Clinical trial NCT03988335
Conditions: Palmoplantar Pustulosis
Keywords: PPP
Sponsor: Aristea Therapeutics, Inc.
Start date: 2019-02-13; Completion date: 2019-11-19
Enrollment: 35 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study to Evaluate the Efficacy and Safety of RIST4721 in Subjects with Palmoplantar Pustulosis

Detailed description:

Arms: arm 1: RIST4721 as once-daily 300mg oral solution for 28 days. arm 2: Placebo as once-daily 300mg oral solution for 28 days.
Interventions: intervention 1: RIST4721 intervention 2: Placebo
Intervention descriptions: intervention 1: RIST4721 oral solution intervention 2: Placebo oral solution

Protocol documents:
Prot_000.pdf: 
  
 
 
 
 
 
 
Confidential and proprietary. Permission should be obtained before any reproduction. 
 
 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PHASE 2A STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 
RIST4721 IN SUBJECTS WITH PALMOPLANTAR PUSTULOSIS 
 
 
PROTOCOL RIST4721-201 
EudraCT Number - 2018-004176-35 
 
 
 
 
FINAL 
 
 
VERSION 3.0_DE 
22 March 2019 
 
Sponsor: 
Aristea Therapeutics, Inc.  
 
  
Sponsor Medical Expert: 
 
Sponsor Signatory: 
 
 
 
 
Medical Monitor: 
 
 
 
 
Clinical Research 
Organization: 
 
 
 
 
 
 


Aristea Therapeutics, Inc. – Protocol RIST4721-201 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................ 2 
PROTOCOL VERSION HISTORY ............................................................................................... 6 
STATEMENT OF COMPLIANCE ................................................................................................ 9 
SIGNATURE PAGE .................................................................................................................... 10 
PRINCIPAL/QUALIFIED INVESTIGATOR SIGNATURE PAGE .......................................... 11 
LIST OF ABBREVIATIONS ....................................................................................................... 12 
1 
PROTOCOL SUMMARY ............................................................................................ 14 
1.1 
Synopsis ........................................................................................................................ 14 
1.2 
Study Diagram .............................................................................................................. 23 
1.3 
Schedule of Events ........................................................................................................ 23 
2 
INTRODUCTION ........................................................................................................ 26 
2.1 
Background ................................................................................................................... 26 
 
Palmoplantar Pustulosis ....................................................................................... 26 
 
RIST4721............................................................................................................... 26 
 
Study Rationale ..................................................................................................... 27 
2.2 
Risk/Benefit Assessment ............................................................................................... 27 
 
Known Potential Risks .......................................................................................... 27 
 
Known Potential Benefits ...................................................................................... 29 
 
Assessment of Risks and Benefits .......................................................................... 29 
3 
OBJECTIVES AND ENDPOINTS .............................................................................. 30 
3.1 
Objectives ...................................................................................................................... 30 
3.2 
Endpoints ...................................................................................................................... 30 
4 
STUDY DESIGN .......................................................................................................... 32 
4.1 
Overall Design .............................................................................................................. 32 
4.2 
Scientific Rationale for Study Design ........................................................................... 33 
4.3 
Justification for Dose .................................................................................................... 33 
4.4 
End of Study Definition ................................................................................................ 34 
5 
STUDY POPULATION ............................................................................................... 34 
5.1 
Inclusion Criteria ........................................................................................................... 34 
5.2 
Exclusion Criteria ......................................................................................................... 36 
5.3 
Lifestyle Considerations ............................................................................................... 38 
5.4 
Screen Failures .............................................................................................................. 38 


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6 
TREATMENT .............................................................................................................. 39 
6.1 
Study Treatment Administered ..................................................................................... 39 
6.2 
Preparation/Handling/Storage/Accountability .............................................................. 39 
 
Preparation/Storage/Handling ............................................................................. 39 
 
Accountability ....................................................................................................... 40 
6.3 
Randomization .............................................................................................................. 40 
 
Blinding ................................................................................................................. 40 
 
Study Treatment Compliance ................................................................................ 41 
6.4 
Concomitant Therapy .................................................................................................... 41 
 
Permitted Therapies .............................................................................................. 42 
 
