Clinical trial NCT05348681
Conditions: Hidradenitis Suppurativa
Sponsor: Aristea Therapeutics, Inc.
Start date: 2022-07-18; Completion date: 2023-02-28
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Randomized, Double-blinded, Placebo-controlled, Phase 2a Study to Evaluate the Efficacy and Safety of RIST4721 in Subjects with Hidradenitis Suppurativa

Detailed description:

Arms: arm 1: RIST4721 400 mg: 4 active (100 mg) tablets once daily for 12 weeks arm 2: Placebo: 4 placebo tablets once daily for 12 weeks
Interventions: intervention 1: RIST4721 intervention 2: Placebo
Intervention descriptions: intervention 1: RIST4721 tablets, 100 mg are blue, oval, biconvex film-coated tablets intervention 2: Matching placebo

Protocol documents:
Prot_000.pdf: 




Protocol RIST4721-221 
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INVESTIGATOR AGREEMENT 
Protocol Title:  
A Randomized, Double-blinded, Placebo-controlled, Phase 2a 
Study to Evaluate the Efficacy and Safety of RIST4721 in 
Subjects with Hidradenitis Suppurativa 
Protocol Number:  
RIST4721-221 
Version and Date: 
Original, Version 1.0 
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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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
INVESTIGATOR AGREEMENT...................................................................................................3 
1. 
PROTOCOL SUMMARY ............................................................................................9 
1.1. 
Synopsis ........................................................................................................................9 
1.2. 
Study Scheme .............................................................................................................12 
1.3. 
Schedule of Activities (SoA) ......................................................................................13 
2. 
INTRODUCTION ......................................................................................................16 
2.1. 
Study Rationale ...........................................................................................................16 
2.2. 
Background .................................................................................................................16 
2.2.1. 
Hidradenitis Suppurativa ............................................................................................16 
2.2.2. 
Study Treatment: RIST4721 .......................................................................................17 
2.3. 
Benefit/Risk Assessment ............................................................................................18 
2.3.1. 
Risk Assessments........................................................................................................18 
2.3.1.1. 
Risks of Study Participation .......................................................................................20 
2.3.2. 
Benefit Assessment .....................................................................................................20 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................20 
3. 
OBJECTIVES, ENDPOINTS, AND ESTIMAND ....................................................21 
4. 
STUDY DESIGN .......................................................................................................23 
4.1. 
Overall Study Design ..................................................................................................23 
4.2. 
Scientific Rationale for Study Design ........................................................................23 
4.3. 
Dose Rationale ............................................................................................................23 
4.4. 
Study Duration ............................................................................................................24 
4.5. 
End of Study Definition ..............................................................................................24 
5. 
STUDY POPULATION .............................................................................................26 
5.1. 
Inclusion Criteria ........................................................................................................26 
5.2. 
Exclusion Criteria .......................................................................................................27 
5.3. 
Lifestyle Considerations .............................................................................................29 
5.4. 
Screen Failure .............................................................................................................30 
6. 
STUDY TREATMENT AND CONCOMITANT THERAPY ..................................31 
6.1. 
Study Treatment Administered ...................................................................................31 
6.2. 
Shipping/Handling/Storage/Accountability ................................................................31 


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6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................32 
6.3.1. 
Randomization ............................................................................................................32 
6.3.2. 
All subjects will be centrally randomized 2:1 to RIST4721 400 mg QD or 
placebo QD using interactive response technology (IRT). .........................................32 
6.3.3. 
Assignment of Subject Number ..................................................................................32 
6.3.4. 
Assignment of Study Treatment Kit Number .............................................................32 
6.3.5. 
Blinding and Unblinding of an Individual Subject .....................................................32 
6.4. 
Study Treatment Compliance .....................................................................................33 
6.5. 
Stopping Rules and Dose Modifications ....................................................................33 
6.5.1. 
Treatment-related AEs ................................................................................................33 
6.5.2. 
Neutrophil Count Laboratory Abnormality ................................................................34 
6.6. 
Treatment of Overdose ...............................................................................................36 
6.7. 
Concomitant Medications and Therapies ...................................................................36 
6.7.1. 
Antiseptic Therapy ......................................................................................................37 
6.7.2. 
Analgesia ....................................................................................................................37 
6.7.3. 
Wound Care ................................................................................................................37 
6.7.4. 
Lesion Intervention .....................................................................................................37 
6.7.5. 
Prohibited Medications ...............................................................................................37 
6.7.6. 
Restricted Medications ...............................................................................................38 
7. 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
WITHDRAWAL FROM STUDY ..............................................................................40 
7.1. 
Discontinuation of Study Treatment and Withdrawal from the Study .......................40 
7.1.1. 
Premature Termination of the Study ...........................................................................41 
7.1.2. 
Pregnancy ...................................................................................................................41 
7.2. 
Lost to Follow-up .......................................................................................................41 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................43 
8.1. 
Key Screening Assessment(s) .....................................................................................43 
8.1.1. 
Hurley Stage ...............................................................................................................43 
8.2. 
Efficacy Assessments .................................................................................................43 
8.2.1. 
Hidradenitis Suppurativa Clinical Response (HiSCR) ...............................................43 
8.2.2. 
International Hidradenitis Suppurativa Severity Score System (IHS4) .....................44 
8.2.3. 
Numeric Rating Scale for Skin Pain ...........................................................................44 


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8.2.4. 
Hidradenitis Suppurativa-Investigator's Global Assessment (HS-IGA) ....................44 
8.2.5. 
Hidradenitis Suppurativa -Physician Global Assessment (HS-PGA) ........................45 
8.2.6. 
Hidradenitis Suppurativa Quality of Life (HiSQOL) .................................................45 
8.2.7. 
Dermatology Life Quality Index (DLQI) ...................................................................46 
8.2.8. 
Medical Photography ..................................................................................................46 
8.3. 
Safety Assessments .....................................................................................................46 
8.3.1. 
Physical Examinations ................................................................................................46 
8.3.2. 
Vital Signs ..................................................................................................................47 
8.3.3. 
Electrocardiograms .....................................................................................................47 
8.3.4. 
Clinical Safety Laboratory Assessments ....................................................................48 
8.4. 
Adverse Events and Serious Adverse Events .............................................................48 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................49 
8.4.2. 
Method of Detecting AEs and SAEs ..........................................................................49 
8.4.3. 
Follow-up of AEs and SAEs .......................................................................................49 
8.4.4. 
Regulatory Reporting Requirements for SAEs ...........................................................49 
8.4.5. 
Pregnancy ...................................................................................................................50 
8.4.6. 
Death Events ...............................................................................................................50 
8.5. 
Pharmacokinetics, Biomarkers and Pharmacodynamics ............................................50 
8.5.1. 
Pharmacokinetics ........................................................................................................50 
8.5.2. 
Biomarkers and Pharmacodynamics ...........................................................................51 
8.5.3. 
Storage and Handling of Blood Samples ....................................................................51 
9. 
STATISTICAL CONSIDERATIONS .......................................................................52 
9.1. 
Sample Size Determination ........................................................................................52 
9.2. 
Populations for Analyses ............................................................................................52 
9.3. 
Statistical Analyses .....................................................................................................52 
9.3.1. 
General Considerations ...............................................................................................52 
9.3.2. 
Baseline Descriptive Statistics ....................................................................................53 
9.3.3. 
Efficacy Analysis ........................................................................................................53 
9.3.4. 
Safety Analyses ..........................................................................................................53 
9.3.4.1. 
Extent of Exposure .....................................................................................................53 
9.3.4.2. 
Adverse Events ...........................................................................................................53 
9.3.4.3. 
Clinical Laboratory .....................................................................................................54 


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9.3.4.4. 
Vital Signs ..................................................................................................................54 
9.3.4.5. 
Electrocardiograms .....................................................................................................54 
9.3.5. 
Pharmacokinetics Analyses ........................................................................................54 
9.4. 
Planned Interim Analyses ...........................................................................................54 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................55 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations (Site 
Responsibilities) .........................................................................................................55 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................55 
10.1.2. 
Informed Consent Process ..........................................................................................55 
10.1.3. 
Data Protection ...........................................................................................................56 
10.1.4. 
Dissemination of Clinical Study Data ........................................................................56 
10.1.5. 
Data Quality Assurance ..............................................................................................56 
10.1.6. 
Source Documents ......................................................................................................57 
10.1.7. 
Study and Site Closure................................................................................................57 
10.1.8. 
Publication Policy .......................................................................................................58 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................59 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................61 
10.3.1. 
Definition of AE .........................................................................................................61 
10.3.2. 
Definition of SAE .......................................................................................................62 
10.3.3. 
Definition of Suspected and Unsuspected Adverse Reaction .....................................63 
10.3.4. 
Recording and Follow-Up of Adverse Events and Serious Adverse Events ..............63 
10.3.5. 
Reporting of SAEs ......................................................................................................65 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................67 
10.4.1. 
Definitions ..................................................................................................................67 
10.4.2. 
Contraception Guidance .............................................................................................68 
10.4.3. 
Collection of Pregnancy Information .........................................................................70 
10.5. 
Appendix 5: Guidance to Address the COVID-19 Pandemic and Potential 
Impact on the Clinical Study ......................................................................................71 
10.6. 
Appendix 6: List of Abbreviations .............................................................................74 
11. 
REFERENCES ...........................................................................................................76 


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LIST OF TABLES 
Table 1: 
Schedule of Activities .................................................................................................13 
Table 2: 
RIST4721 Potential Risks and Risk Mitigation Strategy ...........................................18 
Table 3: 
Study Treatment Description ......................................................................................31 
Table 4: 
Hidradenitis Suppurativa-Investigator’s Global Assessment (HS-IGA) Score ..........45 
Table 5: 
Hidradenitis Suppurativa -Physician Global Assessment (HS-PGA) ........................45 
Table 6: 
Pharmacokinetic Collection Schedule ........................................................................51 
Table 7: 
Protocol-required Safety Laboratory Assessments .....................................................59 
 
LIST OF FIGURES 
Figure 1: 
Study Scheme .............................................................................................................12 
Figure 2: 
Steps for Addressing Neutrophil Counts ....................................................................35 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Randomized, Double-blinded, Placebo-controlled, Phase 2a Study to Evaluate 
the Efficacy and Safety of RIST4721 in Subjects with Hidradenitis Suppurativa 
Short Title: RIST4721 in subjects with hidradenitis suppurativa 
Rationale 
RIST4721 is a small-molecule 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 hidradenitis suppurativa (HS). HS is a chronic, inflammatory 
skin disease characterized by recurrent painful nodules and abscesses that rupture, leading to the 
formation of sinus tracts and scarring. Recruitment of neutrophils to HS lesion sites may play an 
essential role in the development of the painful inflammatory nodules and abscesses that 
characterize the disease (Narla, 2021). 
CXCR2 is a G-protein coupled receptor (GPCR) expressed on the epithelium and on a variety of 
inflammatory cells (including neutrophils and macrophages). It 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 interleukin (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 HS (Boppana, 2014; Aarts, 2021). 
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 
(Nicholls, 2015). 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 evaluated in 5 Phase 1 clinical studies in healthy subjects and is also being 
evaluated in clinical setting for treatment of palmoplantar pustulosis (PPP) and familial 
Mediterranean fever (FMF). RIST4721 was generally well tolerated in completed clinical 
studies. The present study will evaluate the safety, tolerability, and efficacy of RIST4721 
monotherapy in subjects with moderate-to-severe HS. 


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Objectives, Endpoints, and Estimand (Primary and Secondary) 
Objectives 
Endpoints 
Primary 
 
• To assess the safety and tolerability of 
RIST4721 monotherapy in subjects with 
moderate-to-severe HS 
• Incidence of treatment-emergent adverse 
events (TEAEs) and serious adverse events 
(SAEs) 
Key Secondary 
 
• To assess the efficacy of RIST4721 in 
subjects with moderate-to-severe HS 
• Proportion of subjects achieving 
Hidradenitis Suppurativa Clinical Response 
(HiSCR) 50 at Week 12 
Key Secondary Estimand 
Treatment regimen: RIST4721 400 mg, placebo 
Target population: Subjects with HS as defined by the inclusion and exclusion criteria 
(Section 5), grouped per randomization assignment 
Variable of interest: Proportion of subjects achieving HiSCR50 at Week 12 defined as at 
least a 50% reduction in the total abscess and inflammatory nodule (AN) count with no 
increase in abscess count and no increase in draining fistula count relative to baseline. 
Intercurrent events and corresponding strategy: For subjects who discontinue study 
treatment prior to Week 12 due to any reason, their last observation will be used to impute 
response status. 
Population-level summary variable: Difference in proportions 
Secondary 
• Additional secondary efficacy endpoints 
• Proportion of subjects achieving HS 
Clinical Response 75 (HiSCR75) at Week 
12 
• Proportion of subjects with flare (≥ 25% 
increase and ≥ 2 absolute increase in AN 
count relative to baseline) at Week 12.  
• Proportion of subjects achieving AN count 
of 0, 1, or 2 at Week 12 
• Change from baseline in skin pain score 
using the numeric rating scale (NRS) at 
Week 12 
• 
Change from baseline in International HS 
Severity Score System (IHS4) at Week 12 
• To assess pharmacokinetics (PK) of 
RIST4721 in subjects with moderate-to-
severe HS 
• RIST4721 PK characterization in subjects 
with moderate-to-severe HS 


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Overall Design 
This is a Phase 2a, randomized, double‑blind, placebo-controlled, multicenter, 12-week study to 
evaluate the efficacy and safety of RIST4721 once daily (QD) in subjects with moderate-to-
severe HS.  
The study will consist of a screening period, a treatment period, and a follow-up period. Study 
schema is shown in Section 1.2. Subjects will be evaluated throughout the study as specified in 
the Schedule of Activities (SoA; Section 1.3). 
After signing an informed consent form (ICF), subjects will be screened for study eligibility over 
4 weeks. 
On Day 1 (baseline visit), eligible subjects will be randomized in 2:1 ratio to receive oral study 
treatment for 12 weeks: 
• RIST4721 400 mg QD 
• Placebo QD 
All subjects who remain on study treatment through and including Week 12 will be asked to 
return for a follow-up visit, approximately 4 weeks after their last dose of study treatment, to 
assess safety and efficacy. Subjects who permanently discontinue study treatment will be 
followed as described in Section 7.1. 
Treatment Groups and Number of Subjects: 
Approximately 33 subjects are planned to be enrolled (~22 subjects expected in the RIST4721 
group and 11 subjects in the placebo group). 
Duration 
For each subject, the total study duration is expected to be approximately 20 weeks as follows:  
Screening period:  
4 weeks 
Treatment period:  
12 weeks 
Follow-up period 
4 weeks from last dose of study treatment 
Data Review Committee: No 
 
 


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1.2. 
Study Scheme 
Figure 1: 
Study Scheme 
 
Abbreviations: EOT, end of treatment; EOS, end of study; QD, once daily, R, randomization 
 
 








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2. 
INTRODUCTION 
2.1. 
Study Rationale 
RIST4721 is a small-molecule high-potency antagonist of human CXCR2 that is proposed to 
have potential as a novel oral treatment for neutrophil-mediated inflammatory diseases, 
including HS. HS is a chronic, inflammatory skin disease characterized by recurrent painful 
nodules and abscesses that rupture, leading to the formation of sinus tracts and scarring. 
Recruitment of neutrophils to HS lesion sites may play an essential role in the development of 
the painful inflammatory nodules and abscesses that characterize the disease (Narla, 2021). 
CXCR2 is a GPCR expressed on the epithelium and on a variety of inflammatory cells 
(including neutrophils and macrophages). It 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 HS 
(Boppana, 2014; Aarts, 2021). 
RIST4721 antagonism of CXCR2 was demonstrated in vitro by measuring both primary binding 
affinity in 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 CXCR1 and CCR2, respectively 
(Nicholls, 2015). 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 MSU crystal-induced 
inflammation. When rats were previously challenged with MSU injection, RIST4721 caused 
significant, dose-dependent decreases in exudate volume, total WBC count, and neutrophil 
infiltration at doses 30, 100, and 300 μmol/kg. 
RIST4721 was evaluated in 5 Phase 1 clinical studies in healthy subjects and is also being 
evaluated in clinical setting for treatment of PPP and FMF. RIST4721 was generally well 
tolerated in completed clinical studies. The present study will evaluate the safety, tolerability, 
and efficacy of RIST4721 monotherapy in subjects with moderate-to-severe HS. 
2.2. 
Background 
2.2.1. 
Hidradenitis Suppurativa 
HS is a recurrent inflammatory skin disease characterized by comedones, painful inflammatory 
nodules, abscesses, dermal tunnels, and scarring, with a predilection for intertriginous areas of 
the body (axillae, inguinal, and anogenital regions) (Wipperman, 2019; Sabat, 2020). Due to its 
chronic nature and frequently occurring relapses, HS has a great impact on the patient’s quality 
of life, deeply affecting social, working, and psychological aspects (Alikhan, 2009). Prevalence 
estimates of HS in North America and Europe range from < 1 to 4%. HS typically occurs after 


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puberty, with the average age of onset in the second or third decades of life and with a female 
predominance (Revuz, 2008; Cosmatos, 2013; Vazquez, 2013; Deckers, 2014; Garg, 2017). 
HS is a multifactorial disease in which genetic and environmental factors play a key role 
including smoking and obesity. The diagnosis of HS is made by lesion morphology (nodules, 
abscesses, tunnels, and scars), location (axillae, inframammary folds, groin, perigenital, or 
perineal), and lesion progression (2 recurrences within 6 months or chronic or persistent lesions 
for ≥3 months) (Saunte, 2017; Preda-Naumescu, 2021). 
The precise pathogenesis of HS remains still unclear. The primary event in disease development 
is thought to be follicular occlusion, based on histopathological observations in very early 
lesions. The occlusion of the terminal hair follicle results in dilation and cyst formation, 
followed by rupture of the hair follicle. The introduction of follicular contents to the surrounding 
dermis induces an inflammatory response and subsequent formation of abscess, sinus tracts, 
fibrosis, and scars (von Laffert, 2010; Prens, 2015; Napolitano, 2017). 
HS management usually consists of the combination of anti-inflammatory therapies in addition 
to surgical intervention and lifestyle changes such as smoking cessation and weight loss (Saunte, 
2017; van Straalen, 2020). Therapeutic approaches have evolved rapidly in the last decade and 
include the use of topical therapies, systemic antibiotics, hormonal therapies, and a wide range 
of immunomodulating medications (Napolitano, 2017; Alikhan, 2019). First-line treatment 
options may include the use of systemic antibiotics like tetracyclines and the combination of 
clindamycin and rifampicin. Adalimumab, a monoclonal antibody against tumor necrosis factor 
(TNF)-α, is the only biologic which has been approved by the United States Food and Drug 
Administration (FDA) and European Medicines Agency (EMA) for treatment of moderate to 
severe HS (Lim, 2019). 
The inflammatory response in HS has in recent years been better characterized, although there 
are many components that remain to be elucidated. In particular, it has been recently established 
that innate pro-inflammatory cytokines (eg, IL-1β, and TNF-α), mediators of activated T helper 
(Th)1 and Th17 cells (eg, interferon gamma [IFN-γ], and IL-17), and effector mechanisms of 
neutrophilic granulocytes, macrophages, and plasma cells are involved (Kelly, 2015; Moran, 
2017; Vossen, 2018; Wolk, 2020; Scala, 2021). It is hypothesized that pharmacologic 
manipulation of the various pathways involved in the process of neutrophil recruitment and 
activation could allow for successful control and stabilization of HS lesions and the remission of 
active, severe flares (Narla, 2021). 
2.2.2. 
Study Treatment: RIST4721 
RIST4721 is a high-potency antagonist of human CXCR2 as validated in in vitro and in vivo 
studies. Five Phase 1 clinical studies of RIST4721 in healthy subjects and one Phase 2a study in 
patients with moderate-to-severe PPP have been completed. Phase 2 studies in subjects with PPP 
and FMF are ongoing. RIST4721 was generally well tolerated in the clinical setting.  
For more detailed information on nonclinical and clinical studies with RIST4721 refer to the 
Investigator’s Brochure (IB). 
 
