase 2a study, RIST4721-201 more subjects in the 
RIST4721 group (87%) compared to the placebo group (37%) experienced treatment-emergent 
adverse events (TEAEs). Most TEAEs were mild in severity, belonged to the system organ class 
(SOC) Gastrointestinal Disorders (diarrhea, abnormal feces, and nausea) or Musculoskeletal and 
Connective Tissue Disorders, and were resolved at the time of study completion. Two subjects in 
the RIST4721 group experienced mild, transient, and asymptomatic neutropenia during the 
study, which did not lead to treatment discontinuation. Neutrophil concentrations in both 
subjects returned to within the reference range by the time of the study follow-up visit. No SAEs 
or deaths were reported. 

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Table 3 summarizes identified and potential risks associated with RIST4721 as well as risk 
mitigation strategies. Further information related to nonclinical and clinical studies as well as 
other potential risks are available in the IB. 
Table 3: 
RIST4721 Potential Risks and Risk Mitigation Strategy 
Safety 
Considerations 
of RIST4721 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Safety Consideration Based on Clinical Data 
Neutropenia 
In both the SAD and MAD studies 
with RIST4721, dose-dependent 
reductions in neutrophils were 
observed. These reductions were 
rapidly reversible following 
discontinuation of RIST4721. Values 
resolved within 6 days following 
dosing. Similar reductions in 
neutrophils and leukocytes were 
observed in patients with PPP during 
treatment with RIST4721 300 mg QD 
for 28 days. Values returned to within 
the normal range by 14 days following 
completion of dosing. 
• 
Relative and absolute neutrophil 
counts will be measured and monitored 
during the study. 
• 
Monitor AEs associated with 
neutropenia. 
• 
Stopping rules based on blood 
neutrophil count (refer to Section 7.1). 
• 
Based on studies with other CXCR2 
inhibitors, the reduction in blood 
neutrophils associated with this 
CXCR2 inhibitor may be rapidly 
reversed by administration of G-CSF. 
• 
Address baseline neutrophil counts in 
clinical study inclusion criteria. 
Gastrointestinal 
effects 
Gastrointestinal effects are potential 
risks with RIST4721. In the conscious 
rat, single doses of RIST4721 at 2 
mg/kg increased gastric emptying, 
whereas it was decreased at 100 mg/kg 
and above. In clinical studies, AEs in 
the Gastrointestinal Disorders SOC 
were frequently reported. Events 
included diarrhea, abnormal feces, 
nausea, abdominal pain, constipation, 
flatulence, dyspepsia.  
• 
Monitor AEs associated with GI tract. 
Safety Considerations Based on Theoretical Concern (not observed in clinical or nonclinical studies) 
Immune 
Suppression  
No specific risk of infection has been 
identified from the non-clinical data or 
human data with RIST4721. However, 
the CXCR2 antagonist activity of 
RIST4721 could potentially interfere 
with mechanisms important in normal 
host defenses against infection. 
• 
Monitor immune-mediated AEs. 
• 
Monitor incidence of AEs associated 
with infections. 
• 
Complete blood counts with 
differentials will be monitored 
frequently at the protocol-specified 
frequency. 

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Safety 
Considerations 
of RIST4721 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Potential Drug 
Interactions 
In vitro assays suggest that RIST4721 
is primarily metabolized by 
CYP3A4/5. RIST4721 was determined 
to be a P-gp/MDR1 and BCRP efflux 
transporter substrate in vitro. 
 RIST4721 induced CYP3A4 and 
inhibited the efflux transporter BCRP 
and the uptake transporters OAT1, 
OAT3, OATP1B1, and OATP1B3 in 
vitro. Data from a clinical drug-drug 
interaction study, however, suggested 
that there does not appear to be a 
clinically relevant effect of RIST4721 
on CYP3A4 or these transporters.  
No clinical drug-drug interaction 
studies have been conducted to 
examine the effect of other drugs on 
RIST4721. 
• 
Caution should be used when co-
administering RIST4721 with known 
inhibitors of P-gp or BCRP; or with 
moderate  inhibitors or inducers of 
CYP3A4/5 (strong inhibitors/inducers 
are prohibited). 
Abbreviations: AE, adverse event; BCRP, breast cancer resistance protein; CXCR2, CXC chemokine receptor-2; 
CYP, cytochrome P450; G-CSF, granulocyte colony-stimulating factor; GI, gastrointestinal; MAD, multiple 
ascending dose; MDR1, multidrug resistance protein 1; OAT, organic anion transporter; OATP, organic anion-
transporting polypeptide; P-gp, P-glycoprotein; QD, once daily; SAD, single ascending dose; SOC, system organ 
class. 
2.3.1.1. 
Risks of Study Participation 
There are some risks to participation in any clinical study. The risks associated with this clinical 
study include the potential risks or discomforts from venipuncture such as temporary discomfort 
from the needle stick, bruising, bleeding, and rarely may cause infection or fainting. 
Additionally given the known risk and potential for transmission of severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2), there is a potential for increased risk of contracting 
SARS-CoV-2 infection as a result of study participation. The risks associated with RIST4721 
and co-administration of vaccines for SARS-CoV-2 are not known. 
2.3.2. 
Benefit Assessment 
It is anticipated that subjects randomized to the RIST4721 will have an improvement in their 
PPP condition, specifically with respect to the PPPASI score, as over a shorter timeframe there 
were trends in favor of RIST4721 on a number of efficacy endpoints (refer to Section 2.1). 
Specifically, potential benefits may include fewer pustules, less pain, decreased redness and 
desquamation, smaller involved surface areas, and less functional impairment. 
A longer duration of therapy than the 4 weeks of therapy in the initial Phase 2a study 
(RIST4721-201) with RIST4721 in subjects with PPP is expected to demonstrate a larger 
treatment effect in this challenging disease. 

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Participation in this study may help generate future benefit for larger groups of subjects with 
PPP if RIST4721 proves to be successful in treating this condition. 
Please refer to RIST4721 IB for additional details. 
2.3.3. 
Overall Benefit: Risk Conclusion 
While there are potential risks associated with the study treatment and the study procedures for 
this Phase 2 clinical study, the risk is expected to be minimal. The risks associated with 
RIST4721 and co-administration of vaccines for SARS-CoV-2 are not known, therefore the 
SARS-CoV-2 vaccine is listed as a restricted medication while a subject is participating in this 
study. If a subject requests or requires new or additional vaccination for SARS-CoV-2, the 
investigator should consider and discuss the potential risks and benefits with the subject. Once a 
determination has been made, the investigator will notify the medical monitor. Regardless of 
their vaccination status, subjects will be tested at each study visit as part of the routine safety 
assessments for SARS-CoV- 2 to determine if a new infection has taken place. Additionally, all 
adverse events (AEs) from previous clinical studies were reported as mild or moderate in 
severity and there were no reported SAEs. The main safety consideration for the current study is 
the expected mechanism of action-mediated reduction in peripheral blood neutrophils, which is 
to be closely monitored via the procedure outlined in Figure 2. 
Against these minimal risks stands the benefit of information on the safety and efficacy of a 
promising new substance, which is intended to be used in the treatment of PPP. Despite these 
potential risks, it is expected that subjects randomized to RIST4721 might see an improvement 
in their PPP condition, such as fewer pustules, less pain, decreased redness and desquamation, 
smaller involved surface areas, and less functional impairment. As there are currently no 
approved therapies for PPP, RIST4721 has the potential to improve subjects’ quality of life and 
daily functional mobility. This dose ranging study may inform future pivotal studies of 
RIST4721 in PPP, with the ultimate goal of providing much needed treatment to patients who 
today do not have effective alternative treatment options. 
All quality, pharmacology, and toxicology data, and satisfactory safety and tolerability results, 
demonstrated in clinical and nonclinical studies are considered sufficient to expect a positive 
benefit/risk ratio for the treatment of PPP with RIST4721, and therefore to initiate this study. 
The risk to subjects in this study will be minimized by compliance with the eligibility criteria, 
proper study design, and close monitoring. 
Given the potential for efficacy in combination with the tolerated safety profile of RIST4721, the 
benefits of study participation outweigh the risks of participation in the study. 

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3. 
OBJECTIVES, ENDPOINTS, AND ESTIMAND 
 
Objectives 
Endpoints 
Primary 
 
• To assess the efficacy of RIST4721 in 
the treatment of subjects with moderate 
to severe PPP  
• Proportion of subjects achieving a 50% 
reduction in PPPASI score at Week 12 
Primary Estimand 
For the primary objective, the primary estimand is as follows: 
Treatment regimen: RIST4721 400 mg, RIST4721 200 mg, and placebo 
Target population: Subjects with moderate to severe PPP as defined by the inclusion and 
exclusion criteria (Section 5), grouped per randomization assignment 
Variable of interest: responders who achieve a 50% reduction in PPPASI score at Week 12 
Intercurrent events and corresponding strategy: Subjects who withdraw from the study prior 
to Week 12 due to any reason will be imputed as non-responders. Subjects who permanently 
discontinue study treatment but continue in the study will have their response statuses derived 
based on their observed data.  
Population-level summary variable: Difference in proportions of responders 
Key Secondary 
• Key efficacy secondary endpoints 
• Proportion of subjects achieving 
Palmoplantar Pustulosis Physician Global 
Assessment (PPPGA) of 0 or 1 at Week 12 
• Proportion of subjects achieving 75% 
reduction in PPPASI score at Week 12 
Secondary 
 
• Additional secondary efficacy endpoints 
• Absolute change from baseline in PPPGA at 
Week 12 
• Absolute change from baseline in PPPASI at 
Week 12 
Safety 
• To assess the safety of RIST4721 in this 
population 
• Incidence of TEAEs and SAEs 
• Change from Baseline in clinical laboratory 
parameters, electrocardiogram (ECG) 
parameters, and vital signs 

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Objectives 
Endpoints 
Exploratory 
 
• To assess the impact of treatment with 
RIST4721 on the health-related quality 
of life (QoL) 
• Absolute change from baseline in PPPASI at 
each visit 
• Achieving a 50% or 75% reduction from 
baseline in PPPASI score at each visit and 
during the study 
• Absolute and relative change from baseline 
in DLQI at each visit 
• Proportion of subjects achieving a score of 0 
or 1 on each of the component (pustules, 
erythema, and scaling) in the Patient Global 
Assessment (PtGA) 
• Change from baseline at each visit in: 
− Pain Numerical Rating Scale (NRS) 
− Pruritus NRS 
− Burning NRS 
− Palmoplantar Quality of Life (PPQLI) 
− 36-Item Short Form Survey (SF-36) 
• To evaluate the relationship between 
efficacy and pharmacokinetics (PK) 
exposure to RIST4721 at different doses 
• Plasma PK concentrations of RIST4721 and 
its metabolites, if appropriate 
• To evaluate the pharmacodynamics (PD) 
of RIST4721 in this population 
• Changes from baseline in biomarkers and 
cytokines measured in blood samples 
• To evaluate translational biomarkers in 
the skin and blood of participants treated 
with RIST4721  
• Change from baseline in the expression of 
select biomarkers in skin (adhesive strips) 
and peripheral blood. 
 