Prohibited Therapies or Procedures .................................................................... 42 
7 
DISCONTINUATION AND LOST TO FOLLOW-UP ............................................... 43 
7.1 
Discontinuation ............................................................................................................. 44 
7.2 
Lost to Follow-Up ......................................................................................................... 44 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................ 45 
8.1 
Efficacy Assessments .................................................................................................... 45 
 
Fresh and Total Pustule Count ............................................................................. 45 
 
Palmoplantar Pustulosis Psoriasis Area Severity Index ...................................... 45 
 
Palmoplantar Pustulosis Physician Global Assessment ....................................... 45 
 
Palmoplantar Pustulosis Severity Index ............................................................... 46 
 
Pain Visual Analog Scale...................................................................................... 46 
 
Body Surface Area ................................................................................................ 46 
 
Psoriasis Area Severity Index ............................................................................... 47 
 
Physician Global Assessment ............................................................................... 47 
8.2 
Quality-of-Life Assessments ......................................................................................... 47 
 
Dermatology Life Quality Index Questionnaire ................................................... 47 
8.3 
Safety and Other Assessments ...................................................................................... 48 
 
Vital Signs ............................................................................................................. 48 
 
Physical Examination ........................................................................................... 48 
 
Brief Physical Examination .................................................................................. 48 
 
Clinical Laboratory Tests ..................................................................................... 49 
 
Electrocardiogram ................................................................................................ 51 
 
Plasma Concentration Assessment in Blood......................................................... 51 
 
Pharmacodynamic Assessments in Skin Biopsies ................................................. 52 
 
Medical Photography............................................................................................ 52 
8.4 
Adverse Events and Serious Adverse Events ............................................................... 53 
 
Definition of Adverse Event .................................................................................. 53 


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Definition of Treatment-Emergent Adverse Event ................................................ 53 
 
Definition of Serious Adverse Event ..................................................................... 53 
 
Classification of an Adverse Event ....................................................................... 54 
 
Time Period and Frequency for Event Assessment and Follow-Up ..................... 54 
 
Adverse Event Reporting....................................................................................... 55 
 
Serious Adverse Event Reporting.......................................................................... 55 
 
Suspected Unexpected Serious Adverse Reactions Reporting .............................. 56 
 
Pregnancy Reporting ............................................................................................ 57 
 
Overdose ........................................................................................................... 57 
9 
STATISTICAL CONSIDERATIONS .......................................................................... 57 
9.1 
Sample Size Determination ........................................................................................... 57 
9.2 
Populations for Analyses .............................................................................................. 58 
9.3 
Statistical Analyses ....................................................................................................... 58 
 
General Approach ................................................................................................. 58 
 
Efficacy Analyses .................................................................................................. 59 
 
Safety Analyses...................................................................................................... 59 
 
Plasma Concentration Analyses ........................................................................... 60 
 
Pharmacodynamic Analyses ................................................................................. 60 
 
Other Analyses ...................................................................................................... 60 
 
Planned Interim Analyses ..................................................................................... 60 
10 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS .... 61 
10.1 
Local Regulations/Declaration of Helsinki ................................................................... 61 
10.2 
Ethical Review .............................................................................................................. 61 
10.3 
Informed Consent Process ............................................................................................ 61 
10.4 
Study Discontinuation and Closure ............................................................................... 62 
10.5 
Confidentiality and Privacy .......................................................................................... 62 
10.6 
Clinical Monitoring ....................................................................................................... 63 
10.7 
Quality Assurance and Quality Control ........................................................................ 63 
10.8 
Data Handling and Record Keeping ............................................................................. 63 
10.9 
Protocol Deviations ....................................................................................................... 64 
10.10 Publication Policy ......................................................................................................... 64 
11 
REFERENCES .............................................................................................................. 65 
APPENDIX A: Palmoplantar Pustulosis Psoriasis Area and Severity Index ............................... 67 
APPENDIX B: Palmoplantar Pustulosis Severity Index .............................................................. 68 
APPENDIX C: Psoriasis Area Severity Index.............................................................................. 69 
APPENDIX D: Dermatology Life Quality Index ......................................................................... 70 