 


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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 5 Phase 1 clinical studies in healthy subjects (155 
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 once daily [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 serious adverse events (SAEs) or deaths were reported. 
Table 2 summarizes identified and potential risks associated with RIST4721 as well as risk 
mitigation strategies. 
Table 2: 
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 6.5.2)  
• 
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. 


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Safety 
Considerations 
of RIST4721 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Gastrointestinal 
effects 
GI 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 nonclinical 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. 
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. 


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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 
Evaluation of the serum and lesional skin from patients with HS compared to healthy volunteers 
suggests that HS is a condition driven by neutrophils (Navrazhina, 2021). Reduction in 
migration of neutrophils to the skin of patients with HS in participants randomized to the 
RIST4721 treatment arm may have an improvement in their HS condition. Additionally, 
participation in this study may help generate future benefit for larger groups of subjects with HS 
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 risk to subjects in this study 
will be minimized by compliance with the eligibility criteria, proper study design, and close 
monitoring. 
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 
receiving treatment during 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 also 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. 
It is expected that subjects treated with RIST4721 might see an improvement in their HS 
condition and improved quality of life. This study may inform future studies of RIST4721 in HS. 
All quality, pharmacology, and toxicology data, as well as 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 HS with RIST4721, and therefore to initiate this 
study. 
Considering the potential benefits, potential risks, and risk mitigation measures that have been 
implemented in clinical studies with RIST4721, the Sponsor considers the benefit-risk profile of 
administering RIST4721 for the treatment of HS to be favorable. The overall benefit-risk 
associated with administration of RIST4721 will be continually reassessed with the emergence 
of additional data. 


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3. 
OBJECTIVES, ENDPOINTS, AND ESTIMAND 
Objectives 
Endpoints 
Primary 
 
• To assess the safety and tolerability of 
RIST4721 monotherapy in subjects with 
moderate-to-severe HS 
• Incidence of TEAEs and SAEs 
Key Secondary 
 
• To assess the efficacy of RIST4721 in 
subjects with moderate-to-severe HS 
• Proportion of subjects achieving 
HiSCR50 at Week 12 
Key Secondary Estimand 
Treatment regimen: RIST4721 400 mg, placebo 
Target population: Subjects with HS as defined by the inclusion and exclusion criteria 
(Section 5), grouped per randomization assignment. 
Variable of interest: Proportion of subjects achieving HiSCR50 at Week 12 defined as at 
least a 50% reduction in the total abscess and inflammatory nodule (AN) count with no 
increase in abscess count and no increase in draining fistula count relative to baseline. 
Intercurrent events and corresponding strategy: For subjects who discontinue study 
treatment prior to Week 12 due to any reason, their last observation will be used to impute 
response status. 
Population-level summary variable: Difference in proportions 
Secondary 
• Additional secondary efficacy endpoints 
• Proportion of subjects achieving HS 
Clinical Response 75 (HiSCR75) at 
Week 12.  
• Proportion of subjects with flare (≥ 25% 
increase and ≥ 2 absolute increase in AN 
count relative to baseline) at Week 12.  
• Proportion of subjects achieving AN 
count of 0, 1, or 2 at Week 12. 
• Change from baseline in skin pain score 
using the numeric rating scale (NRS) at 
Week 12.  
• 
Change from baseline in International 
HS Severity Score System (IHS4) at 
Week 12 
• To assess pharmacokinetics (PK) of 
RIST4721 in subjects with moderate-to-
severe HS 
• RIST4721 PK characterization in 
subjects with moderate-to-severe HS 


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Objectives 
Endpoints 
Exploratory 
 
• To evaluate the effect of RIST4721 on 
exploratory measures of efficacy 
• Proportion of subjects achieving at least 
2-grade improvement on the HS-
Physician Global Assessment (HS-
PGA). 
• Proportion of subjects achieving 0 or 1 
on the HS-PGA 
• Proportion of subjects with HS-
Investigator’s Global Assessment (HS-
IGA) with at least 2-grade improvement 
relative to baseline at Week 12 
• Proportion of subjects achieving 0 or 1 
on the HS-IGA 
• Change from baseline in AN count at 
Week 12 
• Change from baseline in: 
− 
HS Quality of Life (HiSQOL) 
− 
Dermatology Life Quality Index 
(DLQI) Total Score at Week 12. 
 


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4. 
STUDY DESIGN 
4.1. 
Overall Study Design 
This is a Phase 2a, randomized, double‑blind, placebo-controlled, multicenter, 12-week study to 
evaluate the efficacy and safety of RIST4721 QD in subjects with moderate-to-severe HS. 
Approximately 33 subjects are planned to be enrolled (approximately 22 subjects expected in the 
RIST4721 group and 11 subjects in the placebo group). 
The study will consist of a screening period, a treatment period, and a follow-up period. Study 
schema is shown in Section 1.2. Subjects will be evaluated throughout the study as specified in 
the Schedule of Activities (SoA; Section 1.3). 
After signing an informed consent form (ICF), subjects will be screened for study eligibility over 
4 weeks.  
On Day 1 (baseline visit), eligible subjects will be randomized in 2:1 ratio to receive oral study 
treatment for 12 weeks: 
• RIST4721 400 mg QD 
• Placebo QD 
All subjects who remain on study treatment through and including Week 12 will be asked to 
return for a follow-up visit, approximately 4 weeks after their last dose of study treatment, to 
assess safety and efficacy. Subjects who permanently discontinue study treatment will be 
followed as described in Section 7.1. 
4.2. 
Scientific Rationale for Study Design 
This Phase 2a, randomized, double‑blind, placebo-controlled, multicenter study is designed to 
assess the safety and efficacy of RIST4721 over 12 weeks in adult subjects with moderate-to-
severe HS. Other therapeutic regimens for the treatment of moderate to severe HS have 
demonstrated treatment success in a 12-week timeframe.  
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 
HS. 
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 (eg, demographic and 
baseline characteristics) are evenly balanced across treatment groups, and to enhance the validity 
of statistical comparisons across treatment groups. Blinded treatment will be used to reduce 
potential bias during data collection and evaluation of clinical endpoints. 
4.3. 
Dose Rationale 
The dose of RIST4721 to be tested in this proof-of-concept Phase 2a study is 400 mg QD. 
RIST4721 was well tolerated in multiple Phase 1 studies in healthy volunteers at single doses up 
to 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. 


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RIST4721 dose level of 400 mg QD was selected based on safety and PK data (including 
absorption, half-life, and bioaccumulation after repeated doses) from previously conducted 
studies. The 400 mg QD dose level is expected to be clinically safe and effective. In case of 
treatment-related adverse events (AEs) (Section 6.5.1) or absolute neutrophil count (ANC) 
laboratory abnormalities (Section 6.5.2), the dose can be reduced to 200 mg QD (refer to 
Section 6.5); this dose is anticipated to be a potentially effective dose in subjects with HS. 
Modeling was conducted using the safety data of RIST4721 by dose in PPP patients from Study 
RIST4721-201 coupled with data from normal healthy volunteers from 5 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 × 109 cells/L at study entry (refer to inclusion criterion 
number 7). 
Systemic exposure to RIST4721 tablets has been demonstrated to be modestly influenced by 
food with an increase of in maximum observed plasma concentration (Cmax) of 52% and area 
under the curve (AUC)inf of 18% when administered with a high fat meal compared with fasted. 
It is considered that the increase of 18% in AUCinf is small and would not be clinically important 
with respect to either safety or efficacy. The increase of Cmax is more substantial, however, with 
the solution formulation (given under fasted conditions): Cmax is approximately 25% higher 
compared to the tablet in fed conditions. Safety data are available for the solution formulation in 
healthy subjects at single doses up to 730 mg and repeated doses of up to 500 mg QD and in 
patients with PPP at repeated doses of 300 mg QD. Cmax at those doses would be expected to be 
comparable to or greater than that from fed tablets at 400 mg QD. In addition, tablets at the 
400 mg dose (fed) QD over 14 days were recently demonstrated to be well tolerated in healthy 
subjects (RIST4721-103). Based on the modest effect of food on AUCinf and the good safety 
profile at Cmax concentrations achieved with 400 mg tablets (fed), it is considered that RIST4721 
can be administered without respect to food intake. 
4.4. 
Study Duration 
For each subject, the total study duration is expected to be approximately 20 weeks as follows:  
Screening period:  
4 weeks 
Treatment period:  
12 weeks 
Follow-up period 
4 weeks from 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 
(Section 1.3). 


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• For subjects who permanently discontinued study treatment, the end of study will be 
defined as the completed Week 12 visit or the follow-up evaluation 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 
SoA 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 of age at the time of consent. 
Subject and Disease Characteristics 
2. Diagnosis of HS based on documented clinical history for at least 1 year prior to 
screening (information obtained from medical chart or subject’s physician, or directly 
from the subject). 
3. HS lesions must be present in at least 2 distinct anatomic areas (eg, left and right axilla; 
or left axilla and left inguinal fold), one of which must be Hurley Stage II, at both the 
screening and baseline visits. 
4. Moderate-to-severe HS defined as a total AN count (sum of abscesses and inflammatory 
nodules) > 6 across all anatomical sites at both the screening and baseline visits. 
5. Inadequate response to a course of at least 3-months of a systemic antibiotic or 
demonstrated intolerance to/have a contraindication to oral antibiotics for treatment of 
their HS, as assessed by the investigator through study participant interview and review 
of medical records. 
6. Agree to continue use of current over-the-counter topical therapies for HS, if any, at the 
same strength and frequency for the duration of the study. 
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. 
10. Female subject agrees to use a contraceptive method that is highly effective from consent 
through 5 days after the last study treatment administration. 
11. Male subject agrees to use contraception/barrier (a male condom) and spermicide from 
consent through 5 days after the last study treatment administration. 


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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. 
5.2. 
Exclusion Criteria 
A subject must be excluded from participating in the study if he/she meets any of the following: 
Medical Conditions and Diagnostic Assessments 
1. Presence of other skin conditions which may interfere with study assessments (eg, 
bacterial cellulitis, keloids, candida intertrigo, extensive condyloma, excessive scarring) 
2. Draining fistula count >20 at baseline 
3. Evidence of active or 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). 
Subjects with latent TB, who have been ruled out for active TB according to local 
country guidelines, (eg, chest X ray); have completed an appropriate course of TB 
prophylaxis treatment are eligible to enroll in the study. 
4. Known active bacterial, viral, fungal, mycobacterial systemic infection, or other infection 
(including atypical mycobacterial disease) or any major episode of infection that required 
hospitalization or treatment with intravenous antibiotics within 4 weeks prior to 
screening or during screening, or oral antibiotics within 2 weeks prior to screening or 
during screening. Superficial fungal infection of the nail bed is allowed.  
5. Any condition that, in the opinion of the investigator, would make participation not be in 
the best interest (eg, compromise the well-being) of the subject or that could prevent, 
limit, or confound the protocol-specified assessments, including, but not limited to: 
a. Positive results for SARS-CoV-2 using antigen test and confirmatory 
polymerase chain reaction (PCR) test at screening. 
b. Primary or secondary immunodeficiency syndromes (eg, hereditary 
immunodeficiency syndrome, acquired immunodeficiency syndrome, drug-
induced immune deficiency). 
c. History of organ transplant (except corneal transplant). 
d. Any clinically significant history of infection (except for localized herpes 
simplex) within 4 weeks prior to Day 1. 
e. 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). 
f. Uncontrolled thyroid disease (unless the subject is taking a stable dose of thyroid 
hormone or antithyroid medications [hyperthyroidism] for at least 12 weeks), 


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which in the opinion of the investigator should exclude the subject from the 
study. 
g. Diagnosis of active peptic ulcer disease as determined by endoscopy, 
radiography, angiography, or other appropriate means within 12 months prior to 
screening. 
h. Coagulopathy (regardless if controlled by pharmacotherapy or not). 
i. Significant central nervous system effects including vertigo and dizziness, or 
major neurologic event, including cerebrovascular events, within 60 days of 
screening. 
j. 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. 
k. Major surgery within 8 weeks prior to Day 1 or has a major surgery planned 
during the study, including planned endodontic and periodontal procedures. 
l. QT corrected interval by Fridericia (QTcF) >440 msec as confirmed by triplicate 
electrocardiogram (ECG) measurement at screening or Day 1 assessment. 
m. A positive test for drugs of abuse (amphetamines, methamphetamines, 
barbiturates, cocaine, phencyclidine) or use of opioids without prescription for 
pain management. Retest may be performed for potential false positive results 
with approval from the Sponsor’s Medical Monitor (or designee). 
n. Serious hepatic disorder (Child-Turcott-Pugh scores B or C). 
o. History of clinically significant anemia or hemoglobin (Hgb) value ≤9.5 g/dL at 
screening. 
p. Body mass index (BMI) >48 kg/m2. 
q. Confirmed chronic kidney disease (CKD) as per National Kidney Foundation 
stages ≥3: estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m2 based 
on the CKD-Epidemiology Collaboration (EPI) equation. 
r. Concurrent uncontrolled diabetes. 
s. Significant cardiovascular disease including poor peripheral circulation and 
venous stasis. 
t. Peripheral capillary oxygen saturation (SpO2) ≤94%. 
u. Uncontrolled hyperlipidemia. 
v. Uncontrolled other rheumatological, dermatological, and autoimmune disease.  
Any other clinically significant medical condition or ECG, physical examination, 
laboratory, or vital signs abnormality that would, in the opinion of the 
investigator, put the subject at undue risk or interfere with interpretation of study 
results (eg, celiac disease, streptococcal infection, allergy/delayed type 
hypersensitivity to tobacco and products within which tobacco is contained). 
6. Confirmed 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 (eg, ascites, peri-umbilical veins, esophageal varices) at 
screening. Note: A confirmed result means there have been 2 consecutive assessments 
showing a consistent clinically relevant abnormal result. 


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Prior Therapy and Prior/Concurrent Clinical Study Experience 
7. Received any systemic non-biologic therapies for HS including oral antibiotics within 30 
days prior to the baseline visit. 
8. Received prescription topical therapies for the treatment of HS within 14 days prior to 
the baseline visit. 
9. Use of any biologic agents (eg, adalimumab, ustekinumab, secukinumab) regardless of 
indication, within 5 half-lives (if known) or 12 weeks prior to screening, whichever is 
longer, or during screening. Refer to Section 6.7.5 for additional list of medications.  
10. Received any live or live-attenuated vaccines ≤ 4 weeks prior to baseline. 
11. Received any investigational drug within a minimum of 30 days or 5 half-lives of the 
drug prior to the baseline visit, whichever is longer, or during screening. 
12. 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, 
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). 
Other Exclusion Criteria 
13. Pregnant or breastfeeding or intends to become pregnant during the duration of the study. 
14. Consumption of any food or drinks 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. Prior participation in RIST4721 studies. 
17. Close affiliation with the investigator (eg, a close relative), including any study staff of 
the sites or persons working at the contract research organization CRO or subject is an 
employee of Sponsor. 
18. 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. 


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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 3: 
Study Treatment Description 
Study Treatment Name 
Active: RIST4721 
Control: Placebo 
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 
4 tablets QD 
Route of Administration 
and Instructions 
Oral. 
On Day 1, the clinical study team will instruct the subject how to 
administer the study treatment. 
Study treatment (RIST4721 or placebo) 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 
bottles containing 70 tablets. 
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  
6.3.2. 
All subjects will be centrally randomized 2:1 to RIST4721 400 mg QD or 
placebo QD using interactive response technology (IRT). 
Before the study is initiated, appropriate IRT training, log-in information, and instructions will 
be provided to each site. 
6.3.3. 
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 (eg, 02-010 for the 10th subject 
screened at Site #02). 
6.3.4. 
Assignment of Study Treatment Kit Number 
Study treatment will be dispensed at the study visits as summarized in the SoA. 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. 
6.3.5. 
Blinding and Unblinding of an Individual Subject 
This study 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 final safety and efficacy results 
will remain blinded to treatment assignments until after the completion of the study and the 
database has been locked. 
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, and performance of bioanalytical analysis of PK. These personnel will not 
be directly involved in the conduct of the study. 
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 
has been broken will be discontinued from the study and undergo the end of treatment (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 


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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. 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 laboratory, 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). 
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 
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. 