 

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4. 
STUDY DESIGN 
4.1. 
Overall Study Design 
This is a 2-part Phase 2 study in subjects with moderate to severe PPP (defined by a PPPASI ≥12 
and a PPPGA ≥3 at screening ).  
• Part A is a Phase 2, randomized, double‑blind, placebo-controlled, multicenter, 
12‑week study evaluating the efficacy and safety of 2 doses of RIST4721. 
Approximately 156 subjects are planned to be enrolled into Part A (approximately 52 
per treatment group). 
• Part B is an open-label extension, 72 weeks evaluating the safety, tolerability and 
efficacy of RIST4721 400 mg QD. 
A non-independent, internal Data Review Committee (DRC), comprised of Sponsor 
representatives not directly involved in the conduct of the study, and/or external expert 
physician(s), will regularly monitor overall safety and emerging efficacy results on an unblinded 
basis, as well as general aspects of study conduct, to ensure that the benefits and risks of study 
participation remain acceptable (refer to Section 9.6.1). 
The study will consist of a screening period, a treatment period (12 weeks in Part A and 72 
weeks in Part B), and a follow-up period. All subjects will attend a Follow-up visit at the clinic 4 
weeks after last dose of study treatment. Subjects who permanently discontinue study treatment 
will be followed as described in Section 7.1. 
Study schema is shown in Section 1.2. 
4.1.1. 
Part A – Double-Blind 
After signing an informed consent form (ICF), subjects will be screened for study eligibility over 
4 weeks. PPPASI assessments will be performed and recorded to determine eligibility for the 
study. Additionally, medical photographs of the palms of hands and soles of feet from all 
subjects will be collected and centrally read to confirm eligibility for the study. Subjects will be 
required to discontinue any topical medications (with the exception of emollients) used to treat 
PPP 4 weeks prior to first dose of study treatment (at screening). 
On Day 1 (baseline visit) eligible subjects will be randomized in 1:1:1 ratio to receive oral study 
treatment for 12 weeks: 
• RIST4721 400 mg QD 
• RIST4721 200 mg QD 
• Placebo QD 
Randomization will be stratified by smoking status (current smoker vs. former or non-smoker). 
After initiation of study treatment on Day 1, subjects will return to the clinic and be evaluated as 
specified in the Schedule of Activities (SoA; Table 1 – Part A). 
All subjects who remain on study treatment through and including Week 12 will be eligible to 
enter Part B (OLE) as specified in Section 4.1.2. . 

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4.1.2. 
Part B – OLE 
Subject may participate in Part B if they have completed Part A, have been compliant with study 
procedures, are currently receiving study treatment (RIST4721 or placebo), and meet eligibility 
criteria for Part B (refer to Section 5.1.1). 
Subjects who consent to participate in this portion of the study will commence with the 
extension enrollment visit, which will occur on the same day as Part A End of Treatment (EOT) 
visit; these subjects will not complete Part A follow-up visit. Subjects must enroll into Part B 
portion of the study within 7 days of Part A EOT visit. 
After signing Part B informed consent, eligible subjects will receive RIST4721 400 mg QD for 
72 weeks of treatment. Subjects who received lower doses of RIST4721 or placebo will be 
switched to RIST4721 400 mg QD. Throughout the study, subjects will be evaluated as specified 
in the SoA (Table 2 – Part B). 
4.2. 
Scientific Rationale for Study Design 
This Phase 2, randomized, placebo-controlled, multicenter study is designed to assess the 
efficacy and safety of RIST4721 in adult subjects with PPP. This is the second study with 
RIST4721 administration in subjects with PPP. The overall design of the study, including dose 
levels, was selected based on the data from a Phase 2 proof-of-concept study (RIST4721-201) 
and a relative bioavailability study conducted with a tablet formulation of RIST4721 
(RIST4721-101). 
A placebo control will be used to establish the frequency and magnitude of changes in clinical 
endpoints that may occur in the absence of active treatment. A placebo control is considered 
appropriate as opposed to a comparator control because there is no common standard of care for 
PPP in any of the countries that this study will be conducted. Randomization will be used to 
minimize bias in the assignment of subjects to treatment groups, to increase the likelihood that 
known and unknown subject attributes (e.g., demographic and baseline characteristics) are 
evenly balanced across treatment groups, and to enhance the validity of statistical comparisons 
across treatment groups (refer to Section 6.3.1). Blinded treatment will be used to reduce 
potential bias during data collection and evaluation of clinical endpoints. 
The OLE portion of the study is designed to assess the long-term safety, tolerability, and 
efficacy of RIST4721 in adult subjects with PPP.  
4.3. 
Dose Rationale 
Based on data from previous clinical studies with RIST4721, a dose of approximately 
200 mg/day is anticipated to be a minimally effective dose in patients with PPP. 
RIST4721 was well tolerated in multiple Phase 1 studies in healthy volunteers at single doses as 
high as 730 mg and multiple doses up to 500 mg/day for 10 days. In addition, one Phase 2a 
study in patients with PPP evaluated a dose of 300 mg QD for 4 weeks. 
Study RIST4721-102 was a Phase 1, randomized, single-blind, placebo-controlled, crossover 
study that investigated the effect of multiple doses of 150 mg or 300 mg RIST4721 on the 
inflammatory response in healthy male subjects using a standardized blister model. The primary 
endpoint of inflammatory response was evaluated by measuring absolute neutrophil count 

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(ANC) in the blister exudate at various timepoints. In the assessment of the primary endpoint, 
ANC values demonstrated significant variability across both placebo and RIST4721 treatments 
at both doses and there was no discernible RIST4721 dose-related effect in this study. However, 
CXCR2-related cytokine (e.g., CXCL1, CXCL2, CXCL5, IL-8) levels were significantly higher 
in the blister exudate for RIST4721 300 mg compared to placebo at the 24-hour post-blister 
application timepoint, consistent with the mechanism of RIST4721. Less of an effect was 
observed at the 150 mg dose and differences between groups did not reach statistical 
significance for any parameter. Based upon these data and clinical effects observed with the 
300 mg dose in RIST4721-201, it appears that the minimally efficacious dose of RIST4721 is 
likely to be a QD dose between 150 mg and 300 mg RIST4721. Consequently, a daily dose of 
200 mg has been selected as the lower dose for investigation in the Phase 2 study RIST4721-
202. 
The higher dose level of 400 mg/day of RIST4721 was selected based on safety and PK data 
(including absorption, half-life, and bioaccumulation after repeated doses) from previously 
conducted studies. Modeling was conducted using the safety data of RIST4721 by dose in 
patients from Study RIST4721-201 coupled with data from normal healthy volunteers from 
completed Phase 1 studies with respect to the potential to develop an ANC of <1.0 x 109/L. The 
modeling results indicate that doses of 400 mg or higher provide greater estimated probabilities 
of reducing ANC to levels needed for maximal activity and doses of 400 mg or lower yield 
estimated probabilities of meeting the safety threshold at or below 5% if the mean baseline ANC 
is 3.0 x 109 cells/L or higher. These results suggest that a 400 mg dose of RIST4721 may be 
utilized for further clinical evaluation in populations with ANC ≥ 3.0 x 109 cells/L at study entry 
(refer to inclusion criterion number 7). 
4.4. 
Study Duration 
For each subject, the total study duration is expected to be as follows:  
Study Period 
Part A 
Part B 
Screening/observation period:  
4 weeks 
Not applicable 
Treatment period:  
12 weeks 
72 weeks 
Follow-up period 
4 weeks after last dose of study treatment 
4.5. 
End of Study Definition 
A subject is considered to have completed the study if he or she has completed all phases of the 
study, including the last visit or the last scheduled procedure shown in the SoA (Table 1 – Part 
A; Table 2 – Part B). 
For subjects who permanently discontinued treatment, the end of study will be defined if they 
completed the EOT visit and follow-up visit 4 weeks after the last dose of study treatment. 
The end of the study is defined as completion of the last visit or procedure shown in the 
corresponding SoA (Table 1 – Part A; Table 2 – Part B) for the last enrolled subject in the study 
globally for all sites. 

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5. 
STUDY POPULATION 
5.1. 
Inclusion Criteria 
To be eligible for participation in this study, subjects must meet all the following: 
Age and Sex 
1. Male or female subject aged ≥18 years and <75 years of age at the time of consent. 
Type of Subject and Disease Characteristics 
2. A confirmed diagnosis of PPP (sterile, macroscopically visible pustules on the palms 
and/or soles) for at least 6 months prior to screening based on documented clinical history 
(information obtained from medical chart or subject’s physician, or directly from the 
subject), with presence of active pustulation and without evidence of infection on palms 
and/or soles at screening. 
3. Moderate or severe PPP, as defined by PPPASI ≥12 and PPPGA ≥3 at screening and 
confirmed by central photographic assessment of PPGA at screening. Subjects must have 
an area involvement of at least 30% on 2 palmoplantar surfaces or at least 60% on one 
palmoplantar surface. 
4. At randomization visit, all of the following must be met: 
• PPPASI score must be ≥ 90% of the score at screening and PPPASI score of ≥12; 
• PPPGA score must be ≥3 and ≥ the score at screening; 
• PPPASI subscore of pustules/vesicles on at least one palm or sole ≥2. 
5. Candidate for systemic therapy, defined as having PPP inadequately controlled by topical 
treatment, phototherapy, and/or previous systemic therapy. Eligible subjects shall 
demonstrate a lack of response or tolerability to local standard of care therapy for PPP or 
be contraindicated to such therapies. 
6. Subject who wants to use an emollient should agree to use the same emollient, at the same 
frequency of application, for 7 days before Day 1/baseline and throughout the study. Note: 
On the day of scheduled visits, subjects cannot apply emollient before their scheduled visit 
time. For more information on concomitant therapies, please refer to Section 6.8. 
7. At screening, the results of the ANC performed at the central laboratory must be 
≥3.0 x 109 cells/L. 
8. Subject has been previously vaccinated for SARS-CoV-2 or has chosen not to be 
vaccinated at the start of participation (screening) in the clinical study. 
Contraception 
Contraception use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. Refer to Section 10.4 for 
more details. 
9. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at 
screening and negative urine pregnancy test at baseline, prior to randomization. 

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10. Female subject agrees to use a contraceptive method that is highly effective from consent 
until at least 5 days after the last study treatment administration 
11. Male subject agrees to use condom and spermicide from consent until at least 5 days after 
the last study treatment administration. 
Informed Consent 
12. Evidence of a personally signed and dated ICF indicating that the subject has been 
informed of all pertinent aspects of the study prior to initiation of any subject-mandated 
procedures. 
13. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, 
and other study procedures. 
5.1.1. 
Part B Inclusion Criteria 
In addition, to be eligible for participation in Part B, subjects must meet all the following at the 
extension enrollment visit: 
Subject and Disease Characteristics 
14. Must have completed Part A, been compliant with study procedures, and currently 
receiving study treatment (RIST4721 or placebo). 
15. Subject does not have any new or existing condition that, in the opinion of the investigator, 
would make participation not be in the best interest (e.g., compromise the well-being) of 
the subject or that could prevent, limit, or confound the protocol-specified assessments. 
Informed Consent 
16. Evidence of a personally signed and dated ICF indicating that the subject has been 
informed of all pertinent aspects of the study prior to initiation of any subject-mandated 
procedures. 
17. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, 
and other study procedures. 
 