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LIST OF TABLES 
 
Table 1: Schedule of Events ......................................................................................................... 24 
Table 2: Study Treatments ............................................................................................................ 39 
Table 3: Prohibited Therapies or Procedures ................................................................................ 42 
Table 4: Palmoplantar Pustulosis Physician Global Assessment (Averaged Over all Palmoplantar 
Lesions) ......................................................................................................................................... 46 
Table 5: Physician Global Assessment ......................................................................................... 47 
Table 6: Clinical Laboratory Testing ............................................................................................ 50 
 
LIST OF FIGURES 
 
Figure 1: Study Diagram ............................................................................................................... 23 
Figure 2: Pain Visual Analog Scale .............................................................................................. 46 
Figure 3: Diagram for Addressing Neutrophil Counts ................................................................. 51 




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• Section 10.1–A reference to the 
German Drug Law (AMG) §40 and 
§41 was added to provide an 
example of the “applicable laws” 
referred to in Section 10.1. 
• Section 
10.3–To 
provide 
clarification regarding the informed 
consent process and for alignment 
with the exclusion criterion 2 added 
to this amended version of the 
protocol. 
• Synopsis, Sections 1.2 (Table 1), and 
4.1– To specify that subjects who 
consent to either biopsy or plasma 
concentration 
procedures 
must 
consent to both. 
• Synopsis and Section 4.1–To clarify 
that blood sample collection for 
plasma concentration analyses will 
be performed on approximately 
20 subjects. These changes were 
applied to align with the footnote of 
Table 1 and with the number of 
subjects who will have biopsy 
sample collection.  
• Section 2.2.1–To specify that the 
Reference Safety Information for 
RIST4721 
can 
be 
found 
in 
Section 6.1 
of 
the 
Investigator 
Brochure. 
3.0  / 22 March 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Synopsis 
and 
Section 
5.2—To 
exclude from the study subjects who 
have 
used 
strong 
systemic 
cytochrome P450 3A4/5 inhibitors 
or inducers within 4 weeks or 
5 half‑lives, whichever is longer, 
prior to baseline (Day –1). However, 
subjects who have used topical 
cytochrome P450 3A4/5 inducers or 
inhibitors 
with 
known 
limited 
systemic 
availability 
may 
be 
permitted. 
• Section 8.1.8 and Section 11—To 
add missing information to the 
description of psoriasis of Moderate 
severity, as per supportive reference. 
The citation of the corresponding 
reference was also updated in the 
reference list for alignment. 


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• Section 
5.3—To 
specify 
that 
subjects will be instructed to avoid 
food 
or 
beverages 
containing 
grapefruit within 7 days prior to 
Day –1 and during the study. 
 


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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with the protocol, the Declaration of Helsinki, 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP), and applicable local 
regulations. The principal investigator will assure that no planned deviation from, or changes to 
the protocol will take place without prior agreement from the sponsor and documented approval 
from the institutional review board (IRB)/research ethics board (REB)/ethics committee (EC), 
except where necessary to eliminate an immediate hazard(s) to the trial subjects. All personnel 
involved in the conduct of this study have completed ICH GCP training. 
 
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IRB/REB/EC for review and approval. Approval of both the protocol and the 
consent form must be obtained before any subject is enrolled. Any amendment to the protocol will 
require review and approval by the IRB/REB/EC before the changes are implemented to the study. 
All changes to the consent form will be IRB/REB/EC approved. 




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PRINCIPAL/QUALIFIED INVESTIGATOR SIGNATURE PAGE 
 
 
Investigator Name: 
 
 
 
Signature: 
 
Date: 
 
 
 
 
 
 
(DD-MMM-YYYY) 
 
Institution Name: 
 
 
 
 
 
By my signature, I agree to personally supervise the conduct of this study at my study site and 
to ensure its conduct is compliant with the protocol, informed consent, IRB/REB/EC 
independent ethics committee procedures, instructions from sponsor’s representatives, the 
Declaration of Helsinki, ICH GCP guidelines, and applicable local regulations governing the 
conduct of clinical studies. 
 