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6.5.2. 
Neutrophil Count Laboratory Abnormality 
There will be evaluation of the neutrophil counts and WBC performed by an independent 
Medical Monitor in order to reduce the risk of breaking the blind. 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. The investigator must notify the Sponsor’s Medical Monitor (or designee) within 
48 hours of dose interruption. Once the ANC result is above the LLN, subjects may re-initiate 
blinded study treatment by reducing the study treatment dose to 2 tablets QD (regardless of 
treatment group) with approval from the Sponsor’s Medical Monitor (or designee). 
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: 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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Figure 2: 
Steps for Addressing Neutrophil Counts 
 
 
Abbreviations: ANC, absolute neutrophil count, LLN, lower limit of normal (central laboratory) 
 


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6.6. 
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 (refer to Section 10.3.1), 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. 
6.7. 
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 6.7.5) 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. 
The Sponsor’s Medical Monitor (or designee) should be contacted if there are any 
questions regarding concomitant or prior therapy. 


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6.7.1. 
Antiseptic Therapy 
Subjects are required to agree to continue use of current over-the-counter topical 
therapies, if any, for the duration of the study. 
6.7.2. 
Analgesia  
Subjects may remain on any type of analgesia (oral, topical, and opioid) provided that 
they are on a stable dose within 4 weeks prior to baseline visit.  
6.7.3. 
Wound Care 
Concomitant use of wound care dressings on HS wounds is allowed. 
6.7.4. 
Lesion Intervention 
In the event that an acutely painful lesion occurs that requires an immediate intervention, 
physicians will have the option to perform protocol-allowed interventions. 
Only 2 types of lesion interventions are allowed:  
1. Injection with intralesional triamcinolone acetonide suspension (up to a strength 
of 10 mg/mL and no more than 1 mL). 
2. Incision and drainage.  
No more than 2 lesions may receive either intervention through the course of the study.  
The specific treated lesion will be excluded from lesion count efficacy assessment for the 
reminder of the study. 
New systemic and topical therapies following incision and drainage (including 
antibiotics) are prohibited. Concomitant use of wound care dressings is allowed. 
6.7.5. 
Prohibited Medications 
Medications specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study (Section 5.2).  
The list of medications below is not exhaustive. If there are any questions regarding a 
medication, the investigator can consult with the Sponsor’s Medical Monitor (or 
designee). 
The following treatments are prohibited for all subjects during the study: 
• Phototherapy (PUVA and/or UVB) 
• All biologic therapy with a potential therapeutic impact on the disease being 
studied, including but not limited to the following: anakinra (Kineret®), abatacept 
(Orencia®), adalimumab (Humira®), natalizumab (Tysabri®), ustekinumab 
(Stelara®), etanercept (Enbrel®), infliximab (Remicade®), rituximab (Rituxan®), 
tocilizumab (Actemra®), efalizumab (Raptiva®), golimumab (Simponi®), 
certolizumab (Cimzia®), belimumab (Benlysta®), secukinumab (Cosentyx®) 
• Any investigational agents 


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• Any oral antibiotic treatment for HS or other systemic non-biologic therapies with 
potential therapeutic impact on HS, including but not limited to antibiotics, 
methotrexate, cyclosporine, retinoids, corticosteroids, and fumaric acid esters  
• Live or live-attenuated vaccines (during the study and for 28 days after the last 
dose of study treatment) 
• New use of oral, topical, and opioid analgesics for HS  
• Prescription topical therapies for the treatment of HS, including topical steroids, 
calcineurin inhibitors, and phosphodiesterase inhibitors 
• New use of over-the-counter topical antiseptic washes, creams, soaps, ointments, 
gels, and liquids containing antibacterial agents to treat HS not listed in 
Section 6.7.1 
• Surgical, intense pulsed light and laser intervention for an HS lesion except as 
outlined in Section 6.7.4 
• Strong CYP3A inhibitors including but not limited to: cobicistat, boceprevir, 
ritonavir, indinavir, telaprevir, nelfinavir, danoprevir, dasabuvir, elvitegravir, 
lopinavir, ombitasvir, paritaprevir, saquinavir, tipranavir, itraconazole, 
ketoconazole, posaconazole, voriconazole, troleandomycin, clarithromycin, 
idelalisib, conivaptan, nefazodone 
• Strong CYP3A inducers including by not limited to: apalutamide carbamazepine, 
enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort 
6.7.6. 
Restricted Medications 
Restricted medications are defined as medications that should be avoided, if possible; 
however, they are not necessarily prohibited during this study. If such medications are 
required, consider switching to another medication in the class that is not restricted. If a 
restricted medication is required, the restricted medication should be used with caution 
per approved product label and Sponsor’s Medical Monitor (or designee) should be 
notified. 
The list of medications below is not exhaustive. If there are any questions regarding a 
medication, the investigator can consult with the Sponsor’s Medical Monitor (or 
designee). 
• P-glycoprotein inhibitors (eg, amiodarone, carvedilol, clarithromycin, 
dronedarone, itraconazole, lapatinib, lopinavir and ritonavir, propafenone, 
quinidine, ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir 
and ritonavir, verapamil) 
• Breast cancer resistance protein (BCRP) inhibitors (eg, curcumin, 
cyclosporine A, eltrombopag) 
• Moderate inhibitors of CYP3A, including but not limited to aprepitant, 
crizotinib, diltiazem, erythromycin, fluconazole, verapamil 


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• Moderate inducers of CYP3A including but not limited to bosentan, efavirenz, 
etravirine, phenobarbital, primidone 
• 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 the study, 
and the subject will be encouraged to remain in the study, complete the EOT visit at the 
time of study treatment discontinuation, and then continue to complete remaining study 
visits as per the SoA (Section 1.3). 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 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 SoA (Section 1.3). 
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 
• Pregnancy 
• Progressive disease 
• Protocol deviation 
• Withdrawal by subject  


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• 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) for additional details. 
See the SoA (Section 1.3) for data to be collected at the Week 12/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: 
• 
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. 


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• 
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 SoA (Section 1.3). 
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 
(Section 1.3), is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that 
potential subjects meet all eligibility 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 (Section 1.3). 
• Clinical evaluations of HS 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. 
Hurley Stage  
The Hurley severity stage (Hurley, 1996) is based on 3 clinical stages: 
• Stage 1 – abscess formation, single or multiple, without sinus tracts and 
cicatrization 
• Stage 2 – single or multiple, widely separated, recurrent abscesses with tract 
formation and cicatrization 
• Stage 3 – diffuse or near-diffuse involvement, or multiple interconnected tracts 
and abscesses across the entire area. 
A subject’s overall Hurley Stage should be determined by the worst Hurley stage across 
all affected anatomic regions. 
8.2. 
Efficacy Assessments 
8.2.1. 
Hidradenitis Suppurativa Clinical Response (HiSCR)  
The HiSCR is used to assess the inflammatory signs and symptoms of HS (Kimball, 
2014). The score is determined by counting the number of inflammatory nodules, 
abscesses, and draining fistulas before and after an intervention (see below). 


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• HiSCR50 is defined as a 50% or greater reduction in total AN count and no 
increase in abscesses or draining fistulas compared with baseline.  
• HiSCR75 is defined as at least a 75% reduction from baseline in the total AN 
count, with no increase from baseline in abscess or draining fistula count. 
AN count will be done at timepoints specified in the SoA. AN count is correlated with 
disease severity and is used in HiSCR to evaluate HS. Abscess (fluctuant, with or without 
drainage, tender or painful), inflammatory nodules (tender, erythematous, pyogenic 
granuloma lesion), draining fistulas, sinus tracts with communications to skin surface, 
draining purulent fluid, and other lesions (noninflammatory nodules, non-draining 
fistulas) will all be individually counted on the entire body at each visit. The AN count 
will be calculated based on the sum of the abscesses and inflammatory nodules. Draining 
fistulas should also be counted. 
8.2.2. 
International Hidradenitis Suppurativa Severity Score System (IHS4) 
IHS4 is a validated tool to dynamically assess HS severity and can be used both in real-
life and the clinical studies setting (Zouboulis, 2017; Napolitano, 2020). IHS4 score is 
arrived at by the number of nodules (multiplied by 1) plus the number of abscesses 
(multiplied by 2) plus the number of draining tunnels (multiplied by 4). A total score of 3 
or less signifies mild, 4-10 signifies moderate, and 11 or higher signifies severe disease. 
8.2.3. 
Numeric Rating Scale for Skin Pain 
NRS, a self-assessed patient reported outcome, will be used to assess pain. NRS is an 11-
point scale (zero to 10), with score of zero denoting no pain and a score of 10 denotes 
worst possible pain. NRS has been used across different indications, including skin 
disorders and was shown to be valid (Barrett, 2019; Silverberg, 2021). 
8.2.4. 
Hidradenitis Suppurativa-Investigator's Global Assessment (HS-IGA) 
The HS-IGA score is based on the maximum count of abscesses, fistulas (draining and 
non-draining), and nodules (inflammatory and non-inflammatory) in either the upper or 
lower body region. The region used at baseline may not be the same region used at a 
given post-baseline visit. Response is defined as a 2-point improvement (reduction) in 
IGA score relative to baseline. (Table 4). 


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Table 4: 
Hidradenitis Suppurativa-Investigator’s Global Assessment (HS-IGA) 
Score 
HS-IGA Score 
Maximum Lower Body OR Upper Body Count 
0 
0-1 
1 
2-5 
2 
6-10 
3 
11-15 
4 
16-20 
5 
>20 
 
8.2.5. 
Hidradenitis Suppurativa -Physician Global Assessment (HS-PGA) 
The HS‐PGA categorizes HS into 6 degrees of progressive severity based on number of 
nodules, abscesses, and fistulas, as shown in Table 5 (Kimball, 2012). 
Table 5: 
Hidradenitis Suppurativa -Physician Global Assessment (HS-PGA) 
Severity 
Description 
Clear 
0 abscesses, 0 draining fistulas, 0 inflammatory nodules, and 0 
noninflammatory nodules 
Minimal 
0 abscesses, 0 draining fistulas, 0 inflammatory nodules, and presence of 
noninflammatory nodules 
Mild 
0 abscesses, 0 draining fistulas, and 1–4 inflammatory nodules 
or  
1 abscess or draining fistula and 0 inflammatory nodules 
Moderate 
0 abscesses, 0 draining fistulae, and ≥5 inflammatory nodules 
or  
1 abscess or draining fistula and ≥1 inflammatory nodules  
or  
2–5 abscesses or draining fistulas and <10 inflammatory nodules 
Severe 
2–5 abscesses or draining fistulas and ≥10 inflammatory nodules 
Very severe 
>5 abscesses or draining fistulas 
 
8.2.6. 
Hidradenitis Suppurativa Quality of Life (HiSQOL) 
HiSQOL scale was developed and validated for clinical trial measurement of HS-specific 
health-related quality of life. It is a 17-item instrument separated into 3 sub-scales 


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(symptom, psychosocial, and functional concepts) with a 7-day recall period (Kirby, 
2020; Kirby, 2021). 
8.2.7. 
Dermatology Life Quality Index (DLQI) 
The DLQI is a simple 10-question validated questionnaire that has been used in more 
than 40 different skin conditions. It is the most frequently used instrument in studies of 
randomized controlled studies in dermatology. The DLQI includes questions concerning 
symptoms and feelings, daily activities, leisure, work, and school, personal relationships, 
and treatment. All questions relate “to the last week”, and the score ranges from 0 (no 
impairment of life quality) to 30 (maximum impairment) (Finlay, 1994). 
8.2.8. 
Medical Photography 
Medical photographs of HS-affected areas will be performed on subjects at participating 
select sites. 
Photographs will be 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 (Section 1.3). 
Study procedures should be completed within the windows provided in the 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 HS) 
• Head, eyes, ears, nose, throat (HEENT) 
• Respiratory system 
• Cardiovascular system 
• Abdominal region 
• Neurological system 
• Musculoskeletal system 
• 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 HS) 


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• 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. Pulse oximetry will be measured at screening only. 
• 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 on 
Week 12/EOT and Follow-up. 
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 at timepoints specified in the 
SoA (Section 1.3) 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 approximately 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. 
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 (eg, 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. 


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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 at the visits designated in the SoA (Section 1.3). 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). 
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. 


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8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
AEs and SAEs will be collected from consent until the follow-up visit (4 weeks from last 
dose of study treatment). 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 regulatory 
requirements relating to safety reporting to regulatory authorities, IRB/IEC, and 
investigators. 


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• 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 (eg, 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 (eg, spontaneous abortion, 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 trough measurement of plasma concentrations of 
RIST4721 and its metabolites, if applicable, as specified in Table 6. Subjects will be 
requested to hold their dose on clinic visits until after PK samples are obtained. The 24-
hour clock actual time and calendar 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 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. 


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Table 6: 
Pharmacokinetic Collection Schedule 
Timepoint  
Dose 
Time 
PK Collection 
Time Window 
Day 1/baseline 
Weeks 2, 4, and 8 
morning 
predose 
within 1 hour prior 
to dosing 
Week 12/EOT 
morning 
predose, if applicable 
within 1 hour prior 
to dosing 
Unscheduled visit any time after 
baseline visit (in case of SAEs 
or AE leading to study 
treatment discontinuation) 
none 
anytime 
 
Abbreviations: AE, adverse event; EOT, end of treatment; PK, pharmacokinetic; SAE, serious adverse 
event. 
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, ie, placebo subjects 
will not have their samples analyzed. For RIST4721-treated subjects, the baseline (ie, 
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. 
Biomarkers and Pharmacodynamics 
Serum biomarkers will be collected as specified in the SoA (Table 1) and stored for 
future analyses. 
Details about the collection, processing, handling, storage, and shipping of biomarker 
samples will be provided in the Laboratory Manual. 
8.5.3. 
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 
Group sample sizes were chosen empirically for this initial Phase 2 study to determine 
the safety and tolerability of RIST4721. 
9.2. 
Populations for Analyses  
The following analysis populations are planned: 
Analysis Set 
Definition 
Full Analysis Set 
All subjects who are randomized. Subjects will be classified 
according to the treatment assigned at randomization. The Full 
Analysis Set will be the primary population for evaluating all 
efficacy endpoints and subject characteristics. 
Per-protocol 
Analysis Set 
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 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 
All treated subjects who have at least 1 concentration above the 
limit of quantitation of the study treatment in RIST4721 arm 
only. 
9.3. 
Statistical Analyses 
9.3.1. 
General Considerations 
All individual data will be listed as measured. All statistical summaries and analyses will 
be performed using SAS software 
. 
Continuous data will be summarized using an 8-point descriptive summary (n, mean, 
standard deviation [SD], median, IQR [25% quartile, 75% quartile], minimum, and 
maximum) or 7 point descriptive summary (n, mean, SD, coefficient of variation [CV], 
median, minimum, and maximum) unless otherwise specified. 


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Categorical data will be summarized using the frequency of events and percentage of 
total events. 
Data will be presented by treatment group. Changes in primary, secondary, and 
exploratory endpoints will be analyzed over time, with change from baseline summarized 
for each post baseline time point measured. 
9.3.2. 
Baseline Descriptive Statistics 
Demographics and baseline characteristics (including age, sex, race, ethnicity, height, 
weight, and body mass index) will be summarized for the Full Analysis Set. 
Baseline clinical characteristics and history will be summarized. 
9.3.3. 
Efficacy Analysis 
The key secondary endpoint, proportion of subjects achieving HiSCR50 at Week 12, will 
be analyzed using Fisher’s exact test. Proportions and difference in proportions between 
treatment groups, and their associated 95% confidence intervals (CIs) will be reported. 
For subjects who discontinue study treatment prior to Week 12 due to any reason, their 
last observation will be used to impute response status. 
Fisher’s exact test will also be used to analyze additional secondary endpoints which are 
dichotomized in nature, eg, proportion of subjects achieving HiSCR75 at Week 12, 
proportion of subjects with flare by Week 12, and other proportion endpoints. 
Change from baseline in NRS skin pain score, change from baseline in IHS4, and other 
continuous endpoints will be summarized using descriptive statistics. Change from 
baseline of these continuous endpoints will also be analyzed by a Mixed-effects model 
for repeated measures (MMRM). MMRM will include baseline as a covariate, treatment 
and visit as factors, and treatment-by-visit and baseline-by-visit interactions in the model.  
9.3.4. 
Safety Analyses 
The Safety Analysis Set will be used for all safety analyses. All safety data will be 
presented in listings. Summary tables will be provided for concomitant medications, AE, 
hematology and chemistry laboratory results, vital signs, and ECG findings. Safety data 
will be summarized by treatment group using frequency of event or descriptive statistics, 
as appropriate. 
9.3.4.1. 
Extent of Exposure 
Dosing information for individual subjects will be listed. Using dosing data, estimates of 
exposure to study treatment will be summarized. Dose discontinuations and reasons for 
study treatment discontinuation will be listed and summarized. 
9.3.4.2. 
Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
TEAE summaries will be presented by SOC, Preferred Term, severity, and frequency and 
percentage of subjects reporting each observed event.  


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AEs that occur before the first dose of study treatment will be distinguished from TEAEs. 
All AEs and TEAEs will be listed by subject. The frequency of subjects who experience 
TEAEs will be summarized. TEAEs will also be summarized by relationship to study 
treatment and severity. A TEAE will be defined as an AE that 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. 
Listings will be provided for subjects who experience an SAE or discontinue study 
treatment/withdraw from the study because of an AE. 
9.3.4.3. 
Clinical Laboratory 
Clinical laboratory (eg, 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 (eg, 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. 
9.3.4.4. 
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. 
9.3.4.5. 
Electrocardiograms 
QT intervals will be corrected for heart rate (QTc) using standard correction factors (eg, 
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. 
9.3.5. 
Pharmacokinetics Analyses 
A descriptive summary of observed plasma concentrations of RIST4721will be displayed 
by time and by treatment group. Full details of the PK analysis will be provided in the 
SAP. 
9.4. 
Planned Interim Analyses 
No interim analysis is planned for this study. 