5.2. 
Exclusion Criteria (Part A only) 
A subject must be excluded from participating in the study if he/she meets any of the following: 
Medical Conditions and Diagnostic Assessments 
1. Current diagnosis of superinfected hand dermatitis as a variant of contact or atopic hand 
dermatitis. 
2. Any condition that, in the opinion of the investigator, would make participation not be in 
the best interest (e.g., compromise the well-being) of the subject or that could prevent, 
limit, or confound the protocol-specified assessments, including, but not limited to: 
a. Evidence of erythrodermic, generalized pustular psoriasis, predominantly guttate 
psoriasis, or drug-induced psoriasis. 

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b. Concomitant active systemic autoimmune or chronic inflammatory disease, 
including but not limited to: inflammatory  bowel disease (Crohn’s disease or 
ulcerative colitis), rheumatoid arthritis, systemic lupus erythematosus, Sjogren’s 
syndrome, or multiple sclerosis. 
c. A history of synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO 
syndrome) or pustulotic arthro-osteitis (PAO syndrome). 
d. A history of skin disease or presence of skin condition (except psoriasis) that, in 
the opinion of the investigator, would interfere with the study assessments. 
e. Moderate to severe psoriasis, as defined by plaque psoriasis covering ≥10% of 
total body surface area (BSA) at Day 1. 
f. Pompholyx dermatitis. 
g. Known immune deficiency or is immunocompromised. 
h. History of cancer or lymphoproliferative disease within 5 years prior to Day 1. 
Subjects with successfully treated nonmetastatic cutaneous squamous cell or 
basal cell carcinoma and/or localized carcinoma in situ of the cervix are not to be 
excluded. 
i. Major surgery within 8 weeks prior to Day 1 or has a major surgery planned 
during the study, including planned dental procedures. 
j. Any clinically significant history of infection (except for localized controlled 
herpes simplex) within 4 weeks prior to Day 1. 
k. Uncontrolled thyroid disease (unless the subject is taking a stable dose of thyroid 
hormone or antithyroid medications [hyperthyroidism] for at least 12 weeks), 
which in the opinion of the investigator should exclude the subject from the 
study. 
l. Diagnosis of active peptic ulcer disease as determined by endoscopy, 
radiography, angiography, or other appropriate means within 12 months prior to 
screening. 
m. Primary coagulopathy excluding expected coagulation abnormalities due to 
concomitant pharmacotherapy. 
n. Significant central nervous system (CNS) effects including vertigo and dizziness, 
or major neurologic event, including cerebrovascular events, within 60 days of 
screening. 
o. QT corrected interval by Fridericia (QTcF) >440 msec as confirmed by triplicate 
ECG measurement at screening or Day 1 assessment. 
p. A positive test for drugs of abuse (amphetamines, methamphetamines, 
barbiturates, cocaine, phencyclidine [PCP], methadone, and opioids [narcotics]). 
Retest may be performed for potential false positive results with approval from 
the Sponsor’s Medical Monitor (or designee). 
q. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total 
bilirubin values ≥2 times the upper limit of normal (ULN), or other clinical 
evidence of significant hepatic impairment (e.g., ascites, peri-umbilical veins, 
esophageal varices) at screening. 
r. Serious hepatic disorder (Child-Turcott-Pugh scores B or C). 
s. History of clinically significant anemia or hemoglobin (Hgb) value ≤10 g/dL at 
screening. 

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t. Chronic kidney disease as per National Kidney Foundation stages >2: estimated 
glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m2. 
u. Positive results for hepatitis B surface antigens (HbsAg), antibodies to anti-core 
hepatitis B (HBc), hepatitis C virus (HCV), or human immunodeficiency virus 
(HIV) at screening (refer to Appendix 2, Section 10.2). 
v. Positive result indicating active  SARS-CoV-2 infection. 
w. History of malabsorption including bariatric surgery (gastric bypass). 
x. Any other clinically significant medical condition or 
ECG/physical/laboratory/vital signs abnormality that would, in the opinion of the 
investigator, put the subject at undue risk or interfere with interpretation of study 
results (e.g., celiac disease, streptococcal infection, allergy/delayed type 
hypersensitivity to tobacco and products within which tobacco is contained). 
3. Evidence of latent tuberculosis (TB) infection (either purified protein derivative [PPD] 
≥5 mm of induration or positive QuantiFERON-TB Gold test, irrespective of bacille 
Calmette-Guérin vaccination status). 
Note: Subject will be evaluated for latent TB infection with a PPD test or a 
QuantiFERON-TB Gold test if one has not been performed in the last 6 months. Subjects 
with documented completed treatment for latent TB will be allowed to participate in the 
study without retesting. 
4. Breastfeeding, pregnant, or planning to become pregnant during the study. 
Prior Therapy and Prior/Concurrent Clinical Study Experience 
5. Any topical medication (exception of emollients [see Section 6.8]) to treat PPP, including 
corticosteroids, dapsone, retinoids, vitamin D analogs (such as calcipotriol), or tar within 
2 weeks prior to Day 1. 
6. Any systemic treatment that affects PPP, including, but not limited to, corticosteroids, 
oral retinoids, immunosuppressive medication, methotrexate, cyclosporine, dapsone, 
colchicine, or apremilast within 4 weeks prior to Day 1. Note: Intranasal corticosteroids 
and inhaled corticosteroids for stable medical conditions are allowed if subject has been 
on a stable dose for at least 4 weeks prior to Day 1 and agrees to maintain the same dose 
for the duration of the study. Eye drops containing corticosteroids are allowed. 
7. Any ultraviolet (UV)-B phototherapy (including tanning beds) or excimer laser within 
4 weeks prior to Day 1. 
8. PUVA treatment within 4 weeks prior to Day 1. 
9. Use of any marketed or investigational biological agent within 12 weeks or 5 half-lives 
(whichever is longer) prior to screening. 
10. Currently receiving a nonbiological investigational product or investigational device or 
has received one within 4 weeks prior to Day 1. 
11. Received strong cytochrome P450 (CYP)3A inhibitors and/or CYP3A inducers within 4 
weeks prior to Day 1  
Examples of strong CYP3A inhibitors include but not limited to: cobicistat, boceprevir, 
ritonavir, indinavir, telaprevir, nelfinavir, danoprevir, dasabuvir, elvitegravir, lopinavir, 

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ombitasvir, paritaprevir, saquinavir, tipranavir, itraconazole, ketoconazole, posaconazole, 
voriconazole, troleandomycin, clarithromycin, idelalisib, conivaptan, nefazodone. 
Examples of strong CYP3A inducers include by not limited to: apalutamide, 
carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort. 
12. Received RIST4721 in prior study. 
Other Exclusion Criteria 
13. Excessive sun exposure or has used tanning booths within 4 weeks prior to Day 1, or 
subject is planning a trip where excessive sun exposure is expected or is not willing to 
minimize natural and artificial sunlight exposure during the study. Use of sunscreen 
products and protective apparel are permitted when exposure cannot be avoided. 
14. Consumption of any food or beverages containing cranberry, pomegranate, starfruit, 
grapefruit, pomelos, exotic citrus fruits, or Seville oranges (including marmalade and 
juices made from these fruits) within 7 days before baseline and unwillingness to avoid 
these during the study. 
15. Known or suspected allergy to RIST4721 or any component of the study treatment. 
16. Close affiliation with the investigator (e.g., a close relative), including any study staff of 
the sites, persons working at the contract research organization (CRO), or subject is an 
employee of Sponsor. 
17. Institutionalized because of legal or regulatory order. 
5.3. 
Lifestyle Considerations 
Subjects will be instructed to avoid food or beverages containing cranberry, pomegranate, starfruit, 
grapefruit, pomelos, exotic citrus fruits, or Seville oranges (including marmalade and juices 
made from these fruits) during the study. 
5.4. 
Screen Failure 
Screen failures are defined as individuals who consent to participate in the clinical study but are 
not subsequently randomly assigned to the study treatment. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements, and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs and SAEs. 
Retesting of abnormal laboratory parameters can be done during the initial screening period at 
the discretion of the investigator in consultation with the Sponsor’s Medical Monitor (or 
designee). 
Subjects who are not enrolled into the study can be rescreened for inclusion in the study one 
additional time. These subjects will be assigned a new screening number; such subjects will be 
determined a permanent screen failure after the second screening determines the subject is 
ineligible.  
 

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6. 
STUDY TREATMENT AND CONCOMITANT THERAPY 
6.1. 
Study Treatment Administered 
Table 4: 
Study Treatment Description 
Study Treatment Name 
Active: RIST4721  
(Part A and Part B) 
Control: Placebo  
(Part A only) 
Dose Formulation 
Blue, oval, biconvex film-coated tablets 
Matching tablets containing 
placebo 
Unit Dose Strength(s) 
100 mg per tablet 
placebo tablet 
Dose Regimen 
400 mg: 4 tablets QD (Part A and Part B) 
4 tablets QD 
200 mg: 2 active tablets QD + 2 placebo 
tablets (Part A only) 
 
Route of Administration 
and Instructions 
Oral. 
On Day 1, the clinical study team will instruct the subject how to 
administer the study treatment. 
RIST4721 should be taken QD with or without food. 
Sourcing 
Study treatment will be provided to the site centrally by the Sponsor or 
designated representative. 
Packaging 
RIST4721 and placebo tablets will be centrally sourced by the Sponsor in 
blister packages or bottles.   
Labeling 
Label text will at a minimum include the protocol number, lot number, 
storage conditions, and Sponsor name and address. Labels will comply with 
local regulatory requirements for study treatments. 
6.2. 
Shipping/Handling/Storage/Accountability 
All study treatment must be stored in a secure environmentally-controlled and monitored area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff. The study treatment may only be supplied by authorized site staff and may 
only be given to subjects enrolled into the study. 
All study treatment accountability forms and treatment logs must be retained in the 
investigator’s study files. Study treatment inventory and accountability records will be 
maintained as per International Council for Harmonisation (ICH) Good Clinical Practice (GCP). 
These records must be available for inspection at any time by the Sponsor, its designees, or by 
regulatory agencies. 
Further guidance and information for final disposition of study treatment are provided in the 
study manual. 