 
 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
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 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CCR2b 
chemokine motif receptor 2b 
CONSORT 
Consolidated Standards of Reporting Trials 
CRO 
contract research organization 
CV 
coefficient of variation 
CXCR1 
CXC chemokine receptor type 1 
CXCR2 
CXC chemokine receptor type 2 
DLQI 
Dermatology Life Quality Index 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ET 
early termination 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl-transferase 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCT 
hematocrit 
HCV 
hepatitis C virus 
HEENT 
head, eyes, ears, nose, throat 
HEK293 
human embryo kidney 293 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
hs-CRP 
high-sensitivity C-reactive protein 
ICH 
International Council for Harmonisation 
IHC 
immunohistochemistry 
INR 
international normalized ratio 
IQR 
interquartile range 
IL 
interleukin 
IRB 
institutional review board 
IWRS 
Interactive Web Response System 
LDH 
lactate dehydrogenase 
LMW 
low molecular weight  
LS 
least squares 
MAD 
Multiple Ascending Dose 


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MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MDRD 
Modification of Diet in Renal Disease 
MedDRA  
Medical Dictionary for Regulatory Activities 
mITT 
modified intent‑to‑treat 
MMRM 
mixed model repeated measures 
MPV 
mean platelet volume 
MSU 
monosodium urate 
MTD 
maximum tolerated dose 
NSAID 
nonsteroidal anti-inflammatory drug 
PD 
pharmacodynamics 
PLT 
platelets 
PASI 
Psoriasis Area Severity Index 
PGA 
Physician Global Assessment 
PPD 
purified protein derivative  
PPP 
palmoplantar pustulosis 
PPPASI 
Palmoplantar Pustulosis Psoriasis Area and Severity Index 
PPPASI-50 
50% reduction in PPPASI 
PPPASI-75 
75% reduction in PPPASI 
PPPGA 
Palmoplantar Pustulosis Physician Global Assessment 
PPSI 
Palmoplantar Pustulosis Severity Index 
PPSI-50 
50% reduction in PPSI 
PPSI-75 
75% reduction in PPSI 
PT 
prothrombin time 
PUVA 
psoralen and ultraviolet A 
QC 
quality control 
QD 
once daily 
QTcF 
QT interval by Fredericia 
RBC 
red blood cell (count) 
REB 
research ethics board 
RT-PCR 
reverse transcription polymerase chain reaction 
SAD 
Single Ascending Dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SUSAR 
suspected unexpected serious adverse reactions 
TB 
tuberculosis  
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
UV-B 
ultraviolet B 
VAS 
visual analog scale 
WBC 
white blood cell (count) 
WHO-DD 
World Health Organization-Drug Dictionary 
WOCBP 
women of childbearing potential 


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1 PROTOCOL SUMMARY 
1.1 Synopsis  
Name of Sponsor/Company:  
Aristea Therapeutics, Inc. 
Name of Investigational 
Product: RIST4721 
Name of Active Ingredient: 
RIST4721 
Title of Study:  
A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study to Evaluate the Efficacy and Safety 
of RIST4721 in Subjects with Palmoplantar Pustulosis 
Phase of Development:  
Phase 2a 
Study Center(s): 
Approximately 10–16 study centers located in Canada and Germany will participate in this study. 
Number of Subjects (planned):  
Approximately 30 subjects will be included in this study. 
Duration of Study:  
The maximum study duration per subject is approximately 73 days, including up to 30 days for the 
screening period, one day for eligibility confirmation and randomization (Day –1), 28 days for the 
treatment phase, and 14 days for the follow-up period. 
Study Drugs, Dosage, and Mode of Administration:  
Subjects will be randomized to a 1:1 ratio at baseline (Day –1) to receive oral RIST4721 300 mg solution 
or placebo, once daily for 28 days. 
Objectives: 
Primary: 
The primary objective is: 
• 
To assess the efficacy of RIST4721 versus placebo in adult subjects with moderate to severe 
palmoplantar pustulosis (PPP) using a range of efficacy endpoints 
Secondary: 
The secondary objective is: 
• 
To assess the safety of RIST4721 versus placebo in adult subjects with moderate to severe PPP 
 
 
 


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Name of Sponsor/Company:  
Aristea Therapeutics, Inc. 
Name of Investigational 
Product: RIST4721 
Name of Active Ingredient: 
RIST4721 
Exploratory: 
The exploratory objectives are: 
• 
To evaluate the effects of RIST4721 on skin biomarkers in adult subjects with moderate to severe 
PPP 
• 
To evaluate the plasma concentration of RIST4721 in adult subjects with moderate to severe PPP 
 