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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 (eg, 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 


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meets the requirements of 21 CFR 50, ICH guidelines, local regulations, and data privacy 
laws (eg, The General Data Protection Regulation (EU) 2016/679 [GDPR] and Health 
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. 
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 (eg, 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. 


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Details describing monitoring strategy (eg, 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 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 (eg, 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. 


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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. 
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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ratio; LDH, lactate dehydrogenase; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular 
hemoglobin concentration; MCV, mean corpuscular volume; MPV, mean platelet volume; PCR, polychain 
reaction; PLT, platelets; PPD, purified protein derivative; PT, prothrombin time; RBC, red blood cell; WBC, 
white blood cell; WOCBP, women of childbearing potential. 














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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 (eg, 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, (eg, 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. 


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10.4.2. 
Contraception Guidance 
There is no known drug interaction between RIST4721 and hormonal contraception. 
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 
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 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 WOCBP. 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: 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 (eg, 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 (eg, 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, eg, 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 (eg, 
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 reassessed 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 (eg, 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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REFERENCES 
 
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Alikhan, A., Lynch, P. J. and Eisen, D. B. (2009). "Hidradenitis suppurativa: a 
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Deckers, I. E., van der Zee, H. H. and Prens, E. P. (2014). "Epidemiology of Hidradenitis 
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EMA (April 2020). Guidance on the management of clinical trials during the COVID-19 
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Garg, A., Kirby, J. S., Lavian, J., Lin, G. and Strunk, A. (2017). "Sex- and Age-Adjusted 
Population Analysis of Prevalence Estimates for Hidradenitis Suppurativa in the United 
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Health Canada (April 7, 2020). Management of clinical trials during the COVID-19 
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Hurley, H. (1996). " Axillary hyperhidrosis, apocrine bromhidrosis, hidradenitis 
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Jamieson, T., Clarke, M., Steele, C. W., Samuel, M. S., Neumann, J., Jung, A., et al. 
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Kelly, G., Hughes, R., McGarry, T., van den Born, M., Adamzik, K., Fitzgerald, R., et al. 
(2015). "Dysregulated cytokine expression in lesional and nonlesional skin in hidradenitis 
suppurativa." Br J Dermatol 173(6): 1431-1439. 
 
Kimball, A. B., Jemec, G. B., Yang, M., Kageleiry, A., Signorovitch, J. E., Okun, M. M., 
et al. (2014). "Assessing the validity, responsiveness and meaningfulness of the 
Hidradenitis Suppurativa Clinical Response (HiSCR) as the clinical endpoint for 
hidradenitis suppurativa treatment." Br J Dermatol 171(6): 1434-1442. 
 
Kimball, A. B., Kerdel, F., Adams, D., Mrowietz, U., Gelfand, J. M., Gniadecki, R., et al. 
(2012). "Adalimumab for the treatment of moderate to severe Hidradenitis suppurativa: a 
parallel randomized trial." Ann Intern Med 157(12): 846-855. 
 


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Kirby, J. S., Hereford, B., Thorlacius, L., Villumsen, B., Ingram, J. R., Garg, A., et al. 
(2021). "Validation of global item for assessing impact on quality of life of patients with 
hidradenitis suppurativa*." British Journal of Dermatology 184(4): 681-687. 
 
Kirby, J. S., Thorlacius, L., Villumsen, B., Ingram, J. R., Garg, A., Christensen, K. B., et 
al. (2020). "The Hidradenitis Suppurativa Quality of Life (HiSQOL) score: development 
and validation of a measure for clinical trials." British Journal of Dermatology 183(2): 
340-348. 
 
Lim, S. Y. D. and Oon, H. H. (2019). "Systematic review of immunomodulatory 
therapies for hidradenitis suppurativa." Biologics 13: 53-78. 
 
MHRA (March 19, 2020). Guidance: Managing clinical trials during Coronavirus 
(COVID-19). Last updated November 16, 2021. from 
https://www.gov.uk/guidance/managing-clinical-trials-during-coronavirus-covid-19. 
 
Moran, B., Sweeney, C. M., Hughes, R., Malara, A., Kirthi, S., Tobin, A. M., et al. 
(2017). "Hidradenitis Suppurativa Is Characterized by Dysregulation of the Th17:Treg 
Cell Axis, Which Is Corrected by Anti-TNF Therapy." J Invest Dermatol 137(11): 2389-
2395. 
 
Napolitano, M., Mastroeni, S., Fusari, R., Mazzanti, C., Ciccone, D., Pallotta, S., et al. 
(2020). "The International Hidradenitis Suppurativa Severity Score System (IHS4) is a 
valuable tool to assess gender-associated differences." Eur J Dermatol. 
 
Napolitano, M., Megna, M., Timoshchuk, E. A., Patruno, C., Balato, N., Fabbrocini, G., 
et al. (2017). "Hidradenitis suppurativa: from pathogenesis to diagnosis and treatment." 
Clin Cosmet Investig Dermatol 10: 105-115. 
 
Narla, S., Azzam, M., Townsend, S., Vellaichamy, G., Marzano, A. V., Alavi, A., et al. 
(2021). "Identifying key components and therapeutic targets of the immune system in 
hidradenitis suppurativa with an emphasis on neutrophils." Br J Dermatol 184(6): 1004-
1013. 
 
Navrazhina, K., Garcet, S., Gonzalez, J., Grand, D., Frew, J. W. and Krueger, J. G. 
(2021). "In-Depth Analysis of the Hidradenitis Suppurativa Serum Proteome Identifies 
Distinct Inflammatory Subtypes." J Invest Dermatol 141(9): 2197-2207. 
 
Nicholls, D. J., Wiley, K., Dainty, I., MacIntosh, F., Phillips, C., Gaw, A., et al. (2015). 
"Pharmacological characterization of AZD5069, a slowly reversible CXC chemokine 
receptor 2 antagonist." J Pharmacol Exp Ther 353(2): 340-350. 
 
Preda-Naumescu, A., Ahmed, H. N., Mayo, T. T. and Yusuf, N. (2021). "Hidradenitis 
suppurativa: pathogenesis, clinical presentation, epidemiology, and comorbid 
associations." Int J Dermatol. 
 


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Prens, E. and Deckers, I. (2015). "Pathophysiology of hidradenitis suppurativa: An 
update." J Am Acad Dermatol 73(5 Suppl 1): S8-11. 
 
Revuz, J. E., Canoui-Poitrine, F., Wolkenstein, P., Viallette, C., Gabison, G., Pouget, F., 
et al. (2008). "Prevalence and factors associated with hidradenitis suppurativa: results 
from two case-control studies." J Am Acad Dermatol 59(4): 596-601. 
 
Sabat, R., Jemec, G. B. E., Matusiak, Ł., Kimball, A. B., Prens, E. and Wolk, K. (2020). 
"Hidradenitis suppurativa." Nature Reviews Disease Primers 6(1): 18. 
 
Saunte, D. M. L. and Jemec, G. B. E. (2017). "Hidradenitis Suppurativa: Advances in 
Diagnosis and Treatment." Jama 318(20): 2019-2032. 
 
Scala, E., Cacciapuoti, S., Garzorz-Stark, N., Megna, M., Marasca, C., Seiringer, P., et al. 
(2021). "Hidradenitis Suppurativa: Where We Are and Where We Are Going." Cells 
10(8). 
 
Silverberg, J. I. (2021). "Validity and reliability of a novel numeric rating scale to 
measure skin-pain in adults with atopic dermatitis." Arch Dermatol Res. 
 
van Straalen, K. R., Schneider-Burrus, S. and Prens, E. P. (2020). "Current and future 
treatment of hidradenitis suppurativa." Br J Dermatol 183(6): e178-e187. 
 
Vazquez, B. G., Alikhan, A., Weaver, A. L., Wetter, D. A. and Davis, M. D. (2013). 
"Incidence of hidradenitis suppurativa and associated factors: a population-based study of 
Olmsted County, Minnesota." J Invest Dermatol 133(1): 97-103. 
 
von Laffert, M., Helmbold, P., Wohlrab, J., Fiedler, E., Stadie, V. and Marsch, W. C. 
(2010). "Hidradenitis suppurativa (acne inversa): early inflammatory events at terminal 
follicles and at interfollicular epidermis." Exp Dermatol 19(6): 533-537. 
 
Vossen, A., van der Zee, H. H. and Prens, E. P. (2018). "Hidradenitis Suppurativa: A 
Systematic Review Integrating Inflammatory Pathways Into a Cohesive Pathogenic 
Model." Front Immunol 9: 2965. 
 
Wipperman, J., Bragg, D. A. and Litzner, B. (2019). "Hidradenitis Suppurativa: Rapid 
Evidence Review." Am Fam Physician 100(9): 562-569. 
 
Wolk, K., Join-Lambert, O. and Sabat, R. (2020). "Aetiology and pathogenesis of 
hidradenitis suppurativa." Br J Dermatol 183(6): 999-1010. 
 
Zouboulis, C. C., Tzellos, T., Kyrgidis, A., Jemec, G. B. E., Bechara, F. G., Giamarellos-
Bourboulis, E. J., et al. (2017). "Development and validation of the International 
Hidradenitis Suppurativa Severity Score System (IHS4), a novel dynamic scoring system 
to assess HS severity." Br J Dermatol 177(5): 1401-1409. 
 

SAP_001.pdf: 
 Proprietary & Confidential
Page 1 of 57
Statistical Analysis Plan
Study Title:
A Randomized, Double-blinded, Placebo-Controlled, 
Phase 2a Study to Evaluate the Efficacy and Safety of 
RIST4721 in Subjects with Hidradenitis Suppurativa
Protocol Number and Version:
RIST4721-221 V1.0 USA, dated 11-Feb-2022
RIST4721-221 V1.1 Canada, dated 08-Apr-2022
Product:
RIST4721
Sponsor:
Aristea Therapeutics
Date:
21-Feb-2023
Version:
Final, V1.0
Prepared by:


STATISTICAL ANALYSIS PLAN, Final, V1.0
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STATISTICAL ANALYSIS PLAN REVISION SUMMARY
Version
Version Date
Author
Summary of Changes
Final V1.0
21-Feb-2023
Initial version


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SIGNATURE PAGE
AUTHOR:
Name
Title
Signature
Date
(DD-MMM-YYYY)
APPROVALS:
Name
Title
Signature
Date
(DD-MMM-YYYY)
This statistical analysis plan will be reviewed and revised as needed. The most recent version will replace 
the previous version in place.


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TABLE OF CONTENT
1 
INTRODUCTION..................................................................................................................10 
2 
STUDY OBJECTIVES, ENDPOINTS, AND ESTIMAND ...............................................10 
3 
STUDY DESIGN....................................................................................................................12 
3.1 
Overall Design ................................................................................................................12 
3.2 
Schedule of Activities.....................................................................................................14 
3.3 
Treatment .......................................................................................................................19 
3.4 
Randomization, Replacement, and Unblinding Procedures ......................................19 
3.5 
Absolute Neutrophil Count Laboratory Abnormality................................................20 
3.6 
Changes to the Analysis from the Protocol..................................................................23 
4 
POPULATIONS FOR ANALYSIS......................................................................................26 
4.1 
All Screened Subjects Analysis Set...............................................................................26 
4.2 
Full Analysis Set.............................................................................................................26 
4.3 
Per-Protocol Analysis Set ..............................................................................................27 
4.4 
Safety Analysis Set .........................................................................................................27 
4.5 
Pharmacokinetic Analysis Set.......................................................................................27 
5 
GENERAL CONSIDERATIONS ........................................................................................27 
5.1 
Reference Start Date and Study Day............................................................................27 
5.2 
Baseline ...........................................................................................................................28 
5.3 
On-Treatment.................................................................................................................28 
5.4 
Change and Percent from Baseline ..............................................................................28 
5.5 
Handling of Retests Data...............................................................................................28 
5.6 
Windowing Conventions................................................................................................28 
6 
STATISTICAL CONSIDERATIONS .................................................................................29 
6.1 
Sample Size.....................................................................................................................29 
6.2 
Descriptive Statistics......................................................................................................29 
6.3 
Handling of Dropouts or Missing data.........................................................................30 
6.3.1 
Efficacy Endpoints.........................................................................30 
6.3.1.1 
LOCF ...........................................................................30 
6.3.1.2 
Non-Responder Imputation..........................................30 
6.3.1.3 
Modified LOCF ...........................................................30 
6.3.1.4 
MMRM ........................................................................31 
6.3.2 
Safety Endpoints............................................................................31 
6.4 
Multicenter Studies........................................................................................................31 
6.5 
Adjustments for Covariates ..........................................................................................31 
6.6 
Statistical Tests...............................................................................................................31 
6.7 
Interim Analysis and Data Monitoring........................................................................31 


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6.8 
Multiple Comparisons/Multiplicity..............................................................................31 
6.9 
Examination of Subgroups............................................................................................32 
6.10 
Software Version............................................................................................................32 
7 
STUDY SUBJECTS...............................................................................................................32 
7.1 
Disposition of Subjects...................................................................................................32 
7.2 
Protocol Deviations ........................................................................................................33 
8 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................34 
9 
SURGICAL AND MEDICAL HISTORY...........................................................................35 
10 
PRIOR AND CONCOMITANT MEDICATIONS.............................................................35 
11 
EXPOSURE TO AND COMPLIANCE WITH STUDY TREATMENT .........................36 
12 
EFFICACY ANALYSIS........................................................................................................37 
12.1 
Primary Efficacy Analysis.............................................................................................37 
12.2 
Key Secondary Efficacy Analysis .................................................................................37 
12.2.1 
Definition and Estimand of Key Secondary Efficacy 
Endpoint.........................................................................................37 
12.2.2 
Hypothesis Testing.........................................................................38 
12.2.3 
Main Analysis of Key Secondary Efficacy Endpoint....................38 
12.2.4 
Sensitivity Analyses to Main Analysis of the Key 
Secondary Efficacy Endpoint ........................................................39 
12.3 
Other Secondary Efficacy Analyses .............................................................................40 
12.3.1 
Definition of Other Secondary Efficacy Endpoints.......................40 
12.3.2 
Main Analysis of Other Secondary Efficacy Endpoints................41 
12.3.3 
Sensitivity Analyses to Other Secondary Efficacy Endpoint
........................................................................................................42 
12.4 
Exploratory Efficacy Analyses......................................................................................42 
12.4.1 
Definition of Exploratory Efficacy Endpoints...............................42 
12.4.2 
Main Analysis of Exploratory Efficacy Endpoints........................46 
12.4.3 
Sensitivity Analyses to Exploratory Efficacy Endpoint ................46 
12.5 
Additional Efficacy Analyses ........................................................................................46 
12.6 
Subgroup Analyses.........................................................................................................47 
13 
SAFETY ANALYSIS.............................................................................................................47 
13.1 
Adverse Events...............................................................................................................47 
13.2 
Clinical Laboratory........................................................................................................49 
13.3 
Vital Signs.......................................................................................................................49 
13.4 
ECG.................................................................................................................................50 


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13.5 
Physical Examination ....................................................................................................50 
14 
PHARMACOKINETICS ANALYSIS.................................................................................50 
15 
REFERENCES.......................................................................................................................51 


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ABBREVIATIONS
AE
adverse event
AICC
Akaike’s information criteria corrected
ALT
alanine aminotransferase
AN
abscess and inflammatory nodule
ANC
absolute neutrophils count
ANTE(1)
first-order ante dependence
aPTT
activated partial thromboplastin time
ARH(1)
heterogenous first-order autoregressive
AST
aspartate aminotransferase
ATC
anatomical therapeutic chemical
β-hCG
β-human chorionic gonadotropin
BLQ
below the limit of quantification
BMI
body mass index
BUN
blood urea nitrogen
CI
confidence interval
CRO
contract research organization
CSR
clinical study report
CV
coefficient of variation
DBP
diastolic blood pressure
DLQI
dermatology life quality index
ECG
electrocardiogram
eCRF 
electronic case report form 
EOT
end of treatment
FAS
full analysis set
FSH
follicle stimulating hormone
GGT
gamma-glutamyl-transferase
HBsAG
hepatitis B surface antigens
HBc
anti-core hepatitis B
HCT
hematocrit
HCV
hepatitis C virus
Hgb
hemoglobin
HiSCR50
hidradenitis suppurativa clinical response 50
HiSCR75
hidradenitis suppurativa clinical response 75
HiSQOL
hidradenitis suppurativa quality of life
HIV
human immunodeficiency virus
HR
heart rate
HRQOL
health-related quality of life
HS
hidradenitis suppurativa
hs-CRP
high-sensitivity C-reactive protein
HS-IGA
hidradenitis suppurativa-Investigator’s global assessment
HS-PGA
hidradenitis suppurativa-physician global assessment
ICF
informed consent form


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INR
international normalized ratio
IHS4
hidradenitis suppurativa severity score system
IWRS
interactive web response system
LDH
lactate dehydrogenase
LLN
lower limit of normal
LOCF
last observation carried forward
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM
mixed model for repeated measurements
MPV
mean platelet volume
msec
millisecond
NRI
non-responder imputation
NRS
numerical rating scale
PCR
polymerase chain reaction
PD
protocol deviation
PDMP
protocol deviation management plan
PLT
platelets
PP
per-protocol (population)
PPD
purified protein derivative
PK
pharmacokinetic
PT
preferred term
Q1
25% percentile
Q3
75% percentile
QD
once a day
QTcF
Fridericia’s correction formula for QT interval
RBC
red blood cell
S
serum
SAE
serious adverse event 
SAP
statistical analysis plan 
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SAS
statistical analysis system®
SBP
systolic blood pressure
SD
standard deviation
SE
standard error
SI
international system of units, universally abbreviated as SI (from the French 
‘système international')
SoA
schedule of activities
SOC
system organ class
SUSAR
suspected unexpected serious adverse reactions
TB
tuberculosis
TEAE
treatment emergent adverse event 
TLF
tables, listings, and figures


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TOEPH
heterogenous Toeplitz
U
urine
USA
United States of America
WBC
white blood cell
WHO-DD
World Health Organization Drug Dictionary 
WOCBP
women of childbearing potential