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6.3. 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1. 
Randomization and Stratification 
In Part A, Day 1, all subjects will be centrally randomized 1:1:1 to RIST4721 400 mg QD, 200 
mg QD, or placebo QD using interactive response technology (IRT). 
Randomization will be stratified by smoking status (current smoker vs. former or non-smoker). 
Before the study is initiated, appropriate IRT training, log-in information, and instructions will 
be provided to each site. 
6.3.2. 
Assignment of Subject Number 
At the study site, each screened subject will be assigned a subject identifier number during 
screening that will be used on all subject documentation. The subject identifier number will 
contain the site number and the subject number and will be assigned in numerical order at the 
screening visit based on chronological order of screening dates (e.g., 02-010 for the 10th subject 
screened at Site #02). 
6.3.3. 
Assignment of Study Treatment Kit Number 
Study treatment will be dispensed at the study visits as summarized in the corresponding SoA 
(Table 1 – Part A; Table 2 – Part B). The study treatment kit number(s) will be assigned by the 
IRT system upon obtaining the subject’s randomized treatment group. 
For subsequent visits when study treatment is dispensed, the IRT system will assign study 
treatment kits based on the subject’s randomized treatment group. 
6.3.4. 
Blinding and Unblinding of an Individual Subject 
The first 12 weeks of the study (Part A) will be double-blinded. Subjects, investigators, other site 
personnel, and Sponsor (and/or designee) personnel (except as described below) who are directly 
involved in the conduct of the study, collection of the data, and analysis of the data will remain 
blinded to treatment assignments until after a formal Part A unblinding has been performed 
(database lock). 
Sponsor (or designee) personnel will have access to unblinded individual subject treatment 
assignments for the purposes of study-required activities, including management of study 
treatment inventory, production of summaries of data for DRC review, and performance of 
bioanalytical analysis of PK. These personnel will not be directly involved in the conduct of the 
study. 
A non-independent, internal DRC will periodically convene to review unblinded overall safety 
and emerging efficacy results (refer to Section 9.6.1). 
The IRT system will be programmed with blind-breaking instructions. Blinding codes should 
only be broken in emergency situations for reasons of subject safety. If the blind is broken, the 
investigator should immediately inform (within 24 hours) the Sponsor’s Medical Monitor (or 
designee). The date, reason why the blind was broken, and the names of the personnel involved 
must be recorded in the source documentation. The date and reason why the blind was broken 
will also be collected in the electronic case report form (eCRF). The subject for whom the blind 

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has been broken will be discontinued from the study and undergo the EOT procedures as 
specified in SoA. 
Appropriate personnel at the Sponsor will unblind suspected unexpected serious adverse 
reactions (SUSARs) for the purpose of regulatory reporting. The Sponsor will submit SUSARs 
to regulatory agencies in blinded or unblinded fashion according to local law. The Sponsor will 
submit SUSARs to investigators in a blinded fashion. 
In order to reduce risk of breaking the blind, starting on Day 1 (baseline), investigators, the study 
staff, the CRO personnel, and the Sponsor’s study team will not receive absolute or relative 
neutrophil and WBC count results during Part A. A Medical Monitor will review the blinded 
data and ensure that the safety of all enrolled subjects is preserved. 
Absolute and relative neutrophil and WBC count results will only be disclosed to the respective 
investigators if the ANC reach values below the reference range of the lower limit of normal 
(LLN) for the central, in which case immediate actions will be taken, as described in Figure 2 
(Section 6.5.2). 
6.4. 
Study Treatment Compliance 
Study treatment compliance will be assessed, as appropriate, by direct questioning, and by 
maintaining adequate study treatment dispensing and return records. Deviation(s) from the 
prescribed dosage regimen will be evaluated. Subjects who demonstrate poor study treatment 
compliance (compliance under 80%) should be reeducated on the importance of taking their 
study treatment as prescribed. 
Subjects who are significantly noncompliant with study treatment (subject has missed 7 
consecutive days of dosing) will be counseled and could be discontinued from the study, at the 
discretion of the investigator, following consultation with the Sponsor. A subject will also be 
considered significantly noncompliant if he or she intentionally or repeatedly takes more or less 
than the prescribed amount of study treatment, as judged by the investigator. 
For all clinic visits, study treatment will be administered at the clinic to allow collection of blood 
samples for trough PK sampling predose. Date and time of the 2 doses prior to each PK sample 
will be recorded. 
Guidance for Missed Dose(s) 
If a dose is missed, subjects should be instructed to skip the missed dose if there are less than 
12 hours before the time of the next dose, and resume dosing at their next scheduled dosing time 
±2 hour. 
6.5. 
Stopping Rules and Dose Modifications 
Dose modification, as described below, may be considered for treatment-related AEs 
(Section 6.5.1) and ANC laboratory abnormalities (Section 6.5.2). 
Dose reduction will be performed via the IRT system. 
6.5.1. 
Treatment-related AEs 
Dose modification of study treatment may be undertaken only after consultation and approval 
from the Sponsor’s Medical Monitor (or designee) for moderate or severe AEs assessed by the 

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investigator as treatment-related, such as tolerability-related AEs. Subjects may be requested to 
attend an unscheduled visit after dose reduction to collect blood samples for safety and PK, if 
possible. 
6.5.2. 
Neutrophil Count Laboratory Abnormality 
There will be blinded evaluation of the neutrophil counts performed by an independent Medical 
Monitor in order to reduce the risk of breaking the blind in Part A.  
During Part A, investigators, the study staff, the CRO, and the Sponsor’s study team will not 
receive absolute and relative neutrophil or WBC count results. Absolute and relative neutrophil 
and WBC count results will only be disclosed to the respective investigators if ANC < LLN in 
which case immediate actions will be taken, as described in Figure 2. Retest results will be 
communicated to investigators who will follow up on neutrophil count and the incidence of 
infections in subjects having ANC results 1.0 x 109/L. Neutrophil count will be followed until 
resolution. 
Dose interruption of study treatment must be undertaken for confirmed ANC results 
1.0 x 109/L. Once the ANC result is above the LLN, subjects will re-initiate study treatment by 
reducing the study treatment dose as follows with approval from the Sponsor’s Medical Monitor 
(or designee). 
Part A; subject will receive blinded therapy as follows: 
• For subjects who are on placebo (4 tablets), they will receive placebo (4 tablets). 
• For subjects who are on RIST4721 400 mg (4 tablets), they will receive RIST4721 
200 mg dose (2 tablets of RIST4721 100 mg plus 2 tablets of placebo; total of 4 
tablets to maintain the blind). 
• For subjects who are on RIST4721 200 mg (2 tablets of RIST4721 100 mg plus 2 
tablets of placebo), they will receive 100 mg dose (1 tablet of RIST4721 100 mg plus 
3 tablets of placebo; total of 4 tablets to maintain the blind). 
Part B (all subjects will be receiving RIST4721 400 mg QD prior to dose reduction): 
• Subjects will receive RIST4721 200 mg QD (2 tablets of RIST4721 100 mg) 
Subjects may be requested to attend an unscheduled visit after dose reduction to collect blood 
samples for safety and plasma concentrations, if possible. 
For subjects who have already experienced a dose reduction during the study: If a subject 
experiences another case of ANC results 1.0 x 109/L, they must permanently discontinue study 
treatment (refer to Section 7.1). 

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6.6. 
Continued Access to Study Treatment After the End of the 
Study 
No additional intervention is planned beyond the end of Part B.  
6.7. 
Treatment of Overdose 
Study treatment overdose is defined as any accidental or intentional use of study 
treatment in an amount higher than the dose indicated per protocol for a given subject. 
Study treatment compliance (see Section 6.4) should be reviewed to detect potential 
instances of overdose (intentional or accidental). 
There is no specific treatment recommended to treat an overdose of study treatment, and 
the subject should receive treatment directed toward any symptoms manifested. 
In the event of an overdose, the investigator should: 
• Contact the Medical Monitor (or designee) as soon as possible. 
• Closely monitor the subject for any AEs/SAEs and laboratory abnormalities. 
• Document the quantity of the excess dose as well as the duration of the 
overdose. 
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor (or designee) based on clinical evaluation of the 
subject. 
All AEs associated with an overdose should be entered on the AE eCRF. If the AE 
associated with an overdose does not meet seriousness criteria, it must still be reported 
using the SAEs reporting procedures and in an expedited manner but should be noted as 
non-serious on the form and the AE eCRF. 
6.8. 
Concomitant Medications and Therapies 
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the subject is receiving at the time of 
enrollment or receives during the study must be recorded along with: 
• Name of medication/therapy (generic name) 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
Concomitant medications necessary for the health and well-being of the subject that do 
not interfere with study assessments and are not prohibited by protocol (see 
Section 6.8.2) are permitted during the study at the investigator’s discretion. This 
includes the use of appropriate medications for the treatment of AEs and/or concurrent 
illnesses under the direction of the investigator. All medications must be recorded in the 
source and on the appropriate eCRFs. 

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The Sponsor’s Medical Monitor (or designee) should be contacted if there are any 
questions regarding concomitant or prior therapy. 
6.8.1. 
Permitted Dermatologic Therapies 
• Emollients: Subjects can apply an emollient of their choice (except those 
containing any active ingredients) on their skin, including PPP lesions. 
Subjects who want to use an emollient should use the same emollient, at the 
same frequency of application for 7 days before Day1/baseline and throughout 
the study. However, on the day of scheduled visits, subjects cannot apply 
emollient before their scheduled visit time. 
• Intranasal corticosteroids and inhaled corticosteroids for stable medical 
conditions are allowed. Eye drops containing corticosteroids are allowed. 
• Hydrocortisone and desonide are allowed for psoriasis located on the face, 
genitals, groin, and inframammary areas as long as they are applied with 
gloves. 
• Shampoos containing tar, salicylic acid, or zinc pyrithione are also allowed, 
but they must be applied with gloves. 
• Use of sunscreen products and protective apparel are permitted when sun 
exposure cannot be avoided. 
6.8.2. 
Prohibited Medications 
Medications specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study. Table 5 lists prohibited medications that are not to be used from the 
defined washout periods from 4 weeks prior to Day 1 through the last study visit. 
Subjects who start prohibited medications or therapies as a treatment for PPP or other 
reasons during the study may be withdrawn from study treatment. If in doubt, 
investigators are advised to discuss medications with the Sponsor’s Medical Monitor (or 
designee). 

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• Moderate inhibitors of CYP3A, include but not limited to aprepitant, 
crizotinib, diltiazem, erythromycin, fluconazole, verapamil  
• Moderate inducers of CYP3A, including but not limited to bosentan, 
efavirenz, etravirine, phenobarbital, primodone 
• SARS-CoV-2 vaccines including those approved for emergency use or fully 
approved 

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7. 
DISCONTINUATION OF STUDY TREATMENT AND 
SUBJECT WITHDRAWAL FROM STUDY 
7.1. 
Discontinuation of Study Treatment and Withdrawal from the 
Study 
In some instances, it may be necessary for a subject to permanently discontinue study 
treatment. 
Dosing of study treatment must be interrupted for any SAEs assessed by the investigator 
as related to study treatment. Restart of dosing may be considered upon discussion with 
and approval by the Sponsor’s Medical Monitor (or designee) after resolution of study 
treatment-related events to baseline. 
Permanent discontinuation of study treatment does not mean withdrawal from Part A of 
the study, and the subject will be encouraged to remain in the study, complete Part A 
EOT visit at the time of study treatment discontinuation, and then continue to complete 
remaining study visits as per the SoA (Table 1). At subsequent visits, all study procedures 
will be completed per the SoA except for dispensation/return and accountability of study 
treatment. If a subject permanently discontinues study treatment prior to or at the Week 8 
visit and remains in the study through the Week 12 visit, the subject will not need to 
return for the follow-up visit. If a subject permanently discontinues study treatment after 
the Week 8 visit, the subject will attend an EOT visit and then will attend the follow-up 
visit 4 weeks after last dose of study treatment. Subjects who withdraw from the study, 
regardless of the reason, will be requested to return to the clinic to complete the EOT 
visit. 
Subjects who permanently discontinue RIST4721 during Part B will be withdrawn from 
the study, complete an EOT visit, and be asked to return for the follow-up visit per the 
SoA (Table 2 – Part B). 
Subjects have the right to withdraw from the study at any time and for any reason without 
prejudice to their future medical care by the investigator or at the institution. The reason 
for subject withdrawal from the study will be recorded in the eCRF. At the time of 
withdrawal from the study, an EOT visit should be conducted per the corresponding SoA 
(Table 1 – Part A; Table 2 – Part B). If a subject withdraws from the study, he/she may 
request destruction of any samples taken and not tested, and the investigator must 
document this in the site study records. 
A subject may discontinue study treatment or withdraw from the study for the following 
reasons: 
• Adverse event 
• Death 
• Lost to follow-up 
• Non-compliance with study treatment 
• Physician decision 