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1 INTRODUCTION
This statistical analysis plan (SAP) describes the analyses that were planned to be performed and 
reported for Aristea Therapeutics clinical protocol RIST4721-221 United States of America (USA)
version 1.0, dated 11-Feb-2022, and Canada version 1.1, dated 08-Apr-2022. Due to safety 
reasons, the study Sponsor, Aristea Therapeutics, has reached the decision of terminating the study.
In consequence, an abbreviated clinical study report (CSR) will be produced in lieu of a full CSR.  
At the time the decision was made, the current SAP had been written and reviewed. Rather than 
eliminating the unneeded analyses for the abbreviated CSR, a table of content for selected tables, 
listings, and figures (TLFs) are provided in Appendix 1. The analysis method of the selected TLFs 
for the abbreviated CSR will follow what is stated in this SAP.
This SAP was developed prior to database lock, study unblinding, and final analyses. All final 
analyses will be performed after the signature of this SAP. data are entered into the database, any 
discrepancies in the data are resolved, database is locked, and study is unblinded. The approval of 
this SAP will also stand for the approval of the inclusion/exclusion of each subject into each 
analysis population (refer to Section 4) since all outputs that will be produced for the abbreviated 
CSR are based on an analysis population including only objective criteria in their definition.
Analyses related to biomarker data are not covered in this SAP and will be described in a separate 
document.
2 STUDY OBJECTIVES, ENDPOINTS, AND ESTIMAND
OBJECTIVE
ENDPOINT AND ESTIMAND (when applicable)
Primary
Primary endpoint:
To assess the safety and 
tolerability of RIST4721 
monotherapy in subjects 
with moderate to severe 
hidradenitis suppurativa 
(HS)
x Incidence of treatment emergent adverse events (TEAEs) and 
serious adverse events (SAEs)


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OBJECTIVE
ENDPOINT AND ESTIMAND (when applicable)
Secondary
Secondary endpoint:
To assess the efficacy of 
RIST4721 in subjects 
with moderate to severe 
HS
Key secondary efficacy endpoint and estimand:
Treatment regimen: RIST4721 400 mg and placebo
Target population: Subjects with HS as defined by the 
inclusion and exclusion criteria (refer to protocol Section 5), 
grouped per randomized treatment
Variable of interest (endpoint): Proportion of subjects 
achieving hidradenitis suppurativa clinical response 50 
(HiSCR50) at Week 12 defined as at least 50% reduction in 
the total abscesses and inflammatory nodule (AN) count with 
no increase in abscess count and no increase in draining fistula 
count relative to baseline
Intercurrent events and corresponding strategy: For 
subjects who discontinue study treatment prior to Week 12 
due to any reason, their last observation will be used to impute 
response status
Population-level 
summary 
variable: 
Difference 
in 
proportions
Other secondary efficacy endpoints:
x Proportion of subjects achieving hidradenitis suppurativa
clinical response 75 (HiSCR75) at Week 12
x Proportion of subjects with flare (≥ 25% increase and ≥ 2 
absolute increase in AN count relative to baseline) at Week 12
x Proportion of subjects achieving AN count of 0, 1, or 2 at 
Week 12
x Change from baseline in skin pain score using the numeric 
rating scale (NRS) at Week 12
x Change from baseline in international HS severity score 
system (IHS4) at Week 12
To assess PK of 
RIST4721 in subjects 
with moderate to severe 
HS
x RIST4721 PK characterization in subjects with moderate to 
severe HS


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OBJECTIVE
ENDPOINT AND ESTIMAND (when applicable)
Exploratory
To assess the effect of 
RIS4721 on exploratory 
measures of efficacy in 
subjects with moderate to 
severe HS
x Proportion of subjects achieving at least 2-grade improvement 
on the HS-physician global assessment (HS-PGA) relative to 
baseline
x Proportion of subjects achieving 0 or 1 on the HS-PGA
x Proportion of subjects with HS-Investigator’s global 
assessment (HS-IGA) with at least 2-grade improvement 
relative to baseline at Week 12
x Proportion of subjects achieving 0 or 1 on the HS-IGA
x Change from baseline in AN count at Week 12
x Change from baseline in HS quality of life (HiSQOL) total 
and subscale scores
x Change from baseline in dermatology life quality index 
(DLQI) total score at Week 12
3 STUDY DESIGN
3.1 Overall Design
This is a Phase 2a, randomized, double-blind, placebo-controlled, multicenter, 12-week study to 
evaluate the efficacy and safety of RIST4721 once a day (QD) in subjects with moderate to severe 
HS.  Approximately 33 subjects are planned to be enrolled (approximately 22 subjects expected in 
the RIST4721 group and 11 subjects in the placebo group).
The study will consist of a 4-week screening period, a 12-week treatment period, and a 4-week 
follow-up period. Study scheme is shown in Figure 1.


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Figure 1: Study Scheme
After signing the informed consent form (ICF), subjects will be screened for eligibility over 4 
weeks. At each 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, which will 
contain the stie number and the subject number, will be assigned in numerical order at the 
screening visit based on chronological order of screening dates (eg, 02-010 for the 10th subject 
screened at Site #02).
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.
On Day 1 (baseline visit), eligible subjects will be randomized in 2:1 ratio to receive oral study 
treatment for 12 weeks:
x
RIST4721 400 mg QD
x
Placebo QD
All subjects who remain on study treatment through and including Week 12 will be asked to return 
for a follow-up visit, approximately 4 weeks after their last dose of study treatment, to assess safety 
and efficacy. Permanent discontinuation of study treatment will not mean withdrawal from the 
study, and the subject will be encouraged to remain in the study, complete the end of treatment 


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(EOT) visit at the time of study treatment discontinuation, and then continue to complete remaining 
study visits as per the schedule of activities (SoA; refer to 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 the EOT visit and then will attend the Follow-up visit 4 weeks after last dose 
of study treatment.
3.2 Schedule of Activities
Table 1 provides a description of the procedures planned at each visit.


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Table 1: Schedule of Activities
Screening
Treatment Period
Follow-up
Notes
Study Week
-4 to -1
Baseline 
(Week 0)
2
4
8
12/EOT
+4 Weeks from EOT
End of treatment (EOT); subjects discontinuing 
treatment prematurely will attend EOT visit 
and then continue study visits as planned.
Study Day
-28 to -1
1
15
29
57
85
+28 days from EOT
Visit Window (days)
±3
±3
±3
±7
±3
Screening/Administrative
Informed consent
X
Demographics, social, and family 
history
X
Eligibility criteria
X
X
Medical and medication history
X
Including general medical history, hidradenitis 
suppurativa medical history, and prior 
therapies.
Height
X
Pulse oximetry
X
Hurley Stage Classification
X
X
Serology (HBV [HBsAg, anti-
HBc], HCV, HIV)
X
If a subject has a positive test, confirmatory 
serology will be performed. Refer to protocol 
Appendix 2, Section 10.2.
Hepatitis B surface antigens (HBsAg), 
antibodies to anti-core hepatitis B (HBc), 
hepatitis C virus (HCV), human 
immunodeficiency virus (HIV).
PPD or QuantiFERON-TB Gold 
test
X
Purified protein derivative (PPD); tuberculosis 
(TB)
Refer to protocol Appendix 2, Section 10.2
If done within 6 months and negative result is 
available for documentation, test is not required 
at screening.


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Screening
Treatment Period
Follow-up
Notes
Study Week
-4 to -1
Baseline 
(Week 0)
2
4
8
12/EOT
+4 Weeks from EOT
End of treatment (EOT); subjects discontinuing 
treatment prematurely will attend EOT visit 
and then continue study visits as planned.
Study Day
-28 to -1
1
15
29
57
85
+28 days from EOT
Visit Window (days)
±3
±3
±3
±7
±3
SARS-CoV-2 PCR test 
X
Severe acute respiratory syndrome coronavirus 
2 (SARS-CoV-2); polymerase chain reaction 
(PCR).
Urine drug screen
X
Refer to protocol Appendix 2, Section 10.2.
Pregnancy test (for WOCBP)
S
U
U
U
U
U
U
Serum (S); Urine (U); women of childbearing 
potential (WOCBP)
If urine test is positive, confirm with serum 
test.
FSH (postmenopausal women 
only)
X
Follicle stimulating hormone (FSH)
Study Treatment Administration
Randomization
X
Study treatment distribution
X
X
X
In clinic study treatment 
administration
X
X
X
X
X
Study treatment accountability
X
X
X


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Screening
Treatment Period
Follow-up
Notes
Study Week
-4 to -1
Baseline 
(Week 0)
2
4
8
12/EOT
+4 Weeks from EOT
End of treatment (EOT); subjects discontinuing 
treatment prematurely will attend EOT visit 
and then continue study visits as planned.
Study Day
-28 to -1
1
15
29
57
85
+28 days from EOT
Visit Window (days)
±3
±3
±3
±7
±3
Safety Assessments
Adverse events
Xa
<==================== X ======================>
a. AEs will be collected after signing informed 
consent.
Concomitant medications
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
Assessments should occur in the following 
order:
1. Vital signs
2. 12-lead ECG (refer to protocol 
Section 8.3.3)
3. Blood draws for safety laboratories; refer to 
protocol Appendix 2, Section 10.2
Note: questionnaires are recommended to be 
completed before any of these procedures.
Weight
X
X
X
Physical examination
X
X
12-lead electrocardiogram (ECG) 
X
X
X
X
X
X
X
Serum chemistry 
X
X
X
X
X
X
X
Hematology 
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
SARS-CoV-2 antigen test 
X
X
X
X
X
X
If positive, will be confirmed with SARS-CoV-
2 PCR test.
Efficacy/PK Assessments
HiSCR assessment
X
X
X
X
X
X
HS Clinical Response (HiSCR).
Calculated based on abscess and inflammatory 
nodule (AN) count
Lesion Count
X
X
X
X
X
X
X
Includes AN and draining fistula
NRS for skin pain
X
X
X
X
X
X
X
Numeric rating scale (NRS).
IHS4
X
X
X
X
X
X
International Hidradenitis Suppurativa Severity 
Score System (IHS4).


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Screening
Treatment Period
Follow-up
Notes
Study Week
-4 to -1
Baseline 
(Week 0)
2
4
8
12/EOT
+4 Weeks from EOT
End of treatment (EOT); subjects discontinuing 
treatment prematurely will attend EOT visit 
and then continue study visits as planned.
Study Day
-28 to -1
1
15
29
57
85
+28 days from EOT
Visit Window (days)
±3
±3
±3
±7
±3
HS-IGA
X
X
X
X
X
X
Hidradenitis Suppurativa-Investigator's Global 
Assessment (HS-IGA).
HS-PGA
X
X
X
X
X
X
Physician Global Assessment (HS-PGA).
HiSQOL
X
X
X
HS Quality of Life (HiSQOL).
DLQI
X
X
X
Dermatology Life Quality Index (DLQI).
Medical photography of HS-
affected areas
X
X
To be performed at select sites. 
Serum sample for RIST4721 
concentration
X
X
X
X
X
Blood samples for trough PK will be collected 
pre-dose; subjects will be requested to hold 
their dose on clinic visits until after PK 
samples are obtained; a PK sample will also be 
collected if a subject experience a potentially 
related SAE (refer to protocol Section 8.5.1).
Serum sample for biomarkers
X
X
X
X
X
X
To be collected and stored for future analyses.


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3.3 Treatment
The treatment groups are:
x
RIST4721 400 mg QD (ie, 4 tablets of 100 mg each QD)
x
Placebo QD (ie, 4 tablets QD)
3.4 Randomization, Replacement, and Unblinding Procedures
On Day 1 (baseline visit), eligible subjects will be centrally randomized in 2:1 ratio to receive oral 
study treatment for 12 weeks using interactive web response system (IWRS):
x
RIST4721 400 mg QD
x
Placebo QD
Subjects who withdrew from the study or discontinue study treatment after randomization will not 
be replaced.
This study 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 final safety and efficacy results will remain 
blinded to treatment assignments until after the completion of the study and the database has been 
locked.
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, and performance of bioanalytical analysis of PK. These personnel will not be 
directly involved in the conduct of the study.
The IWRS 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 has 
been broken will be discontinued from the study and undergo the EOT procedures as specified in
the SoA (refer to Table 1).
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 


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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 contract research organization (CRO) personnel, and the Sponsor’s study team will not 
receive absolute or relative neutrophils and white blood cell (WBC) count results. 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 absolute neutrophil count (ANC) reach values below the reference range of the 
lower limit of normal (LLN) for the central laboratory, in which case immediate actions will be 
taken, as described in Section 3.5.
Refer to the study Biostatistics Unblinding Plan for additional information on study blinding and 
unblinding procedures.
3.5 Absolute Neutrophil Count Laboratory Abnormality
There will be evaluation of the neutrophil counts and WBC performed by an independent Medical 
Monitor in order to reduce the risk of breaking the blind. 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 neutrophils 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. 
The investigator must notify the Sponsor’s Medical Monitor (or designee) within 48 hours of dose 
interruption. Once the ANC result is above the LLN, subjects may re-initiate blinded study 
treatment by reducing the study treatment dose to 2 tablets QD (regardless of treatment group) 
with approval from the Sponsor’s Medical Monitor (or designee).
Subjects may be requested to attend an unscheduled visit after dose reduction to collect blood 
samples for safety and plasma concentrations, if possible.


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For subjects who have already experienced a dose reduction: If a subject experiences another case 
of ANC results 1.0 x 109/L, they must permanently discontinue study treatment (refer to protocol 
Section 7.1).


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Figure 2: Steps for Addressing Absolute Neutrophil Counts
Abbreviations: ANC, absolute neutrophil count; LLN, lower limit of normal (central laboratory).


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3.6 Changes to the Analysis from the Protocol
Table 2: Summary of Changes to the Protocol
Description of the change
Rationale for change
Exploratory efficacy endpoint (refer to 
protocol Section 3)
“Proportion of subjects achieving at least 
2-grade improvement on the HS-physician 
global assessment (HS-PGA)” 
was updated to (refer to Section 2)
“Proportion of subjects achieving at least 
2-grade improvement on the HS-physician 
global assessment (HS-PGA) relative to 
baseline”
To clarify period of improvement that needs to be 
considered
Exploratory efficacy endpoint (refer to 
protocol Section 3)
“Change from baseline in HS quality of 
life (HiSQOL)” 
was updated to (refer to Section 2)
“Change from baseline in HS quality of 
life (HiSQOL) total and subscale scores”
To clarify that both the HiSQOL total score and 
HiSQOL subscale scores will be analyzed


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Description of the change
Rationale for change
Per protocol analysis set definition (refer 
to protocol Section 9.2)
“Randomized subjects who received at 
least 1 dose of study treatment and do not 
have major protocol deviations expected 
to impact the primary objective of the 
study.  The Per protocol analysis set will 
be used for sensitivity analyses for the 
primary efficacy endpoint.”
was updated to (refer to Section 4.3)
“Randomized subjects who received at 
least 1 dose of study treatment and do not 
have major protocol deviations expected 
to impact the key secondary efficacy 
endpoint of the study.  The Per protocol 
analysis set will be used for sensitivity 
analyses for the key secondary efficacy 
endpoint.”
The per protocol analysis set should be used to 
perform sensitivity analysis for the key secondary 
efficacy endpoint, corresponding to one of the 
secondary objectives of the study, not to 
performed sensitivity analysis for the incidence 
of TEAEs and SAEs, corresponding to the 
primary objective of the study


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Description of the change
Rationale for change
Summarization of continuous data (refer 
to protocol Section 9.3.1)
“Continuous data will be summarized 
using an 8-point descriptive summary (n, 
mean, standard deviation [SD], median, 
IQR [25% quartile, 75% quartile], 
minimum, and maximum) or 7-point 
descriptive summary (n, mean, SD, 
coefficient of variation [CV], median, 
minimum, and maximum) unless 
otherwise specified” 
was updated to (refer to Section 6.2)
“Continuous variables will be summarized 
using descriptive statistics (number of 
subjects with available data [n], mean, 
standard deviation [SD], median, IQR 
(25% quartile, 75% quartile), minimum, 
and maximum).  For, PK concentration 
data, the geometric mean, coefficient of 
variation (CV), and geometric CV will 
also be provided.”
To clarify that CV will only be used to 
summarize the PK concentration data.


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Description of the change
Rationale for change
Exclusion of lesion that required an 
intervention from lesion count efficacy 
assessment (refer to protocol Section 
6.7.4)
“The specific treated lesion will be 
excluded from lesion count efficacy 
assessment for the remainder of the 
study.”
was updated to (refer to Sections 12.2.1,
12.3.1 and 12.4.1):
“Of note, lesions that required an 
intervention will be included in the lesion 
count efficacy assessment for the 
remainder of the study.”
Lesions that required an intervention will be 
included rather than excluded from the lesion 
count for the remainder of the study for all 
efficacy assessments in order to avoid artificially 
increase the percentage of reduction in lesion 
counts, which, in turn, would artificially increase 
the number of subjects reaching the key 
secondary efficacy endpoint (refer to Section 
12.2.1) and the other secondary/exploratory 
efficacy endpoints that are based on the lesion 
counts (refer to Sections 12.3.1 and 12.4.1).
4 POPULATIONS FOR ANALYSIS
Prior to the database lock, each subject inclusion/exclusion from each analysis set will be reviewed 
and finalized by the Sponsor and CRO in a blinded fashion. 
4.1 All Screened Subjects Analysis Set
The all screened subject analysis set include all subjects who signed the ICF.
This analysis set will be used to summarize subject disposition.
4.2 Full Analysis Set
The full analysis set (FAS) will include all randomized subjects who received at least 1 dose of 
study treatment. All subjects will be analyzed according to the treatment group to which they were 
randomized.
The FAS will be the primary population for evaluating all efficacy endpoints and subject 
characteristics.