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• Pregnancy 
• Progressive disease 
• Protocol deviation 
• Withdrawal by subject  
• Study terminated by Sponsor 
 
The reason for subject discontinuation from study treatment or withdrawal from the study 
will be recorded in the eCRF. 
For neutrophil counts below 1.0 x 109/L, refer to Section 6.5.2 for more details regarding 
procedures to address neutrophil count and dose modification guidelines. 
Pregnancy is a mandatory criterion for permanent discontinuation of study treatment (see 
Section 7.1.2). 
Subjects who withdraw from the study or discontinue study treatment after randomization 
will not be replaced. 
7.1.1. 
Premature Termination of the Study 
The Sponsor may terminate this study prematurely for any reasonable cause. The 
Institutional Review Boards (IRB)/ Independent Ethics Committees (IEC) and regulatory 
authorities should be informed promptly. 
Conditions that may warrant termination include, but are not limited to: 
• The discovery of an unexpected, significant, or unacceptable risk to the 
subjects enrolled in the study, or potential study subjects 
• A decision on the part of the Sponsor to suspend or discontinue development 
of study treatment 
If the study is prematurely terminated or suspended for any reason, the 
investigator/institution should promptly inform the study subjects and ensure appropriate 
follow-up is provided for the subjects. 
7.1.2. 
Pregnancy 
A subject must permanently discontinue study treatment if she becomes pregnant. See 
Appendix 4 (Section 10.4.3) and Section 8.4.5 for additional details. 
See the SoA (Table 1) for data to be collected at the EOT visit. 
7.2. 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to engage for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 

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• 
The site will attempt to contact the subject and reschedule the missed visit. The 
site will then counsel the subject on the importance of maintaining the assigned 
visit schedule. 
• 
Before a subject is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the subject (where possible, 3 telephone 
calls and, if necessary, a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be 
documented in the subject’s medical record or study file. 
• 
If all attempts to contact the subject fail, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the corresponding SoA 
(Table 1 – Part A; Table 2 – Part B). Protocol waivers or exemptions are not 
allowed. 
• Immediate safety concerns should be discussed with the Sponsor immediately 
upon occurrence or awareness of occurrence to determine if the subject should 
continue or discontinue study treatment. 
• Adherence to the study design requirements, including those specified in the 
SoA (Table 1 – Part A; Table 2 – Part B), is essential and required for study 
conduct. 
• All screening evaluations must be completed and reviewed to confirm that 
potential subjects meet all eligibility criteria and randomization entry criteria. 
The investigator will maintain a log to record details of all subjects screened 
(including demographic data) and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the subject’s routine clinical management and 
obtained before signing the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA. 
• Clinical evaluations of PPP will be performed by an experienced and qualified 
dermatologist (board certified or eligible) or other suitably qualified and 
experienced designee. To assure consistency and reduce variability, the same 
assessor should perform all assessments on a given subject whenever possible. 
8.1. 
Key Screening Assessment(s) 
8.1.1. 
Psoriasis Area Severity Index (PASI) 
PASI quantifies the severity of a subject’s psoriasis based on both lesion severity and the 
percentage of BSA affected (Fredriksson, 1978; Marks, 1989). The PASI is a composite 
score ranging from 0 to 72 that that takes into account the degree of erythema, 
induration/infiltration, and desquamation (each scored from 0 to 4 separately) for each of 
four body regions, with adjustments for the percentage of BSA involved for each body 
region and for the proportion of the body region to the whole body. The PASI will be 
evaluated excluding lesions on palms and soles. 
8.2. 
Efficacy Assessments 
8.2.1. 
Palmoplantar Pustulosis Psoriasis Area Severity Index (PPPASI) 
The PPPASI is a scale from 0 to 72 that is used to evaluate the severity of PPP on palms 
and soles (Bhushan, 2001). Refer to Section 10.5 (Appendix 5) for a complete description 
of this scale.  

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All questions relate “to the last week”, and the score ranges from 0 (no impairment 
of life quality) to 30 (maximum impairment) (Finlay, 1994). 
• The SF-36 health survey is a validated questionnaire that includes 36 questions 
covering eight domains of health. 
• The PPQLI assesses relevant dimensions affected by palmoplantar psoriasis 
(pain/discomfort, functionality, and social/activity limitations) on a 1-5 scale 
(Farley, 2009). 
The questionnaires should be completed by the subjects at the scheduled visits before any 
other clinical assessments. The subjects should be given sufficient space and time to 
complete the questionnaires. The study coordinator should check the questionnaires for 
completeness and encourage the subjects to complete any missing responses. The 
questionnaires will be completed on an electronic device, e.g. tablet. 
Completed questionnaires will be reviewed and examined by the investigator for 
responses that may indicate potential AEs or SAEs. The investigator should review not 
only the responses to the questions in the questionnaires, but also any unsolicited 
comments written by the subjects. If AEs or SAEs are confirmed, the investigator must 
record the events as per instructions given in Section 8.4. Investigators should not 
encourage the subjects to change the responses reported in the questionnaires. 
8.2.6. 
Medical Photography 
Medical photographs of PPP areas will be performed on all subjects to confirm eligibility 
related to PPPASI and PPPGA for the study via central reading. In addition, photographs 
will be taken, labeled, and stored as instructed in the study reference manual. 
8.3. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Table 1 – Part A; 
Table 2 – Part B). Study procedures should be completed within the windows provided in 
the corresponding SoA and as specified in this section. 
8.3.1. 
Physical Examinations 
A complete physical examination will be performed and will include, at a minimum, 
assessments of: 
• General appearance 
• Dermatological system (except PPP) 
• Head, eyes, ears, nose, throat (HEENT) 
• Respiratory system 
• Cardiovascular system 
• Abdominal region 
• Neurological system 
• Musculoskeletal system 

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• Lymphatic system 
A symptom-oriented physical examination may be performed during the study, if deemed 
necessary by the investigator and may include: 
• General appearance 
• Dermatological system (except PPP) 
• Musculoskeletal system 
• Respiratory system 
• Cardiovascular system 
• Abdominal region 
Information for all physical examinations must be included in the source documents. If 
deemed appropriate by the investigator, clinically significant findings in the physical 
examination will exclude a subject from study participation. Any significant change will 
be reported as an AE in the source document and eCRF. 
8.3.2. 
Vital Signs 
• Vital signs (heart rate, respiratory rate, body temperature, and blood pressure) 
will be measured after the subject in a seated position after at least 5 minutes 
rest and prior to ECG measurements. 
• Blood pressure and heart rate measurements will be assessed with the subject 
in a sitting position using a completely automated device. Manual techniques 
will be used only if an automated device is not available. 
• Weight and height will be collected at screening, and weight will be measured 
as specified in the SoA (Table 1 – Part A; Table 2 – Part B). 
If deemed appropriate by the investigator, clinically significant findings in the vital signs 
will exclude a subject from study participation. Any abnormal finding related to vital 
signs that the investigator considers to be clinically significant must be recorded as an 
AE. 
8.3.3. 
Electrocardiograms 
Single 12-lead ECGs will be obtained and evaluated locally using an ECG machine that 
automatically calculates heart rate and measure PR, QRS, QT, and QTc intervals. 
In all cases in which an ECG has a potentially clinically significant finding, it will be 
repeated in triplicate within about 30 minutes and reviewed by the investigator or 
designee prior to subsequent dosing or study disposition decisions that do not constitute a 
subject emergency. 
Clinically significant findings in the ECG obtained at screening should exclude a subject 
from study participation (as deemed appropriate by the investigator). Any clinically 
significant change will be reported as an AE. 

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Subjects should be in the supine position after the subject has rested for at least 10 
minutes with minimal movement and minimal exposure to noise and other environmental 
stimuli (e.g., TV, loud radio, interactions with other subjects, etc.). In the event of 
possible ECG findings, additional ECG reads could be added at follow-up visit(s). 
Clinically significant ECG abnormalities will be recorded on the eCRF and in source 
documents. 
Original paper tracings and tracing copies of the ECGs, including the interpretation, 
should be stored in the source documents. If ECG is thermal paper, it should be 
photocopied and then signed and dated since it fades over time. 
8.3.4. 
Clinical Safety Laboratory Assessments 
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be 
performed. Details for collection, processing, and shipping of samples to the 
central laboratory are provided in a separate Laboratory Manual. 
• The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the eCRF. The signed laboratory reports must be filed with the 
source documents. Clinically significant abnormal laboratory findings are 
those which are not associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the subject’s condition. 
• All laboratory tests with values considered abnormal and clinically significant 
during participation in the study should be repeated per standard practices 
until the values return to normal or baseline or are no longer considered 
clinically relevant by the investigator or Sponsor’s Medical Monitor (or 
designee). 
Note: If such values do not return to normal/baseline within a period of time 
judged reasonable by the investigator, the etiology should be identified and 
the Sponsor notified. 
• If laboratory values from non-protocol-specified laboratory assessments 
performed at the institution’s local laboratory require a change in subject 
management or are considered clinically significant by the investigator, then 
the events must be recorded in the eCRF and retained in source documents. 
• In case of a screening laboratory value abnormality, the test can be repeated 
within the original screening time window, if the investigator believes there is 
a reasonable possibility that the subject would be eligible if re-tested. 
• If deemed appropriate by the investigator, clinically significant findings in 
clinical laboratory testing will exclude a subject from study participation. Any 
clinically significant change will be reported as an AE. 
8.4. 
Adverse Events and Serious Adverse Events 
The definitions of an AE and SAE can be found in Appendix 3 (Section 10.3). 