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4.3 Per-Protocol Analysis Set
The per-protocol (PP) analysis set will include a subset of the FAS ie, randomized subjects who
received at least 1 dose of study treatment and do not have major protocol deviations (PDs)
expected to impact the key secondary efficacy endpoint of the study (refer to Section 7.2). All 
subjects will be analyzed according to the treatment group to which they were randomized.
The PP analysis set will be used for a supportive analysis to the main analysis of the key secondary
efficacy endpoint.
4.4 Safety Analysis Set
The safety analysis set will include all subjects who received at least 1 dose of study treatment. 
All subjects will be analyzed according to the treatment group to which they were randomized 
unless the incorrect treatment is received throughout the dosing period, in which case subjects will 
be analyzed according to the first treatment received.
The safety analysis set will be the primary population for evaluating treatment administration/ 
compliance and safety endpoint.
4.5 Pharmacokinetic Analysis Set
The PK analysis set will include all subjects who have at least 1 concentration above the limit of 
quantification of the study treatment in RIST4721 arm only.
The PK analysis set will be the primary population for evaluating the PK concentrations.
5 GENERAL CONSIDERATIONS
Formats and layouts of TLFs will be provided in a separate document (output general layout is 
described in Appendix 2).
5.1 Reference Start Date and Study Day
Study day will be calculated from the study treatment first dose date and will be used to show 
start/end day of assessments or events.
Study day = (assessment/event date – study treatment first dose date) + 1 if the 
assessment/event date is on or after the study treatment first dose date
or


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(assessment/event date – study treatment first dose date) if the 
assessment/event date is before the study treatment first dose date
In the situation where the assessment/event date is partial or missing, study day will be missing.
5.2 Baseline
Unless otherwise specified, baseline value will be defined as the last non-missing assessment prior 
to the first dose of study treatment (including unscheduled assessments). If the last non-missing 
assessment is performed on the same date as the first dose of study treatment and time is not 
available, the assessment will be considered as baseline, except for adverse events (AEs) not 
associated with a pre-dose assessment and medications starting on the same date as the first dose 
of study treatment which will be considered post-baseline. For partially or completely missing AEs
and medication start date, refer to Appendix 3.
5.3 On-Treatment
A subject is considered on-treatment from the date of his/her first dose of study treatment up to 
the date of the Week 12/EOT visit (refer to Table 1), inclusively.
5.4 Change and Percent from Baseline
Change from baseline will be computed as follows:
Change from baseline = Post-baseline visit value – Baseline value
Percent change from baseline will be computed as follows:
ሺΨሻൌ
େ୦ୟ୬୥ୣ୤୰୭୫ୠୟୱୣ୪୧୬ୣ୴ୟ୪୳ୣ
୆ୟୱୣ୪୧୬ୣ୴ୟ୪୳ୣ
x 100
5.5 Handling of Retests Data
When retests measurements are done for a specific visit, the retests measurements will be 
considered for that visit summary analysis. 
All data (original and retest) will be listed.
5.6 Windowing Conventions
Visits will be summarized and analyzed as scheduled. Data from unscheduled and EOT visits will 
only be included if data from a scheduled visit are not available, and the unscheduled/EOT visit 
falls within the analysis visit windows. Of note, only subjects who permanently discontinued study 


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treatment will complete an EOT visit (refer to Section 3.1) and, unless other specified in the 
efficacy, safety and PK analysis sections (refer to Sections 12, 13, and 14), data collected after the 
EOT visit will not be used in the by-visit summaries and analyses.
If there is more than one unscheduled/EOT visit with available data for a given analysis visit when 
data from the scheduled visit are not available, data from the unscheduled/EOT visit closest to the 
analysis visit target day will be considered for the analysis.
The following analysis visit windows will be used:
Analysis Visit
Target Day
Lower Limit
Upper Limit
Baseline
1
Refer to Section 5.2
Week 2
15
2
22
Week 4
29
23
43
Week 8
57
44
71
Week 12
85
72
99
Follow-up
113
100
N/A
Abbreviation: N/A, not applicable.
All data from scheduled, unscheduled, EOT, and Follow-up visits will be listed, including data 
collected after an EOT visit for subjects who remain in the study after the EOT visit.
6 STATISTICAL CONSIDERATIONS
6.1 Sample Size
Group sample sizes were chosen empirically for this initial Phase 2 study to determine the safety 
and tolerability of RIST4721.
6.2 Descriptive Statistics
Unless otherwise indicated, continuous variables will be summarized using descriptive statistics 
(number of subjects with available data [n], mean, standard deviation [SD], median, 25%
percentile [Q1], 75% percentile [Q3], minimum, and maximum). For, PK concentration data, the 
geometric mean, coefficient of variation (CV), and geometric CV will also be provided. 


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Categorical variables will be summarized using frequencies and percentages.
Summary tables will be presented by treatment group and visit, when applicable.
6.3 Handling of Dropouts or Missing data
Exception of missing data mentioned in the following sub-sections, no missing will be imputed.
6.3.1
Efficacy Endpoints
6.3.1.1
LOCF
For the main analysis of the key secondary efficacy endpoint (refer to Section 12.2.3) and other 
secondary efficacy endpoints that are dichotomous in nature (refer to Section 12.3.2), the last 
observation carried forward (LOCF) method will be used to impute missing post-baseline response 
status. Following the LOCF method, if a value is missing for a given post-baseline assessment, 
this value is imputed with the last non-missing post-baseline assessment (including unscheduled 
assessments) collected while subject was on-treatment (refer to Section 5.3) but prior to the 
missing assessment. That is, should post-baseline data be captured after the EOT visit for subjects 
who discontinued early from study treatment, these data will not be considered for this LOCF 
imputation.
6.3.1.2
Non-Responder Imputation
As a sensitivity analysis to the missing data imputation assumption used for the main analysis of 
the key secondary endpoint (refer to Sections 6.3.1.1 and 12.2.4), missing data will also be imputed 
as per the non-responder imputation (NRI) method . Following this method, if a value is missing 
for a given post-baseline assessment, this value is imputed to ‘No’ (ie, not achieving the endpoint 
criteria).
6.3.1.3
Modified LOCF
As sensitivity analysis to the missing data imputation assumption used for the main analysis of the 
key secondary endpoint (refer to Section 12.2.4), missing data will also be imputed using a 
modified version of the LOCF method (refer to Section 6.3.1.1) in which all non-missing post-
baseline data (including unscheduled assessments) collected prior to the missing assessment will 
be considered, regardless of if they were collected while subject was on-treatment (refer to Section 
5.3) or after as long as data have been collected prior to the missing assessment.


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6.3.1.4
MMRM
For the main analysis of other secondary efficacy endpoints that are continuous in nature (refer to 
Section 12.3.2), missing post-baseline data will not be imputed before being analyzed using a 
Mixed-Model for Repeated Measurements (MMRM) model since, under a MMRM model, the 
missing data are predicted by the observed data via the model of conditional mean.
6.3.2
Safety Endpoints
With the following exception, missing safety data will not be imputed. The exception is that 
partially or completely missing AEs and medication start and stop dates which will be imputed as 
per the algorithm described in Appendix 3. This imputation will be performed only to classify an 
AE as treatment-emergent or not (refer to Section 13.1) and a medication as concomitant or not 
(refer to Section 10). That is, imputed AE and medication dates will not be used for the derivation 
of any other variables (eg, AE start study day, AE duration, medication start study day, etc.) and 
will not be presented in the subject data listing.
6.4 Multicenter Studies
Data from all study sites will be pooled for the summary and analysis of the study data.
6.5 Adjustments for Covariates
For continuous efficacy endpoints, baseline values and baseline-by-visit interaction will be 
included in the MMRM model as covariates.
6.6 Statistical Tests
Unless otherwise specified, all statistical tests will be two-sided and performed with a significant 
level of 0.05. Confidence intervals (CIs) will be two-sided with 95% coverage.
6.7 Interim Analysis and Data Monitoring
No interim analysis (safety or efficacy/futility) is planned for this study.
6.8 Multiple Comparisons/Multiplicity
Given the exploratory nature of this study (eg, no formal sample size calculation was performed), 
no adjustments for multiple comparison will be made for this study. That is, all p-values will be 
nominal.


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6.9 Examination of Subgroups
The following subgroups will be examined for the key secondary efficacy endpoint (refer to 
Section 12.2.1) and other secondary efficacy endpoints (refer to Section 12.3.1):
x
Hurley stage (Stage I, Stage II, and Stage III) at baseline (refer to Section 5.2).
Details for these analyses are described in Section 12.6.
6.10 Software Version
All analyses will be performed using SAS® software Version 9.4 or higher.
7 STUDY SUBJECTS
7.1 Disposition of Subjects
All subjects who provide informed consent will be accounted for in this study. The number of 
subjects screened and rescreened will be presented. The number and percentage of subjects with 
screen failure will be presented based on the ‘all screened subjects’ analysis set. Screen failure will 
be further broken down by reason for screen failure based on the number of subjects with screen 
failure. First screen failure and reason for screen failure of rescreened subjects who did not fail the 
second screening (refer to Section 3.1) will not be reported in the summary table but will be 
included in the subject data listing.
The number of subjects randomized will be presented overall and by treatment group.
Number and percentage of randomized subjects who discontinued early from the study before 
receiving any study treatment (if any), completed study treatment, and discontinued early from 
study treatment will be presented overall and by treatment group based on the FAS. Early 
discontinuation from study treatment will be further broken down by reason for early 
discontinuation based on the number of FAS subjects who discontinued early from study 
treatment.
Number and percentage of subjects who completed or discontinued early from study will be 
presented overall and by treatment group based on the FAS.  Early discontinuation from study will 
be further broken down by reason for early discontinuation based on the number of FAS subjects 
who discontinued early from study.


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Number and percentage of subjects included in and excluded from each analysis set will be 
summarized overall and by treatment group based on the FAS population along with the reason(s) 
for exclusion from each analysis set (when applicable).
Number of days in the study will be calculated as follows and summarized using descriptive 
statistics overall and by treatment group:
Number of days in study (days) = (Date of study completion/ discontinuation – Date of 
first dose of study treatment) +1
A listing of subject’s disposition will be provided. Information on first screening for subjects who 
were rescreened, including the rescreened subject identifier, will be presented under the first 
screening subject identifier. A listing of subject’s randomization information and a listing of 
subjects included in and excluded from each of the analysis sets will also be provided, including 
reason(s) for exclusion.
7.2 Protocol Deviations
A data review will be conducted before database lock by the Medical Monitor and Sponsor to
classify each PD as major or minor (refer to the PD management plan [PDMP] for more details, 
including definition of major and minor PDs). Major PDs expected to impact the key secondary 
objective of the study (refer to Section 2) will also be identified during this data review and will 
result in the exclusion of the concerned subject from the PP analysis set (refer to Section 4.3).  
Major PDs expected to impact the key secondary objective of the study include, but are not limited 
to:
x
Violation of key inclusion/exclusion criteria
x
Randomized to RIST4721 but received Placebo at any time during the study, and vice-
versa
x
Received clinically significant amount of prohibited concomitant medications/treatments 
during the study (refer to protocol Section 6.7.5)
x
Compliance with study treatment (refer to Section 11) < 80%
x
Other
The number and percentage of subjects with at least one major PD and number of major PDs will 
be summarized overall and by treatment group based on the safety analysis set and will be broken 
down further by PD category and sub-category. The subset of major PDs expected to impact the 


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key secondary efficacy endpoint and subset of PDs associated with COVID-19 will be summarized 
similarly.
A listing of all PDs will also be provided. PDs associated with COVID-19 and major PDs will be 
flagged.
8 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
The list of demographics and baseline characteristics to be summarized include: 
x
Age (years) – calculated relative to date of consent
x
Sex
x
Ethnicity
x
Race
x
Baseline height (cm)
x
Baseline weight (kg)
x
Baseline body mass index (BMI; kg/m2)
x
Time since diagnosis of HS (years), defined as the date of screening visit minus the date of 
diagnosis of HS divided by 365.25 days
x
Baseline overall Hurley stage
x
Baseline total AN count (refer to Section 12.2.1)
x
Baseline total abscess count
x
Baseline total inflammatory nodule count
x
Baseline total draining fistula count
x
Baseline total non-inflammatory nodule count
x
Baseline total non-draining fistula count
x
Baseline NRS for skin pain (refer to Section 12.3.1)
x
Baseline IHS4 count (refer to Section 12.3.1)


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x
Baseline HS-IGA score (refer to Section 12.4.1)
x
Baseline HS-PGA score (refer to Section 12.4.1)
x
Baseline HiSQOL total and subscale scores (refer to Section 12.4.1)
x
Baseline DLQI total score (refer to Section 12.4.1)
Continuous endpoints will be summarized using descriptive statistics overall and by treatment 
group based on the FAS while categorical endpoints will be similarly summarized using 
frequencies and percentages.
A listing of all demographics and baseline characteristics will be provided.
9 SURGICAL AND MEDICAL HISTORY
Surgical and medical history will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA), Version 25.0.
The number and percentage of subjects reporting at least one surgical and/or medical event will be 
summarized overall and by treatment group based on the FAS and further broken down by system 
organ class (SOC) and preferred term (PT) based on the FAS. A subject who experienced the same 
event multiple times within the same SOC will be counted only once for the corresponding SOC.
Similarly, if a subject experienced multiple events within the same PT, the subject will be counted 
only once for that PT. Surgical and medical history events will be sorted alphabetically by SOC 
and within each SOC, the PT will be presented by decreasing order of total frequencies.
A listing of all surgical and medical history events will be provided.
10 PRIOR AND CONCOMITANT MEDICATIONS
Medications will be coded according to the World Health Organization Drug Dictionary 
(WHO-DD) B3, March 2022.
Prior medications are defined as any medication started and discontinued prior to the first dose of 
study treatment. Concomitant medications are defined as any medication taken on or after the first 
dose of study treatment, including those who started prior to the date of the first dose of study 
treatment and continued past that date. See Appendix 3 for handling of completely or partially 
missing dates for prior and concomitant medications. 


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Number and percentage of subjects with at least one prior medication will be summarized overall 
and by treatment group based on the FAS and further broken down by anatomical therapeutic 
chemical (ATC) level 3 term and preferred drug name. A subject with the same medication taken 
multiple times within the same preferred drug name will be counted only once for the 
corresponding preferred drug name. Similarly, if a subject has taken more than one medication 
within the same ATC level 3 term, then the subject will be counted only once for that ATC level 
3 term. Concomitant medications will be sorted alphabetically by ATC level 3 term and within 
each ATC level 3 term, the preferred drug name will be presented by decreasing order of total 
frequencies. Concomitant medications will be summarized similarly.
A listing of all prior and concomitant medications will be provided.
11 EXPOSURE TO AND COMPLIANCE WITH STUDY 
TREATMENT
Total exposure to study treatment, in days, will be computed as follows and summarized using 
descriptive statistics by treatment group based on the safety analysis set.
Total exposure (days) = (Date of last dose of study treatment – Date of first dose of study 
treatment) + 1
Number and percentage of subjects with at least one dose interruption (no dose) will be presented 
by treatment group based on the safety analysis set and further broken down by reason for dose 
interruption.  Dose reduction and reason for dose reduction will be summarized similarly.
Total number of doses missed and total exposure to reduced dose, in days, will be summarized 
using descriptive statistics by treatment group based on the safety analysis set, where total 
exposure to a reduced dose will be computed as follows:
ሺሻൌσ
ሺ െ
୫
୧ୀଵ
ሻ൅ͳ
where:
m is the subject’s total number of dose reduction periods during the study.
Compliance with study treatment, in percentage, will be computed as follows and summarized 
using descriptive statistics by treatment group based on the safety analysis set


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ሺΨሻൌ

 ͳͲͲ
where:
Total number of expected doses = (exposure to a reduced dose x 2) + [(total exposure –
exposure to a reduced dose) x 4]
Total number of doses administered = Total number of expected doses – Total number of 
doses missed
12 EFFICACY ANALYSIS
Unless otherwise indicated, all efficacy summaries and analyses will be performed based on the 
FAS (refer to Section 4.2).
12.1 Primary Efficacy Analysis
Not applicable.
12.2 Key Secondary Efficacy Analysis
12.2.1 Definition and Estimand of Key Secondary Efficacy Endpoint
Treatment groups: RIST4721 400 mg and placebo
Target population: Subjects with HS as defined by the inclusion and exclusion criteria (refer to 
protocol Section 5), grouped per randomization assignment
Endpoint: Proportion of subjects achieving HiSCR50 at Week 12
Intercurrent events and corresponding strategy: For subjects who discontinue study treatment 
prior to Week 12 due to any reason, their last observation will be used to impute response status
Population-level summary variable: Difference in proportions between treatment groups
The HiSCR is used to assess the inflammatory signs and symptoms of HS (Kimball, 2014).
To determine if a subject achieves HiSCR50 (yes vs. no) at an analysis visit (refer to Section 5.6),
the number of abscesses, inflammatory nodules, and draining fistulas on the entire body at that 
analysis visit will first be counted separately. Of note, abscesses, inflammatory nodules, and 
draining fistulas that required an intervention during the course of the study will be included in the 
concerned count of lesions for the remainder of the study. That is, if, for example, an abscess that 


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was present at the Week 2 analysis visit required an intervention between the Week 4 and Week 8 
analysis visits, this lesion will be included in the count of abscesses for the Week 2, Week 4, Week 
8, Week 12, and Follow-up analysis visits.
Subject’s achievement of HiSCR50 (yes vs. no) at each post-baseline analysis visit, which is 
defined as follows, will then be determined.
x
Achieving a 50% or greater reduction in total AN count and no increase in abscess or 
draining fistula counts at the concerned post-baseline analysis visit compared with baseline
where:
x
Total AN count is the sum of the total number of abscesses and total number of 
inflammatory nodules at the analysis visit
x
Change from baseline in abscesses, change from baseline in draining fistula, and percent 
change from baseline in total AN count will be computed as calculated as defined in 
Section 5.4.
12.2.2 Hypothesis Testing
H0: PR - PP = 0
versus
H1: PR - PP ≠ 0
where:
PR = Proportion of subjects achieving HiSCR50 at Week 12 in RIST4721 treatment group
PP = Proportion of subjects achieving HiSCR50 at Week 12 in placebo treatment group
The direction of superiority is indicated by a difference in proportions greater than 0.
12.2.3 Main Analysis of Key Secondary Efficacy Endpoint
For subjects who discontinued early from study treatment due to any reason, missing subject’s 
achievement of HiSCR50 status will be imputed as per the LOCF method (refer to Section 
6.3.1.1).
The number and proportion of subjects achieving or not HiSCR50 (refer to Section 12.2.1) will be 
presented by treatment group for each post-baseline analysis visit (refer to Section 5.6) along with 


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the difference in proportions between treatment groups (RIST4721 – placebo). Two-sided 95% 
Clopper-Pearson CI will also be presented for the proportion of subjects achieving HiSCR50 for 
each treatment group while two-sided 95% exact unconditional CI will also be presented for the 
difference in proportions between treatment groups.
The key secondary efficacy endpoint of proportion of subjects achieving HiSCR50 at Week 12
will be analyzed using a Fisher’s exact test and a p-value will be provided. The proportion of 
subjects achieving HiSCR50 at other post-baseline analysis visits will be analyzed similarly and 
p-value will also be provided.
12.2.4 Sensitivity Analyses to Main Analysis of the Key Secondary Efficacy Endpoint
Sensitivity to missing data imputation assumptions
The imputation method used for the main analysis of the key secondary efficacy endpoint (i.e.,
LOCF; refer to Section 6.3.1.1) assumes that achievement of HiSCR50 status of subjects who 
discontinued early from study treatment would not have changed from the last observed 
achievement of HiSCR50 status while subject was on-treatment (refer to Section 5.3) to the end 
of the trial, had they stayed on the study treatment.
In other words, LOCF assumes that no 
improvement or worsening of the lesions count would have occurred after a subject discontinued 
early from study treatment should a subject had stayed on the study treatment.
To assess the robustness of the imputation assumption of the method used for the main analysis of 
the key secondary efficacy endpoint, the following sensitivity analyses will be performed:
x
The main analysis to the key secondary efficacy endpoint will be repeated but missing 
HiSCR50 achievement status at Week 12 will be imputed as per the NRI method (refer to 
Section 6.3.1.2).
x
The main analysis to the key secondary efficacy endpoint will be repeated but missing
HiSCR50 achievement status at Week 12 will be imputed as per a modified LOCF method 
(refer to Section 6.3.1.3).
Sensitivity analysis to analysis set
The main analysis of the key secondary efficacy endpoint (refer to Section 12.2.3) will be 
repeated based on the PP analysis set (refer to Section 4.3).


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12.3 Other Secondary Efficacy Analyses
12.3.1 Definition of Other Secondary Efficacy Endpoints
The other secondary efficacy endpoints are:
x
Proportion of subjects achieving HiSCR75 at Week 12
x
Proportion of subjects with flare at Week 12
x
Proportion of subjects achieving AN count of 0, 1, or 2 at Week 12
x
Change from baseline in NRS skin pain score at Week 12
x
Change from baseline in IHS4 total score at Week 12
Proportion of Subjects Achieving HiSCR75 at Week 12
Achievement of HiSCR75 (yes vs. no) at Week 12 is defined similarly to the achievement of
HiSCR50 at Week 12 (refer to Section 12.2.1) but using a 75% or greater reduction in total AN 
count as criterion instead of a 50% or greater reduction in total AN count. The analysis visit of 
interest will be the Week 12 analysis visit.
Proportion of Subjects with Flare at Week 12
At each post-baseline analysis visit (refer to Section 5.6), subject’s flare status (yes or no) will be 
determined, where a flare is defined as follows:
x
Having ≥ 25% increase and ≥ 2 absolute increase in AN count at the concerned post-
baseline analysis visit compared to baseline
where AN count will be calculated as defined in Section 12.2.1 and change and percent change 
from baseline in AN count will be computed as defined in Section 5.4. The analysis visit of interest 
will be the Week 12 analysis visit.
Proportion of Subjects Achieving AN Count of 0, 1 or 2 at Week 12
At each post-baseline analysis visit (refer to Section 5.6), subject’s achievement (yes or no) of an 
AN count (refer to section 12.2.1) of 0, 1, or 2 will be determined as follows:
x
Having an AN count of 0, 1, or 2 at at the concerned post-baseline analysis visit 
The analysis visit of interest will be the Week 12 analysis visit.


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Change from Baseline in NRS Skin Pain Score at Week 12
The NRS (Barrett, 2019; Silverberg, 2021) for skin pain is a self-assessed patient reported 
outcome. The NRS is an 11-point scale (0 to 10), with a score of zero denoting no pain and a score 
of 10 denoting worst possible pain.
Change from baseline in NRS skin pain score at each post-baseline analysis visit (refer to Section
5.6) will be computed as defined in Section 5.4. The analysis visit of interest will be the Week 12 
analysis visit.
Change from baseline in IHS4 Total Score at Week 12
The IHS4 is a validated tool that dynamically assess HS severity (Zouboulis, 2017; Napolitano, 
2020).  For each analysis visit (refer to Section 5.6), IHS4 total score will be calculated as follows:
IHS4 total score = (Total number of nodules x 1) + (Total number of abscesses x 2) 
+ (Total number of draining fistulas x 4)
Of note, 
x
Only the inflammatory nodules should be considered when calculating the IHS4 total score.
x
Abscesses, inflammatory nodules, and draining fistulas that required an intervention during 
the course of the study will be handle using the same methodology as for the key secondary 
efficacy endpoint (refer to Section 12.2.1) when calculating the IHS4 total score.
An ISH4 total score of 3 or less signifies mild disease, 4 to 10 moderate disease, and 11 or higher 
severe disease.
Change from baseline in IHS4 total score at each post-baseline analysis visit will be computed as 
defined in Section 5.4. The analysis visit of interest will be the Week 12 analysis visit.
12.3.2 Main Analysis of Other Secondary Efficacy Endpoints
Missing other secondary efficacy endpoints that are dichotomous in nature (i.e., proportion of 
subjects) will be imputed as per the LOCF method (refer to Section 6.3.1.1). These endpoints 
will then be summarized and analyzed as for the key secondary efficacy endpoint (refer to 
Section 12.2.3). The analysis visit of interest will be the Week 12 analysis visit.
Missing other secondary efficacy endpoints that are continuous in nature (i.e., change from 
baseline) will not be imputed, but rather predicted using a MMRM model (refer to Section 6.3.1.4).
Hence, the descriptive statistics that will be presented for each of these endpoints by treatment 


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group at baseline and each post-baseline analysis visit (refer to Section 5.6) will be based on 
observed data only. Data collected after a subject discontinued from study treatment, if any, will 
be excluded from these summaries for the Weeks 2, 4, 8, and 12 post-baseline analysis visits.
Descriptive statistics will also be presented similarly for the scale (total) score at each post-baseline 
analysis visit.
The change from baseline will be analyzed using a MMRM model including change from baseline 
as the dependent variable, treatment group (RIST4721 and placebo), visit (Weeks 2, 4, 8, and 12),
treatment group-by-visit interaction as fixed effects, baseline and baseline-by-visit interaction as 
covariates, and subjects as random effect. As for the descriptive statistics, data collected after a 
subject discontinued from study treatment, if any, will be excluded from the MMRM model. An 
unstructured covariance structure will be used to model the within-subject error and the Kenward-
Roger approximation to estimate the degrees of freedom will be used for tests of fixed effects 
derived from the MMRM model. If this analysis fails to converge, the following covariance 
structure will be tested and the covariance structure converging to the best fit, as determined by 
the Akaike’s information criteria corrected (AICC) will be used for the main analysis: 
heterogenous Toeplitz (TOEPH), heterogenous first-order autoregressive (ARH[1]), and first-
order ante dependence (ANTE[1]).
Least square mean (LS mean) estimate (and associated standard error [SE]) will be provided by 
treatment group and visit. Difference in LS mean estimates between the two treatment groups (and 
associated SE) at each visit will also be estimated, along with its two-sided 95% and p-value. The 
contrast of interest will be between the RIST4721 and placebo treatment groups at Week 12.
Additionally, LS mean estimates of the mean change from baseline (+/- SE) over time will be 
displayed graphically by treatment group.
12.3.3 Sensitivity Analyses to Other Secondary Efficacy Endpoint
No sensitivity analyses will be performed for other secondary efficacy endpoints.
12.4 Exploratory Efficacy Analyses
12.4.1 Definition of Exploratory Efficacy Endpoints
The exploratory efficacy endpoints are:
x
Proportion of subjects achieving at least 2-grade improvement on the HS-PGA
x
Proportion of subjects achieving 0 or 1 on the HS-PGA


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x
Proportion of subjects achieving at least 2-grade improvement on the HS-IGA relative to 
baseline at Week 12
x
Proportion of subjects achieving 0 or 1 on the HS-IGA
x
Change from baseline in AN count at Week 12
x
Change from baseline in HiSQOL total and subscale scores
x
Change from baseline in DLQI total score at Week 12
Proportion of Subjects Achieving at Least 2-grade Improvement on the HS-PGA at Week 12
The HS-PGA categorizes HS into 6 categories of progressive severity based on number of nodules, 
abscesses, and fistulas, as shown in Table 3. Of note, nodules, abscesses, and fistulas that required 
an intervention during the course of the study will be handle using the same methodology as for 
the key secondary efficacy endpoint (refer to Section 12.2.1) when establishing the grade/severity 
in HS-PGA.
Table 3: HS-PGA
Grade
Severity
Description
0
Clear
0 abscesses, 0 draining fistulas, 0 inflammatory nodules, and 0 
non-inflammatory nodules
1
Minimal
0 abscesses, 0 draining fistulas, 0 inflammatory nodules, and 
presence of non-inflammatory nodules
2
Mild
0 abscesses, 0 draining fistulas, and 1–4 inflammatory nodules
or
1 abscess or draining fistula and 0 inflammatory nodules
3
Moderate
0 abscesses, 0 draining fistulas, and ≥5 inflammatory nodules
or
1 abscess or draining fistula and ≥1 inflammatory nodules 
or
2–5 abscesses or draining fistulas and <10 inflammatory nodules
4
Severe
2–5 abscesses or draining fistulas and ≥10 inflammatory nodules
5
Very severe
>5 abscesses or draining fistulas


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The HS-PGA score will be established at each analysis visit (refer to Section 5.6) and change from 
baseline in HS-PGA grade to each post-baseline analysis visit will be computed as defined in 
Section 5.4. Achievement at least 2-grade improvement on the HS-PGA (yes or no) at each post-
baseline analysis visit, defined as follows, will then be determined based on the change from 
baseline value:
x
Having a change from baseline in HS-PGA grade ≥ 2
Proportion of Subjects Achieving 0 or 1 on the HS-PGA at Week 12
Achievement of 0 or 1 on the HS-PGA (yes or no) is defined as follows:
x
Having a HS-PGA grade or 0 or 1
Proportion of Subjects Achieving at Least 2-grade Improvement on the HS-IGA at Week 12
The HS-IGA score is based on the maximum count of abscesses, fistulas (draining and non-
draining), and nodules (inflammatory and non-inflammatory) in either the upper or lower body
region as showed in Table 4. Of note, 
x
The region used at baseline may not be the same region used at a given post-baseline 
scheduled visit.
x
Abscesses, fistulas, and nodules that required an intervention during the course of the study 
will be handle using the same methodology as for the key secondary efficacy endpoint
(refer to Section 12.2.1) when establishing the HS-IGA score.
Table 4: HS-IGA
Score
Maximum Lower Body or Upper Body Count
0
0-1
1
2-5
2
6-10
3
11-15
4
16-20
5
> 20


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The HS-IGA score will be established at each analysis visit and change from baseline in HS-IGA 
score to each post-baseline analysis visit will be computed as defined in Section 5.4. Achievement 
at least 2-grade improvement on the HS-IGA score (yes or no) at each post-baseline analysis visit,
defined as follows, will then be determined based on the change from baseline value:
x
Having a change from baseline in HS-IGA score ≥ 2
Proportion of Subjects Achieving 0 or 1 on the HS-IGA at Week 12
Achievement of 0 or 1 on the HS-IGA is defined as follows:
x
Having a HS-IGA score or 0 or 1
Change from Baseline in AN Count at Week 12
AN count is defined in Section 12.2.1.
Change from baseline in AN count to each post-baseline analysis visit (refer to Section 5.6) will 
be computed as defined in Section 5.4.
Change from Baseline in HiSQOL Total and Subscale Scores at Week 12
The HiSQOL scale was developed and validated for clinical trial measurement of HS-specific 
health-related quality of life (HRQOL).  It is a 17-item instrument separated into 3 subscales (4
symptom items, 5 psychosocial items, and 8 functional concept items) with a 7-day recall period 
(Kirby, 2020; Kirby, 2021). Each item is rated from 0 (not at all/I do not normally do this, HS did 
not influence) to 4 (extremely/unable to do, due to HS).
Each subscale score is the sum of its related items. The symptom subscale scores range from 0 to 
16, the psychosocial subscale from 0 to 20, and the functional concept subscale from 0 to 32, with 
higher scores indicating more severe impact on HRQOL. If more than 50% of a subscale related 
items are unanswered, the concerned subscale score will be considered as missing.
The HiSQOL total score is the sum of the and ranges from 0 to 68, with higher scores indicating 
more severe impact on HRQOL. If one or more subscale score is missing, the HiSQOL total score 
will be considered as missing.
Changes from baseline in HiSQOL total and subscale score to each post-baseline analysis visit 
(refer to Section 5.6) will be computed as defined in Section 5.4.


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Change from Baseline in DLQI Total Score at Week 12
The DLQI is a simple 10-question validated questionnaire including questions concerning 
symptoms and feelings, daily activities, leisure, work/school, personal relationships, and treatment 
(Finlay, 1994).  All questions relate “to the last week” and each question is rated from 0 (Not at 
all) to 3 (Very much).
The DLQI total score is the sum of all 10 questions and ranges from 0 (no impairment of life 
quality) to 30 (maximum impairment). If one question is unanswered, this question is allocated a 
score of 0 and the DLQI total score is calculated the usual way. If two or more questions are 
unanswered, the DLQI total score cannot be calculated and is considered as missing.
Change from baseline in DLQI total score to each post-baseline analysis visit (refer to Section 5.6)
will be computed as defined in Section 5.4.
12.4.2 Main Analysis of Exploratory Efficacy Endpoints
Missing exploratory efficacy data will not be imputed.
For each dichotomic exploratory efficacy endpoints, the number and proportion of subjects
achieving or not the endpoint criteria (refer to Section 12.4.1) will be presented by treatment group
for each post-baseline scheduled visit along with the difference in proportions between treatment 
groups (RIST4721 – placebo). Two-sided 95% Clopper-Pearson CI will also be presented for the 
proportion of subjects achieving the endpoint criteria for each treatment group and a two-sided
95% exact unconditional CI will also be provided for the difference in proportions between 
treatment groups.  No statistical inferences will be performed for the exploratory dichotomic 
efficacy endpoint.
For each continuous exploratory efficacy endpoint, descriptive statistics for the change from 
baseline in the AN count or scale total/subscale score at each post-baseline analysis visit (refer to 
Section 5.6) will be presented by treatment group). Descriptive statistics will also be presented by 
treatment group for the AN count or scale total/subscale score at each analysis visit.
12.4.3 Sensitivity Analyses to Exploratory Efficacy Endpoint
No sensitivity analyses will be performed for exploratory efficacy endpoints.
12.5 Additional Efficacy Analyses
Total number of abscesses, total number of inflammatory nodules, and total number of draining 
fistulas will be summarized using descriptive statistics by treatment group and analysis visit (refer 


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to Section 5.6). Of note, abscesses, inflammatory nodules, and draining fistulas that required an 
intervention during the course of the study will be handle using the same methodology as for the 
key secondary efficacy endpoint (refer to Section 12.2.1) when calculating the total number of 
concerned lesions. Change and percent from baseline in each of these total counts at each post-
baseline analysis visit will also be summarized using descriptive statistics by treatment group. 
Additionally, percent change from baseline in total AN count (refer to Section 12.2.1) to each post-
baseline analysis visit will be summarized similarly.
Number and percentage of subjects with a 50% or greater reduction in total AN count, with a 75% 
or greater reduction in total AN count, with no increase in abscess count, with no increase in 
draining fistula, with a 25% or greater increase in total AN count, and with an increase of 2 or 
more in total AN count, all compared to baseline, as well as numbers and percentages of subjects 
with an AN count of 0, of 1, of 2, and of 3 or more will be provided by treatment group and analysis 
visit.
Shift tables from baseline in HS-PGA grade, HS-IGA score, and IHS4 categories (mild [IHS4 total 
score of 3 or less], moderate [IHS4 total score of 4 to 10], and severe [IHS4 total score of 11 or 
higher]) to each post-baseline analysis visit will be provided by treatment group. The number of 
subjects with a non-missing grade/score at both the baseline and a specific post-baseline analysis 
visit will be used as denominator for that post-baseline analysis visit.
All efficacy data will be listed.
12.6 Subgroup Analyses
The main analysis of the key and other secondary efficacy endpoints (refer to Sections 12.2.3 and 
12.3.2) will be repeated for the subgroups specified in Section 6.9.
No subgroup analyses will be performed for the additional efficacy endpoints.
13 SAFETY ANALYSIS
All safety summaries will be conducted based on the safety analysis set (refer to Section 4.4). No
statistical inferences will be performed.
13.1 Adverse Events
AEs will be coded according to the MedDRA, Version 25.0.