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AEs will be reported to the investigator by the subject (or, when appropriate, by a 
caregiver, surrogate, or the subject’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of AE and SAE. 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
AEs will be collected from consent until the end of study follow-up. SAEs will be 
collected beginning at the time of consent until the end of study follow-up. All medical 
occurrences, with the exception of SAEs, that begin after obtaining ICF and before the 
first dose of study treatment will be recorded on the Medical History/Current Medical 
Conditions section of the eCRF and not the AE section. 
All SAEs will be recorded and reported to the Sponsor or designee immediately upon the 
site learning of an event, and under no circumstance should the initial notification exceed 
24 hours, as indicated in Appendix 3 (Section 10.3). The investigator will submit any 
updated SAE data to the Sponsor or designee within 24 hours of it being available. 
Investigators are not obligated to actively seek AEs or SAEs that start after conclusion of 
study participation. However, if the investigator learns of any SAE, including a death, at 
any time after a subject has been withdrawn from the study, and he/she considers the 
event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the Sponsor. 
8.4.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3 
(Section 10.3). 
Care is to be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire 
whether AEs occurred. 
8.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the subject is lost to follow-up (as 
defined in Section 7.2). Further information on follow-up procedures is given in 
Appendix 3 (Section 10.3). 
8.4.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification of an SAE by the investigator to the Sponsor is essential 
so that the Sponsor’s legal obligations and ethical responsibilities toward the 
safety of subjects and the safety of study treatment under clinical investigation 
can be met. 
• The Sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The Sponsor will comply with country-specific 

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regulatory requirements relating to safety reporting to regulatory authorities, 
IRB/ IEC, and investigators. 
• Investigator safety reports must be prepared for SUSARs (defined in 
Section 10.3.3) according to local regulatory requirements and Sponsor policy 
and forwarded to investigators as necessary. 
• An investigator who receives an investigator safety report describing an SAE 
or other specific safety information (e.g., summary or listing of SAEs) from 
the Sponsor will review and then file it along with the IB and will notify the 
IRB/IEC, if appropriate, according to local requirements. 
8.4.5. 
Pregnancy 
• Details of all pregnancies will be collected as outlined in Appendix 4 
(Section 10.4). 
• If a pregnancy is reported, the investigator should inform the Sponsor within 
24 hours of learning of the pregnancy and should follow the procedures 
outlined in Appendix 4 (Section 10.4). 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, elective 
termination of a pregnancy, fetal death, stillbirth, congenital anomalies, 
ectopic pregnancy) are considered SAEs. 
8.4.6. 
Death Events 
Timelines for reporting of death events are identical to the requirements for SAE 
reporting. (Appendix 3, Section 10.3). 
8.5. 
Pharmacokinetics, Biomarkers, and Pharmacodynamics 
8.5.1. 
Pharmacokinetics 
Blood samples will be collected for measurement of plasma concentrations of RIST4721 
and its metabolites, if applicable, as specified in the SoA (Table 1 – Part A). On clinic 
visits, subjects will be requested to hold their study treatment dose until after PK samples 
are obtained. The actual time and date of each sample collection will be recorded in 
eCRF. The actual time and date of the completion of dosing on the PK days and the dates 
and approximate times of the last 2 doses before the PK days will be recorded in eCRF. A 
more detailed description of plasma sample preparation will be provided in the 
Laboratory Manual. 
In case of the occurrence of a potentially related SAE, an unscheduled plasma sample for 
determination of RIST4721 plasma concentration should be collected as soon as possible. 
The approximate time of administration of the dose of study treatment prior to obtaining 
the sample should be recorded. 
PK samples will be analyzed with a validated method; for metabolites, the samples may 
be analyzed with a fit-for-purpose method(s). The samples may be used for metabolite 
profiling or bioanalytical method development and validation. PK samples will only be 
analyzed for subjects who received active treatment with RIST4721, i.e., placebo subjects 

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will not have their samples analyzed. For RIST4721 treated subjects, the baseline (i.e., 
blank) sample taken prior to initiating therapy will not be analyzed unless necessary to 
investigate any unusual findings with the on-treatment samples.  
8.5.2. 
Serum Biomarkers 
Serum biomarkers will be collected as specified in the SoA (Table 1 – Part A; Table 2 – 
Part B) and stored for analysis. 
Details about the collection, processing, handling, storage, and shipping of biomarker 
samples will be provided in the Laboratory Manual. 
 
8.5.3. 
Biomarkers from Skin Tape Strips (Part A only) 
Skin tape discs will be collected from all subjects, at selected sites, for whole RNA 
transcript analysis at the timepoints outlined in the SoA (Table 1 – Part A). The purpose 
of these analyses will be to retrospectively evaluate biomarkers predictive of subject 
response at baseline, before study treatment administration, as well as to potentially 
identify additional correlative and pharmacodynamic biomarkers. 
Samples are to be collected from the active periphery of the target palm or sole after a 
photograph of the target lesion has been taken. The areas where samples were collected 
will be documented in the subject’s medical record at each subsequent visit.  
All samples collected must be from the same location; the skin tape disc sample will 
continue to be collected from that original target palm or sole. 
8.5.4. 
Storage and Handling of Blood Samples 
Blood samples may be stored according to local regulations for a maximum of 15 years at 
a facility selected by the Sponsor or destroyed at the end of the study. 

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9. 
STATISTICAL CONSIDERATIONS 
Statistical considerations are summarized here. A detailed description of statistical 
methods will be provided in the Statistical Analysis Plan (SAP). 
9.1. 
Sample Size Determination 
Assuming proportion of subjects achieving a 50% reduction in PPPASI score at Week 12 
for RIST4721 400 mg arm and placebo arm are 60% and 25% respectively, 47 subjects 
per arm will have 90% power to detect the difference at 2-sided alpha=0.05 based on a 
Chi-square test. Adjusting for 10% drop-out, 52 subjects per arm will be randomized for 
the study. 
9.2. 
Population for Analyses 
The following populations are defined: 
Study Population 
Definitions 
Full Analysis Set 
The Full Analysis Set will include all subjects who are 
randomized. Subjects will be classified according to the 
treatment and stratum assigned at randomization. The Full 
Analysis Set will be the primary population for evaluating 
all efficacy endpoints and subject characteristics. 
Per-protocol Analysis 
Set 
The Per-protocol Analysis Set is a subset of the Full 
Analysis Set and will include subjects who receive at least 
1 dose of study treatment and do not have major protocol 
deviations expected to impact the primary objective of the 
study. Major protocol deviations will be pre-specified in 
the SAP. The Per-protocol Analysis Set will be used for 
sensitivity analyses for the primary efficacy endpoint. 
Safety Analysis Set 
The Safety Analysis Set will include all subjects who 
receive at least 1 dose of study treatment. Subjects will be 
classified according to the treatment assigned at 
randomization unless the incorrect treatment(s) are received 
throughout the dosing period in which case subjects will be 
classified according to the first treatment received. The 
Safety Analysis Set will be the primary population for 
evaluating treatment administration/compliance and safety. 
PK Analysis Set 
The PK Analysis Set will include all treated subjects who 
have at least 1 concentration above the below limit of 
quantitation (BLQ) of the study treatment in RIST4721 
arms only. 
 

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9.3. 
Statistical Analyses 
9.3.1. 
Study Reporting 
There will be two reporting events for this study, one reporting for Part A data and 
another reporting for Part B data. For Part A reporting, when all subjects complete Part 
A, data from Part A will be cleaned and locked at the subject level. The study will be 
unblinded for Part A reporting purposes. For Part B reporting, when all subjects complete 
Part B, data from Part B will be cleaned and the database will be locked. 
9.3.2. 
General Considerations 
All individual data will be listed as measured. All statistical summaries and analyses will 
be performed using SAS software 
. 
Unless specified otherwise, all statistical analyses will be performed using a 2-sided 
hypothesis test at the 5% level of significance. Continuous data will be presented using 
descriptive statistics: number of subjects (n), mean, standard deviation (SD), median, 
minimum, and maximum. Descriptive statistics on continuous efficacy measures will also 
include the standard error (SE) or 95% confidence interval (CI) when needed. Categorical 
data will be summarized by the number and percent of subjects. Time-to-event data will 
be summarized using the median (if estimable) and the 25th and 75th percentiles. CIs will 
be 95% and two-sided, unless otherwise stated. All efficacy and safety data will be 
summarized by treatment group and study part (Part A or Part B). For Part B reporting, 
treatment groups based on study randomization and overall (all three treatment groups 
combined) will be included. 
For Part A, baseline will be defined as the last observed values prior to randomization. 
For Part B, baseline of efficacy endpoints will be RIST4721 baseline (before start of 
active treatment), and baseline of safety endpoints (e.g., lab parameters) will be defined 
as the last observed values on or prior to the Extension Enrollment visit.  
For Part A reporting, statistical modeling and testing as described in the sections below 
will apply to Part A efficacy data analyses. For Part B reporting, only descriptive 
summary statistics will be used.  
9.3.3. 
Efficacy Analysis 
9.3.3.1. 
Analysis of Primary Endpoint 
Primary efficacy endpoint analyses will be performed using the estimand framework 
defined in Section 3. 
The primary endpoint, proportion of subjects achieving a 50% reduction in PPPASI score 
at Week 12, will be analyzed using a logistic regression model. The model will include 
stratification (current smoker vs. former or non-smoker) and treatment (all 3 arms) as 
explanatory variables. 
The null hypothesis for the study is to test if treatment effect of RIST4721 400 mg is 
equal to placebo control. Logistic regression parameter for the difference between 
RIST4721 400 mg and placebo will be tested by a Wald Chi-Square test at 2-sided 
alpha=0.05. Odds ratio of the two arms will also be presented. 

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A stepdown procedure will be used to control the type I error. If 400 mg is significantly 
different from placebo, logistic regression parameter for the difference between 
RIST4721 200 mg and placebo will then also be tested by a Wald Chi-Square test at 2-
sided alpha=0.05. Odds ratio of the two arms will also be presented. 
Subjects who withdraw from the study prior to Week 12 due to any reason (AE, death, 
lack of efficacy, withdrawal informed consent, and others) will be imputed as non-
responders for the primary analyses. Subjects who permanently discontinue study 
treatment but continue in the study will have their response statuses derived based on 
their observed data. 
Logistic regression model without stratification will be conducted as a sensitivity 
analysis. 
9.3.3.2. 
Analyses of Key Secondary Endpoints 
Subjects achieving PPPGA of 0 or 1 at Week 12 will be analyzed using the same logistic 
regression model as in the analyses of the primary endpoint. 
Subjects achieving a 75% reduction in PPPASI score at Week 12 will be analyzed using 
the same logistic regression model as in the analyses of the primary endpoint. 
9.3.3.3. 
Type I Error Control for Primary and Key Secondary Endpoints 
Type I error for the primary endpoint analyses will be controlled by a stepdown 
procedure. Only when the primary comparison between 400 mg and placebo is 
statistically significant at 2-sided alpha=0.05, comparison between 200 mg and placebo 
will then be conducted. 
When both of the above comparisons are significant, treatment comparisons on  subjects 
achieving PPPGA of 0 or 1 at Week 12 will be conducted, starting with 400 mg vs 
placebo, then 200 mg vs placebo. 
9.3.3.4. 
Analyses of Other Efficacy Endpoints 
Absolute change from baseline of PPPGA and PPPASI score will be analyzed using 
mixed-effects model for repeated measures (MMRM). The MMRM model will include 
stratification, visit, and treatment as fixed effects, baseline score as a covariate, 
interaction between visit and treatment, and interaction between visit and baseline score. 
Other secondary efficacy endpoints will be analyzed using the same logistic regression 
model if it is a dichotomous endpoint and MMRM model if it is a continuous endpoint. 
Descriptive summary statistics (e.g., n, mean, SD, median, minimum, and maximum for 
continuous variables; n [%] for categorical variables) will be provided for the exploratory 
endpoints.  
9.3.4. 
Safety Analyses 
9.3.4.1. 
Adverse Events 
AEs verbatim descriptions will be coded using a current version of the Medical 
Dictionary for Regulatory Activities (MedDRA). A TEAE will be defined as an AE that 

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is new or worsening after the subject has received the first dose of study treatment and 
with onset within 30 days after the last dose of study treatment. 
An overall summary of subjects with AEs, TEAEs, and SAEs will be tabulated with 
numbers and percentages of subjects and repeated for severity and relationship to study 
treatment per treatment group. A subject will be counted only once by the highest 
severity grade within an SOC and preferred term, even if the subject experienced more 
than 1 TEAE within a specific SOC and preferred term. The number of TEAEs leading to 
withdrawal and SAEs leading to death will also be summarized. 
The incidence of TEAEs and SAEs will be summarized by body system and treatment 
group. All AEs and SAEs will be listed by subjects. 
9.3.5. 
Clinical Laboratory Tests 
Clinical laboratory (e.g., hematology, clinical chemistry, coagulation, and urinalysis) 
values will be evaluated for each laboratory parameter as appropriate. Abnormal 
laboratory values will be flagged and identified as outside (above or below) the normal 
range. Reference (normal) ranges for laboratory parameters will be provided. 
Descriptive summary statistics (e.g., n, mean, SD, median, minimum, and maximum for 
continuous variables; n [%] for categorical variables) for laboratory parameters and their 
changes from baseline will be calculated. Laboratory values will be summarized by visit. 
9.3.6. 
Electrocardiograms 
QT intervals will be corrected for heart rate (QTc) using standard correction factors (e.g. 
QTcF). Data will be summarized for QT, HR, RR, PR, QRS, and QTc. A categorical QTc 
analysis will also be performed by treatment and visit. 
12-lead ECG data will be listed by subject and visit. 
9.3.7. 
Vital Signs 
Descriptive summary statistics for vital sign parameters (systolic and diastolic blood 
pressure, heart rate, respiratory rate and body temperature) and changes from baseline 
will be presented by visit.  
Vital signs data will be listed by subject and visit. 
9.3.8. 
Treatment Exposure and Disposition 
Exposure to treatment will be summarized descriptively, and compliance on treatments 
for both active and placebo will be evaluated. 
Summary tables for subject disposition and population assignment will be provided. 
9.4. 
Plasma Concentration Analyses 
RIST4721 plasma concentration data will be listed per subject and summarized 
descriptively. 