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A TEAE is defined as an AE that is new or worsening on or after the subject has received the first
dose of study treatment and with an onset within 30 days after the last dose of study treatment. See 
Appendix 3 for handling of completely or partially missing dates for AEs. In the case where it is 
not possible to define an AE as treatment-emergent or not, the AE will be classified as treatment-
emergent, except for AEs associated with a pre-dose assessment which will not be classified as 
treatment-emergent.
An overall summary table of AEs will be provided. The number of events and the number and 
percentage of subjects who experienced AE, TEAE, TEAE by greatest reported relationship with
study treatment (related or not related), TEAE by highest reported severity (mild, moderate, or 
severe), AE with an outcome of death, serious TEAE, treatment-related serious TEAE, TEAE 
leading to study treatment discontinuation, and TEAE leading to study withdrawal will be 
presented by treatment group. TEAE with an unknown relationship with study treatment will be 
considered as related and TEAE with an unknown severity will be considered as severe.
Frequency and percentage of subjects who experience TEAE will be summarized by SOC and PT.
A subject experiencing the same TEAE multiple times within the same SOC will be counted only 
once for that SOC. Similarly, a subject experiencing the same TEAE multiple times within the 
same PT will be counted only once for that PT. TEAEs will be sorted alphabetically by SOC and 
within each SOC, the PT will be presented by decreasing order. Treatment-emergent SAEs, 
TEAEs leading to study treatment discontinuation, and TEAEs leading to study withdrawal will 
be summarized similarly.
Frequency and percentage of subjects who experience TEAE will also be summarized by SOC, 
PT, and greatest reported relationship with the study treatment. A subject experiencing the same 
TEAE multiple times within the same SOC will be counted only once for that SOC under the 
greatest reported relationship with study treatment. Similarly, a subject experiencing the same 
TEAE multiple times within the same PT will be counted only once for that PT under the greatest 
reported relationship with study treatment.
Frequency and percentage of subjects who experience TEAE will be summarized by SOC, PT, 
and highest reported severity. A subject experiencing the same TEAE multiple times within the 
same SOC will be counted only once for that SOC under the highest reported severity. Similarly, 
a subject experiencing the same TEAE multiple times within the same PT will be counted only 
once for that PT under the highest reported severity.
Listings of all AEs, all AEs with an outcome of death, all SAEs, all TEAEs leading to study 
treatment discontinuation, and all TEAEs leading to study withdrawal will be provided.


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13.2 Clinical Laboratory
Laboratory data will be presented as per the international system of units, universally abbreviated 
as SI (from the French ‘système international’).
Hematology, serum chemistry, and quantitative urinalysis tests (refer to Appendix 4) will be 
summarized using descriptive statistics by treatment group and visit. Of note, Q1 and Q3 will not 
be included in the summaries for continuous laboratory tests. Change from baseline values will be 
summarized similarly by treatment group for each post-baseline scheduled visit (refer to Table 1).
Number and percentage of subjects in each qualitative urinalysis test category will be provided by
treatment group and visit.
Shift tables from baseline in each hematology, serum chemistry, and quantitative urinalysis test to 
each post-baseline assessment, describing shifts to abnormality (low, normal, or high), will be 
provided as well. The number of subjects with a non-missing result at both baseline and a specific 
post-baseline scheduled visit will be used as denominator for that post-baseline scheduled visit.
Separate listings of all hematology, serum chemistry, and urinalysis data will be provided. In 
addition, separate listings for hematology, serum chemistry, and urinalysis data will be provided 
for each parameter where a subject had at least one abnormal result.
Urine pregnancy test, virology, and laboratory tests required at screening and/or baseline only will 
be listed.
13.3 Vital Signs
Vital signs (systolic blood pressure [SBP; mmHg], diastolic blood pressure [DBP, mmHg], heart 
rate [HR; beats per minute], respiratory rate [breaths per minute], body temperature [qC], pulse 
oximetry [%], weight [kg], and BMI [kg/m2]) will be summarized using descriptive statistics by 
treatment group and visit (refer to Table 1). Change from baseline values will also be summarized 
similarly for each post-baseline scheduled visit.
Shift tables from baseline in SBP, DBP, heart rate, respiratory rate, and body temperature to each 
post-baseline assessment, describing shifts to abnormality (normal/abnormal, non-clinically 
significant/abnormal, clinically significant), will be provided as well by treatment group. The 
number of subjects with a non-missing result at both baseline and a specific post-baseline 
scheduled visit will be used as denominator for that post-baseline scheduled visit.
A listing of all vital sign assessments will be provided.


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13.4 ECG
Electrocardiogram (ECG) parameters (HR [beats per minute], PR interval [msec], RR interval 
[msec], QRS duration [msec], QT interval [msec], and QTcF [msec]) will be summarized using 
descriptive statistics by treatment group and visit (refer to Table 1). Change from baseline values
in each ECG test to each post-baseline scheduled visit by treatment group.
Number and percentage of subjects with a QTcF interval > 450 msec, > 480 msec, and > 500 msec 
as well as with a change from baseline in QTcF interval > 30 msec and > 60 msec will be provided 
by treatment group and visit.
Shift tables from baseline in ECG overall interpretation to each post-baseline scheduled visit,
describing shifts to abnormality (normal/abnormal, non-clinically significant/abnormal, clinically 
significant), will be provided by treatment group. The number of subjects with a non-missing result 
at both baseline and a specific post-baseline scheduled visit will be used as denominator for that 
post-baseline scheduled visit.
A listing of all ECG assessments will be provided.
13.5 Physical Examination
Information for all physical examinations will be included in the source documents. Any 
significant change will be reported as an AE in the source document and eCRF.
14 PHARMACOKINETICS ANALYSIS
Observed plasma concentration data of RIST4721 will be summarized by visit for the RIST4721 
treatment group based on the PK analysis set (refer to Section 4.5) using the following descriptive 
statistics: n, mean, SD, median, minimum, and maximum as well as the geometric mean, CV, and 
geometric CV. For computation of mean plasma concentrations, data that are below the limit of 
quantification (BLQ) will be set to zero.
Line plots of individual and mean plasma concentrations (+/- SD) over time will also be provided
separately.
PK data will be listed.


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15 REFERENCES
Barrett, A., Hahn-Pedersen, J., Kragh, N., Evans, E. and Gnanasakthy, A. (2019). "Patient-
Reported Outcome Measures in Atopic Dermatitis and Chronic Hand Eczema in Adults." Patient 
12(5): 445-459.
Finlay, A. Y. and Khan, G. K. (1994). "Dermatology Life Quality Index (DLQI)--a simple 
practical measure for routine clinical use." Clin Exp Dermatol 19(3): 210-216.
Kimball, A. B., Jemec, G. B., Yang, M., Kageleiry, A., Signorovitch, J. E., Okun, M. M., et al. 
(2014). "Assessing the validity, responsiveness and meaningfulness of the Hidradenitis 
Suppurativa Clinical Response (HiSCR) as the clinical endpoint for hidradenitis suppurativa 
treatment." Br J Dermatol 171(6): 1434-1442.
Kirby, J. S., Hereford, B., Thorlacius, L., Villumsen, B., Ingram, J. R., Garg, A., et al. (2021). 
"Validation of global item for assessing impact on quality of life of patients with hidradenitis 
suppurativa*." British Journal of Dermatology 184(4): 681-687.
Kirby, J. S., Thorlacius, L., Villumsen, B., Ingram, J. R., Garg, A., Christensen, K. B., et al. 
(2020). "The Hidradenitis Suppurativa Quality of Life (HiSQOL) score: development and 
validation of a measure for clinical trials." British Journal of Dermatology 183(2): 340-348.
Napolitano, M., Mastroeni, S., Fusari, R., Mazzanti, C., Ciccone, D., Pallotta, S., et al. (2020). 
"The International Hidradenitis Suppurativa Severity Score System (IHS4) is a valuable tool to 
assess gender-associated differences." Eur J Dermatol.
Silverberg, J. I. (2021). "Validity and reliability of a novel numeric rating scale to measure skin-
pain in adults with atopic dermatitis." Arch Dermatol Res.
Zouboulis, C. C., Tzellos, T., Kyrgidis, A., Jemec, G. B. E., Bechara, F. G., Giamarellos-
Bourboulis, E. J., et al. (2017). "Development and validation of the International Hidradenitis 
Suppurativa Severity Score System (IHS4), a novel dynamic scoring system to assess HS 
severity." Br J Dermatol 177(5): 1401-1409.


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Appendix 1
Abbreviated CSR - Table of Contents
Table Number
Table/Listing Name
Table 14.1.1
Subject Disposition (All Screened Subjects Analysis Set)
Table 14.1.3.1
Demographic and Baseline Characteristics (Full Analysis Set)
Table 14.1.6
Exposure to and Compliance with Study Treatment (Safety Analysis 
Set)
Table 14.2.1-1
Proportion of Subjects Achieving HiSCR50 Over Time – LOCF (Full 
Analysis Set)
Table 14.2.1-2.1
Proportion of Subjects Achieving HiSCR50 Over Time - Non-
responder Imputation (Full Analysis Set)
Table 14.3.1-1
Overall Summary of Adverse Events (Safety Analysis Set)
Table 14.3.1-2
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term (Safety Analysis Set)
Table 14.3.1-3
Treatment Emergent Adverse Events by System Organ Class, Preferred 
Term, and Greatest Reported Relationship with Study Treatment 
(Safety Analysis Set)
Table 14.3.1-4
Treatment Emergent Adverse Events by System Organ Class, Preferred 
Term, and Highest Reported Severity (Safety Analysis Set)
Table 14.3.2-1.1
List of All Adverse Events with an Outcome of Death (Safety Analysis 
Set)
Table 14.3.2-2.1
Serious Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term (Safety Analysis Set)
Table 14.3.2-2.2.1
List of All Serious Adverse Events (Safety Analysis Set)
Table 14.3.2-2.2.2
Additional Information for Serious Adverse Events – Part I (Safety 
Analysis Set)
Table 14.3.2-2.2.3
Additional Information for Serious Adverse Events – Part II (Safety 
Analysis Set)
Table 14.3.2-3.1
Treatment-Emergent Adverse Events Leading to Study Treatment 
Discontinuation by System Organ Class and Preferred Term (Safety 
Analysis Set)
Table 14.3.2-3.2
List of Treatment-Emergent Adverse Events Leading to Study 
Treatment Discontinuation (Safety Analysis Set)


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Table Number
Table/Listing Name
Table 14.3.2-4.1
Treatment-Emergent Adverse Events Leading to Study Withdrawal by 
System Organ Class and Preferred Term (Safety Analysis Set)
Table 14.3.2-4.2
List of Treatment-Emergent Adverse Events Leading to Study 
Withdrawal (Safety Analysis Set)
Table 14.3.4-1.1
Observed and Change from Baseline Values in Clinical Laboratory 
Hematology Tests Over Time (Safety Analysis Set)
Table 14.3.4-1.2
Shift Table from Baseline in Clinical Laboratory Hematology Test 
Observed Values Over Time (Safety Analysis Set)
Table 14.3.4-1.3
List of All Abnormal Clinical Laboratory Hematology Test Observed 
Values (Safety Analysis Set)
Table 14.3.4-2.1
Observed and Change from Baseline Values in Clinical Laboratory 
Serum Chemistry Tests Over Time (Safety Analysis Set)
Table 14.3.4-2.2
Shift Table from Baseline in Clinical Laboratory Serum Chemistry 
Test Observed Values Over Time (Safety Analysis Set)
Table 14.3.4-2.3
List of All Abnormal Clinical Laboratory Serum Chemistry Test 
Observed Values (Safety Analysis Set)
Table 14.3.4-3.1
Observed and Change from Baseline Values in Quantitative Clinical 
Laboratory Urinalysis Tests Over Time (Safety Analysis Set)
Table 14.3.4-3.2
Observed Values in Qualitative Clinical Laboratory Urinalysis Tests 
Over Time (Safety Analysis Set)
Table 14.3.4-3.3
Shift Table from Baseline in Quantitative Clinical Laboratory 
Urinalysis Test Observed Values Over Time (Safety Analysis Set)
Table 14.3.4-3.4
List of All Abnormal Clinical Laboratory Urinalysis Test Observed 
Values (Safety Analysis Set)
Listing Number
Listing Name
Listing 16.1.7
Randomization (Full Analysis Set)
Listing 16.2.1-1
Subject Study Disposition (All Screened Subjects Analysis Set)
Listing 16.2.1-2
Subject Treatment Disposition (Safety Analysis Set)
Listing 16.2.2
Protocol Deviations (Full Analysis Set)
Listing 16.2.3
Analysis Set (All Screened Subjects Analysis Set)
Listing 16.2.4-1
Demographic and Baseline Characteristics (Full Analysis Set)
Listing 16.2.4-2
HS Disease History and Hurley Stage (Full Analysis Set)
Listing 16.2.4-3
Surgical and Medical History (Full Analysis Set)


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Listing Number
Listing Name
Listing 16.2.4-4.1
Prior Medications (Full Analysis Set)
Listing 16.2.4-4.2
Concomitant Medications (Full Analysis Set)
Listing 16.2.5-1.1
Dose Management (Safety Analysis Set)
Listing 16.2.5-1.2
Exposure to and Compliance with Study Treatment (Safety Analysis 
Set)
Listing 16.2.6-1.1
Lesion Counts (Full Analysis Set)
Listing 16.2.6-1.2
HS Therapy and Procedure (Full Analysis Set)
Listing 16.2.6-1.3
Total AN Count, HiSCR50, HiSCR75, Flare and Achieving an AN 
Count of 0, 1, or 2 (Full Analysis Set)
Listing 16.2.7
Adverse Events (Safety Analysis Set)
Listing 16.2.8-1
Serology at Screening (Safety Analysis Set)
Listing 16.2.8-2
SARS-CoV-2 Rapid Antigen and PCR Test (Safety Analysis Set)
Listing 16.2.8-3
Pregnancy Test (Safety Analysis Set)
Listing 16.2.8-4
Clinical Laboratory Hematology Tests (Safety Analysis Set)
Listing 16.2.8-5
Clinical Laboratory Serum Chemistry Tests (Safety Analysis Set)
Listing 16.2.8-6
Clinical Laboratory Urinalysis Tests (Safety Analysis Set)
Listing 16.2.9
Vital Signs (Safety Analysis Set)
Listing 16.2.10
ECG Evaluations and Interpretation (Safety Analysis Set)


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Appendix 2
Output Conventions
TLFs will be generated using SAS® and will be displayed on letter size paper with landscape 
orientation, 1-inch margins and 9 pt Courier New font.
The header section will comprise the sponsor’s name, protocol number, delivery description, 
data cut-off date (if applicable), TLF number, TLF title, analysis set, and page number (Page X 
of Y). The footer section will include the TLF footnotes, CRO’s name, date and time of the 
execution of the program, reference listings and name of the program.
The mean, median, and quantiles will be displayed to one more decimal place than the original 
value; minimum and maximum will keep the same number of decimal places as the original 
value; standard deviation, standard error, and CI will be displayed to two more decimal places 
than the original value. If derived parameters are to be summarized, the number of decimals of 
the derived values is to be chosen on a case-by-case basis, but the rule above applies.
For categorical summary tables, percentages will be reported to one decimal place. Percentages 
between 0 and 0.1 (both exclusive) will be displayed as “<0.1” while percentages between 99.9
and 100 (both exclusive) will be displayed as “>99.9”. The denominator for each percentage will 
be the number of subjects within the population per treatment group unless otherwise specified.
P-values from ≥ 0.001 to ≤ 0.999 will be reported to 3 decimal places; p-values less than 0.001 
will be reported as “<0.001”; p-values greater than 0.999 will be reported as “>0.999”.
Listings will be ordered by treatment group, subject number, date, and visit (where applicable). 
Dates & Times Format
Date and time (when available) will be presented in the format yyyy-mm-dd/hh:mm.
Presentation of Treatment Groups
When applicable, study treatments will be represented as follows in the different outputs:
Study Treatment Full Names 
Study Treatment Output Names
RIST4721 400 mg QD
RIST4721
Placebo QD
Placebo


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Appendix 3
Algorithm for Imputation of Start/End Date of Adverse Events and 
Prior/Concomitant Medications
Event Start Date Imputation
x
Imputation of event end date should be done before imputation of event start date. 
x
Completely missing: Impute to the first study treatment date. 
x
Missing day and month: Impute to January 1st, unless year is the same as year of first study 
treatment dose then impute to the first study treatment date. 
x
Missing day: Impute to the 1st of the month, unless month and year are the same as month 
and year of first study treatment dose then impute to the first study treatment date. 
x
If imputed event start date is after event end date (imputed or not), set the event start date 
to the imputed event end date. 
Event End Date Imputation
x
Completely missing (and not flagged as “ongoing”): Impute to the last contact date.
x
Missing day and month: Impute to December 31st, unless year is the same as last contact 
date then impute to the last contact date.
x
Missing day: Impute to the last day of the month, unless year and month are the same as 
year and month of last contact date then impute to the last contact date.


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Appendix 4
Laboratory Testing
Tests Included
Hematology
aPTT, HCT, Hgb, INR, MCH, MCHC, MCV, MPV, PLT, prothrombin 
time, RBC, WBC, and differentials (neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils [relative and absolute])
Serum chemistry
Albumin, alkaline phosphatase, ALT, AST, chloride, cholesterol (non-
fasting), creatinine (enzymatic), GGT, glucose random, hs-CRP, LDH, 
potassium, sodium, total bilirubin, triglycerides, BUN, uric acid
Urinalysis
Dipstick and microscopic analysis
Urine pregnancy test
For WOCBP (at each visit, except screening)
Virology
x
SARS-CoV-2 antigen test at each visit (except screening); if 
positive, will be confirmed by PCR test
Laboratory tests 
required at screening 
only
x
FSH levels for females who have had a cessation of menses for at 
least 12 months without an alternative medical cause
x
β-hCG (serum pregnancy test) for WOCBP (screening only)
x
Tuberculosis test (PPD or QuantiFERON-TB Gold)
If done within 6 months and negative result is available for 
documentation, test is not required at screening
x
Serology (HBV [HBsAg, anti-HBc], HCV, HIV)
x
SARS-CoV-2 antibody test
Laboratory tests 
required at screening 
and baseline only
x
Urine drugs of abuse: amphetamines, methamphetamines, 
barbiturates, cocaine, phencyclidine
Abbreviations: ALT, alanine aminotransferase; anti-HBc, antibody to hepatitis B core antigen; aPTT, activated 
partial thromboplastin time; AST, aspartate aminotransferase; β-hCG, β-human chorionic gonadotropin; BUN, blood
urea nitrogen; FSH, follicle-stimulating hormone; GGT, gamma-glutamyl-transferase; HBsAg, hepatitis B surface 
antigens; HBV, hepatitis B virus; HCT, hematocrit; HCV, hepatitis C virus; Hgb, hemoglobin; HIV, human 
immunodeficiency virus; hs-CRP, high-sensitivity C-reactive protein; INR, international normalized ratio; 
LDH, lactate dehydrogenase; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin 
concentration; MCV, mean corpuscular volume; MPV, mean platelet volume; PCR, polymerase chain reaction; 
PLT, platelets; PPD, purified protein derivative; RBC, red blood cell; WBC, white blood cell; WOCBP, women of 
childbearing potential.