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9.5. 
Pharmacodynamic Analyses 
Biomarker analysis from serum and skin tap strips will be summarized using a MMRM 
with change from baseline as the response variable. The model will include fixed 
covariates for treatment group, week, and baseline biomarker, and a random effect for 
subject. 
9.6. 
Planned Interim Analyses 
No interim analysis is planned for this study. 
9.6.1. 
Data Review Committee 
A non-independent, internal DRC comprised of Sponsor representatives not directly 
involved in the conduct of the study, and/or external expert physician(s), will regularly 
monitor overall safety and emerging efficacy results on an unblinded basis, as well as 
general aspects of study conduct, to ensure that the benefits and risks of study 
participation remain acceptable. 
Based on these regular reviews of emerging results, the DRC will recommend 
continuation, modification, or termination of the study. The DRC charter will include 
potential reasons for modifications and/or termination of the study. 
Composition of the DRC, meeting structure, schedule, and procedures, the content and 
format of DRC reports, and other relevant details will be determined in consultation with 
DRC members and detailed in a separate DRC charter. 

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations (Site Responsibilities) 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines. 
• Applicable ICH GCP Guidelines (E6 R2). 
• Applicable laws and regulations. 
The protocol, protocol amendments, ICF, IB, and other relevant subject-facing 
documents (e.g., surveys, instructions for use, advertisements) must be submitted to an 
IRB/IEC by the investigator and reviewed and approved by the IRB/IEC before the study 
is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study subjects. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of title 21 Code of Federal Regulations (CFR) (or equivalent as 
applicable), ICH guidelines, the IRB/IEC, European regulation 536/2014 for 
clinical studies (if applicable), and all other applicable local regulations. 
10.1.2. 
Informed Consent Process 
Prior to enrolling in the study, and before performance of any procedures, potential 
subjects will attend a screening session at which time they will be provided with full 
information concerning details of the study assessments and procedures. The investigator 
or his/her representative will explain the nature of the study to the subject or his/her 
legally authorized representative and answer all questions regarding the study. 
Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, ICH guidelines, local regulations, and data privacy 
laws (e.g., The General Data Protection Regulation (EU) 2016/679 [GDPR] and  Health 

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Insurance Portability and Accountability Act [HIPAA]) requirements, where applicable, 
and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained 
before the subject entered the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
Subjects entering Part B will sign an OLE-specific ICF. 
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative. 
10.1.3. 
Data Protection 
Subjects will be assigned a unique identifier by the Sponsor. Any subject records or 
datasets that are transferred to the Sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred. 
The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law(s). The level of disclosure must also 
be explained to the subject. 
The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.4. 
Dissemination of Clinical Study Data 
A clinical study report will be developed by the Sponsor at completion of data analysis. 
This report will be an integrated clinical and statistical report prepared according to the 
ICH E3 guidelines. 
Sponsor will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations. 
10.1.5. 
Data Quality Assurance 
All subject data relating to the study will be recorded on printed or electronic CRFs 
unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
The investigator must maintain attributable, legible, contemporaneous, original, and 
accurate documentation (source data) that supports the information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Details describing monitoring strategy (e.g., risk-based initiatives in operations and 
quality such as risk management and mitigation strategies and analytical risk-based 
monitoring), methods, responsibilities and requirements, including handling of 

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noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan. 
The Sponsor or designee is responsible for the data management of this study including 
quality review of the data. 
The Sponsor maintains ultimate responsibility for the quality and integrity of study data, 
even if study-related duties and functions are transferred to other individuals or 
organizations (e.g., contractors or contract research organizations). 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are attributable, legible, contemporaneous, 
original, and accurate from source documents; that the safety and rights of subjects are 
being protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and applicable regulatory 
requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator per ICH GCP and local regulations or institutional 
policies. No records may be destroyed during the retention period without the written 
approval of the Sponsor. No records may be transferred to another location or party 
without written notification to the Sponsor. 
10.1.6. 
Source Documents 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents should be generated utilizing good 
documentation practices and are filed at the investigator’s site. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained. These include but are not limited to hospital records, clinical and 
office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, and 
correspondence. 
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available. 
10.1.7. 
Study and Site Closure 
The Sponsor or designee reserves the right to close the study site or terminate the study at 
any time for any reason at its sole discretion. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 

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Reasons for the early closure of a study site by the Sponsor or investigator may include 
but are not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP 
guidelines 
• Inadequate recruitment of subjects by the investigator 
• Discontinuation of further study treatment development. 
10.1.8. 
Publication Policy 
The publication policy is located within the Clinical Study Agreement with the 
investigator and/or Institution. 
 

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10.2. 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 7 will be performed by the central laboratory, 
unless otherwise noted. 
• Protocol-specific requirements for inclusion or exclusion of subjects, 
including those based on selected laboratory test results, are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
• Investigators must document their review of each laboratory safety report in 
subject’s source records. 

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10.4. 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information 
10.4.1. 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterilized (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study treatment, additional evaluation should be 
considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry eligibility. 
Note: Documentation can come from the site personnel’s review of the subject’s medical 
records, medical examination, or medical history interview. 
Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
− A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement is required. 
• Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
10.4.2. 
Contraception Guidance 
There is no known drug interaction between RIST4721 and hormonal contraception. 

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Male Subjects: 
Male subjects are eligible to participate if they agree to the following from informed 
consent through 5 days after the last dose of study treatment: 
• Be abstinent and agree to remain abstinent 
OR 
• Must agree to use contraception/barrier (a male condom) and spermicide  
OR 
• Be surgically sterile 
Female Subjects: 
• A female subject is eligible to participate if she is not pregnant or 
breastfeeding, and at least one of the following conditions applies: 
− Is not a woman of childbearing potential (WOCBP) 
OR 
− Is a WOCBP and using a contraceptive method that is highly effective 
(with a failure rate of <1% per year), preferably with low user dependency 
(see table below), from consent through 5 days after the last dose of study 
treatment, and agrees not to donate eggs (ova, oocytes) for the purpose of 
reproduction during this period. The investigator should evaluate the 
effectiveness of the contraceptive method in relationship to the first dose of 
study treatment. 
− A WOCBP must have negative serum pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) at 
screening and a negative urine pregnancy test before first administration of 
study treatment. On-treatment urine pregnancy tests will be done routinely 
as specified in the SoA. If the urine test is positive or cannot be confirmed 
as negative, a serum pregnancy test is required and results must be 
negative. 
Contraceptive use by men or women should be consistent with local regulations 
regarding the use of contraceptive methods for those participating in clinical studies. 

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Highly Effective Methodsa That Have Low User Dependency  
• Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationb 
• Intrauterine device (IUD) (hormonal and non-hormonal) 
• Surgical sterilization 
• Bilateral tubal occlusion or ligation 
• Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used. Spermatogenesis cycle is approximately 90 days.) 
Highly Effective Methodsa That Are User-Dependent  
• Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation 
− oral 
− intravaginal 
− transdermal 
− injectable 
• Progestogen-only hormone contraception associated with inhibition of ovulationb 
− oral 
− injectable 
• Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the subject.) 
a Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from 
those when used consistently and correctly. 
b If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of 
contraception for this study. Male condom and female condom should not be used together (due to risk of 
failure with friction). 
 

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10.4.3. 
Collection of Pregnancy Information 
Male subjects with partners who become pregnant: 
• The investigator will attempt to collect pregnancy information on any male 
subject’s female partner who becomes pregnant while the male subject is in 
this study. 
• After obtaining the necessary signed ICF from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate 
form and submit it to the Sponsor within 24 hours of learning of the partner’s 
pregnancy. The Sponsor will attempt to follow the female partner to determine 
the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to the Sponsor. The Sponsor will follow the female 
partner until birth or termination of pregnancy when possible. Any 
termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
Female subjects who become pregnant 
Any female subject who becomes pregnant while participating in the study will 
discontinue study treatment(s). Additionally: 
• The investigator will collect pregnancy information, which will be recorded 
on the appropriate form and submitted to the Sponsor within 24 hours of 
learning of a subject's pregnancy. 
• The subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the subject and the neonate 
and the information will be forwarded to the Sponsor. The subject will be 
followed until birth or termination of pregnancy. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE 
or SAE. A spontaneous abortion is always considered to be an SAE and will 
be reported as such. Any post study pregnancy related SAE considered 
reasonably related to the study treatment by the investigator will be reported 
to the Sponsor as described in Section 10.3.5. While the investigator is not 
obligated to actively seek this information in former study subjects, he or she 
may learn of an SAE through spontaneous reporting. 

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10.5. 
Appendix 5: Palmoplantar Pustulosis Psoriasis Area and 
Severity Index (PPPASI) Scoring 
Left palm, right palm, left foot, and right foot are assessed based on 3 target symptoms: 
erythema, desquamation (scaling), and pustules, as seen on the day of the examination. 
 
The severity of each sign is assessed using a 5-point scale: 
• 0 = not present 
• 1 = slight 
• 2 = moderate 
• 3 = severe 
• 4 = very severe 
 
The affected area within a given anatomic site (left palm, right palm, left foot, and right 
foot) is estimated as a percentage of the total area of that anatomic site and assigned a 
numerical value according to the degree of PPP involvement as follows: 
• 0 = no involvement 
• 1 =  10% involvement 
• 2 = 10 to  30% involvement 
• 3 = 30 to  50% involvement 
• 4 = 50 to  70% involvement 
• 5 = 70 to  90% involvement 
• 6 = 90 to  100% involvement 
 
The PPPASI score can vary from 0 (absence of disease) to 72 (most severe disease). 
 
The PPPASI score for palms and soles is obtained by using the formula below: 
 
PPPASI =  0.2 (E + P + D) AR palm + 0.2 (E + P + D) AL palm + 0.3 (E + P + D) AR sole +  
0.3 (E + P + D) AL sole. 
 
Where E, D, P, A, L, and R denote erythema, desquamation, pustules, PPP involvement, 
left, and right, respectively. 
 

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10.6. 
Appendix 6: Guidance to Address the COVID-19 Pandemic 
and Potential Impact on the Clinical Study 
In the occurrence of a global health emergency affecting the conduct of the ongoing 
study, such as the COVID-19 pandemic, study conduct may be adjusted due to subjects 
being in self-isolation/quarantine, limited access to public places (including hospitals) 
due to the risk of spreading infections, and health care professionals being committed to 
critical tasks. 
Adjustments to this protocol may be made as described below, in line with global 
regulatory authorities’ guidance in order to ensure the safety of study subjects, maintain 
compliance with GCP, and minimize the risks to study integrity during the COVID-19 
pandemic (Health Canada, April 7, 2020; Australian Government, April 9, 2020; EMA, 
April 2020; MHRA, March 19, 2020; FDA, March 2020). Other countries may issue their 
own guidance requiring country-specific recommendations to be followed. 
Informed Consent 
• If written consent by the study subject is not possible (e.g., because of 
physical isolation due to COVID-19 or other global health emergencies), 
consent could be given orally by the study subject and documented according 
to regulatory guidance. 
• Study subjects and the person obtaining consent could sign and date separate 
ICFs. 
• In case written informed consent cannot be obtained at the clinical site, 
electronic informed consent can be obtained remotely. Alternatively, the 
consent form may be sent to the subject or the subject’s legally authorized 
representative by facsimile or e-mail, and the consent interview may then be 
conducted by telephone/teleconference when the subject or subject’s legally 
authorized representative can read the consent form during the discussion; the 
subject or subject’s legally authorized representative will be requested to sign 
and date a blank piece of paper with a written statement affirming that they 
agree to participate in the study and documented according to regulatory 
guidance. 
• If re-consent is necessary for the implementation of new urgent changes in 
study conduct (mainly expected for reasons related to global health 
emergencies or important safety issues for other studies), alternative ways of 
obtaining consent may include contacting the study subject via phone or 
video-calls and obtaining verbal consent, to be documented in the study 
subjects’ medical records, supplemented with e-mail confirmation. 
• The informed consent procedure is to remain compliant with the study 
protocol as well as local regulatory requirements. All relevant records should 
be archived in the investigator's site master file. A correctly signed and dated 
ICF should be obtained from the study subjects later, as soon as possible. 

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Study Visits and Procedures 
• COVID-19 screening procedures that may be mandated by the health care 
system in which a clinical study is being conducted do not need to be reported 
as an amendment to the protocol even if done during clinical study visits. The 
investigator in consultation with the Sponsor will decide if it is in the best 
interest of COVID-19-positive subjects to remain in the study. 
• In the case of missed visits due to global health emergencies (or other 
pandemic-related reasons): 
− The site should make every effort to contact the study subject to confirm 
and document the reason for the missed visit and at minimum, evaluate 
AEs/SAEs, and concomitant medications to assess subject safety. 
• In order to maintain the integrity of the study, alternative methods of 
collecting study procedures may be considered where possible: 
− In cases where global health emergencies-related circumstances preclude a 
visit to the investigative site, remote visits (e.g., by telemedicine or phone 
contact) will be allowed for relevant study procedures. 
− In certain situations, with Sponsor approval, and according to site business 
continuity plans, home visits may be used, e.g., to collect laboratory 
samples and assessments as required by the protocol. 
− Study assessments will only be conducted in a remote manner if they can 
be done without affecting the well-being of the subject during the study 
and with the same level of scientific integrity as assessments conducted in 
a physical study center. 
− Remote study assessments can be completed via online technology. The 
subject may interact with study personnel using online communication 
tools that incorporate telemedicine. 
− In certain situations, with Sponsor approval, a local laboratory may be 
used to collect laboratory samples as required by the protocol. Local 
analysis can be used for safety decisions. 
− Urine pregnancy tests can be performed if serum pregnancy cannot be 
performed. 
Supply of Study Treatment 
• Alternative methods of supplying study treatment to enrolled study subjects 
(e.g., direct-to-patient shipment from site) may be considered where possible. 
• Additional study treatment will not be released to the subject without an 
evaluation of subject safety, including protocol-required laboratory results (at 
a minimum hematology, clinical chemistry, and pregnancy for WOCBP), and 
clearance communicated to the subject. Subjects must also consent for study 
treatment shipment. 

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Monitoring and Audits 
• Certain Sponsor oversight responsibilities, such as monitoring and quality 
assurance activities, may need to be re-assessed and temporary, alternative 
proportionate mechanisms of oversight may be required. On-site audits will be 
avoided or postponed, and if permitted under local regulations, social 
distancing restrictions should apply. 
• Canceling or postponing on-site monitoring visits and extending the period 
between monitoring visits will be allowed. 
• To the extent on-site monitoring remains feasible, it should take into account 
national, local, and/or organizational social distancing restrictions. 
• Centralized monitoring can be considered for data acquired by electronic data 
capture systems (e.g., eCRFs, central laboratory or ECG data, electronic 
patient reported outcomes) that are in place or could be put in place, providing 
additional monitoring capabilities that can supplement and temporarily replace 
on-site monitoring through remote evaluation of ongoing and/or cumulative 
data collected from study sites, in a timely manner. 
• Off-site monitoring can be conducted and will include phone calls, video 
visits, e-mail, or other online tools in order to discuss the study with the 
investigator and site staff. Remote monitoring should be focused on review of 
critical study site documentation and source data. These activities could be 
used to get information on the clinical study progress, to exchange 
information on the resolution of problems, review of procedures, study subject 
status, as well as to facilitate remote site selection and investigator training for 
critical study procedures. 
Risk Mitigation 
• The Sponsor will continually assess whether the limitations imposed by the 
COVID-19 public health emergency on protocol implementation pose new 
safety risks to study subjects, and whether it is feasible to mitigate these risks 
by amending study processes and/or procedures. 
 

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10.8. 
Appendix 8: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). Prior amendments are provided in 
this section in chronological order. 
Prior Amendments 
Amendment 1.0; 09 August 2021 
Summary of Changes (in order of appearance) 
Section Number and 
Name 
Description of Change 
Rationale for Change 
1.1 Synopsis 
3 Objectives, Endpoints 
and Estimand 
9.3.2.1 Analysis of 
Primary Endpoint 
• Add primary estimand 
• To satisfy updated regulatory 
guidelines 
1.3 Schedule of Activities  
10.2 Appendix 2 Clinical 
Laboratory Tests 
• Change from PCR to antigen test (with 
confirmatory PCR if positive) for 
routine COVID testing 
• To allow results to be 
available during clinic visit.  
1.3 Schedule of Activities 
8.5 Pharmacokinetics 
• Clarify PK samples will also be 
collected in case of potentially related 
SAEs 
• Clarify PK samples will be only 
analyzed in subjects receiving active 
treatment (e.g. RIST4721)  
• To better assess safety  
• For clarity 
2.3.1 Risk Assessment 
• Update potential risk relating to drug 
interaction 
• Based on emerging data from 
recently completed RIST4721-
103 drug interaction study 
5.1 Inclusion Criteria 
6.7.2 Prohibited 
Medications 
• Removal of SARs-CoV-2 vaccination 
requirement (inclusion criterion no. 8)   
• Add SARs-CoV-2 vaccine to 
prohibited medications list 
• Based upon up to date 
information regarding 
vaccination status and 
potential immune protection 
from emerging variants 
• Based upon lack of data with 
RIST4721 and vaccines 
5.2 Exclusion Criteria 
6.7.2 Prohibited 
Medications (Table 4) 
• Clarify Exclusion criterion no. 2u 
regarding SARS-CoV-2 infection 
determination 
• Update duration of exclusion topical 
medication to 2 weeks (exclusion 
criterion no. 5) 
• Clarify exclusion criterion 12 for 
subjects receiving RIST4721 
• To align with SoA 
• To align with standard of care 
in the countries where study is 
being conducted 
• For clarity 
10.1.2 Informed Consent 
Process 
• Clarify requirements for ICF 
• To comply with international 
regulations 

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Section Number and 
Name 
Description of Change 
Rationale for Change 
10.4 Appendix 4 
Contraceptive Guidance  
• Require double barrier for male 
subjects (e.g. condom and spermicide) 
• For safety and consistency 
General 
• Minor administrative changes and 
clarifications made throughout the 
protocol  
• Correct typographical errors, 
hyperlinks/cross-references, style, and 
formatting (not tracked). 
• Align across protocol sections. 
• Update glossary (not tracked). 
• Update header 
• For consistency and clarity 
• Alignment across documents 
 
Amendment 2.0; 08 September 2021 
Summary of Changes (in order of appearance) 
Section Number and 
Name 
Description of Change 
Rationale for Change 
2.3.1 Risk Assessments 
• Update number of completed Phase 1 
studies and number of healthy subjects 
exposed to RIST4721 
• Based on recently completed 
Phase 1 study 
2.3.3 Overall Benefit: 
Risk Conclusion 
• Clarify that SARS-CoV-2 vaccines are a 
prohibited medication  
• For consistency with Section 
5.2 and Section 6.7.2 
5.2 Exclusion Criteria 
• Clarify exclusion criterion 5 that topical 
medications must be discontinued 2 
weeks prior to Day 1 
• For clarity  
 
5.2 Exclusion Criteria 
• Clarify exclusion criterion 14 that 
subjects unwilling to avoid the foods or 
beverages specified are excluded 
• For clarity 
 
Amendment 3.0; 10 November 2021 
Overall Rationale for the Amendment: 
Summary of Changes (in order of appearance) 
Section Number and 
Name 
Description of Change 
Rationale for Change 
2.3.3 Overall Benefit: 
Risk Conclusion 
6.7.2 Prohibited 
Medications 
• Reclassified SARS-CoV-2 vaccine as 
Restricted Medication (vs. Prohibited 
Medication) 
• In the case that a subject requests or 
requires new or additional vaccination 
for SARS-CoV-2, guidance was added 
• To allow flexibility for 
subjects to receive SARS-
CoV-2 vaccine during the 
study 
• To add clarification about the 
benefit : risk discussion 

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Section Number and 
Name 
Description of Change 
Rationale for Change 
6.7.3 Restricted 
Medications 
for the Investigator to discuss the 
potential risks and benefits with the 
subject prior to making a determination 
between the investigator and 
the subject 
 
 
5.1 Inclusion Criteria 
• Added IC #8: Subject has been 
previously vaccinated for SARS-CoV-2 
or has chosen not to be vaccinated at the 
start of participation (screening) in the 
clinical study. 
• To clarify entry criteria 
regarding vaccination status  
10.3.5 Reporting of SAEs 
• Amended contact in the case of an 
SAE/Pregnancy if the electronic system 
is unavailable 
• 
To add clarification 
regarding SAE reporting 
process 
General 
• Minor administrative changes and 
clarifications made throughout the 
protocol  
• Correct typographical errors, 
hyperlinks/cross-references, style, and 
formatting (not tracked). 
• Align across protocol sections. 
• Update glossary (not tracked). 
• Update header 
• For consistency and clarity 
• Alignment across documents 
 
 

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11. 
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