Endpoints: 
Primary Efficacy Endpoints: 
• 
Relative change from baseline in fresh pustule count at Day 28  
• 
Relative change from baseline in total pustule count at Day 28 
Secondary Efficacy Endpoints: 
• 
Absolute change from baseline in fresh pustule count at Day 28  
• 
Absolute change from baseline in total pustule count at Day 28 
• 
Proportion of subjects achieving at least a 50% reduction in fresh pustule count at Day 28 
• 
Proportion of subjects achieving at least a 50% reduction in total pustule count at Day 28 
Secondary Safety Endpoints: 
• 
Incidence of treatment-emergent adverse events (TEAEs)  
• 
Changes in vital signs, electrocardiogram (ECG), and laboratory tests 
Exploratory Endpoints: 
• 
Absolute change from baseline in fresh pustule count at Day 7, Day 14, and Day 21  
• 
Relative change from baseline in fresh pustule count at Day 7, Day 14, and Day 21 
• 
Absolute change from baseline in total pustule count at Day 7, Day 14, and Day 21  
• 
Relative change from baseline in total pustule count at Day 7, Day 14, and Day 21  
• 
Proportion of subjects achieving a 50% reduction in fresh pustule count at Day 7, Day 14, and Day 21 
• 
Proportion of subjects achieving a 75% reduction in fresh pustule count at Day 7, Day 14, Day 21, 
and Day 28  
• 
Proportion of subjects achieving a 50% reduction in total pustule count at Day 7, Day 14, and Day 21 
• 
Proportion of subjects achieving a 75% reduction in total pustule count at Day 7, Day 14, Day 21, 
and Day 28  
• 
Absolute change from baseline in Palmoplantar Pustulosis Psoriasis Area and Severity Index 
(PPPASI) at Day 7, Day 14, Day 21, and Day 28  
• 
Relative change from baseline in PPPASI at Day 7, Day 14, Day 21, and Day 28  


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Confidential and proprietary. Permission should be obtained before any reproduction. 
Name of Sponsor/Company:  
Aristea Therapeutics, Inc. 
Name of Investigational 
Product: RIST4721 
Name of Active Ingredient: 
RIST4721 
• 
Proportion of subjects achieving a 50% reduction in PPPASI (PPPASI-50) at Day 7, Day 14, Day 21, 
and Day 28  
• 
Proportion of subjects achieving a 75% reduction in PPPASI (PPPASI-75) at Day 7, Day 14, Day 21, 
and Day 28  
• 
Absolute change from baseline in Palmoplantar Pustulosis Physician Global Assessment (PPPGA) 
at Day 7, Day 14, Day 21, and Day 28 
• 
Relative change from baseline in PPPGA at Day 7, Day 14, Day 21, and Day 28 
• 
Proportion of subjects achieving a PPPGA of clear (0) or almost clear (1) with at least a 2-point 
decrease at Day 7, Day 14, Day 21, and Day 28  
• 
Proportion of subjects achieving at least a 2-point decrease in PPPGA at Day 7, Day 14, Day 21, and 
Day 28  
• 
Absolute change from baseline in palmoplantar pustulosis severity index (PPSI) at Day 7, Day 14, 
Day 21, and Day 28  
• 
Proportion of subjects achieving a 50% reduction in PPSI (PPSI-50) at Day 7, Day 14, Day 21, and 
Day 28  
• 
Proportion of subjects achieving a 75% reduction in PPSI (PPSI-75) at Day 7, Day 14, Day 21, and 
Day 28  
• 
Relative change from baseline in PPSI at Day 7, Day 14, Day 21, and Day 28 
• 
Absolute change from baseline in pain visual analog scale (VAS) at Day 7, Day 14, Day 21, and 
Day 28  
• 
Relative change from baseline in pain VAS at Day 7, Day 14, Day 21, and Day 28  
• 
Absolute change from baseline in Dermatology Life Quality Index (DLQI) at Day 7, Day 14, Day 21, 
and Day 28 
• 
Relative change from baseline in DLQI at Day 7, Day 14, Day 21, and Day 28 
• 
Absolute change from baseline in body surface area (BSA) at Day 7, Day 14, Day 21, and Day 28 
• 
Relative change from baseline in BSA at Day 7, Day 14, Day 21, and Day 28 
• 
Absolute change from baseline in Psoriasis Area Severity Index (PASI) at Day 7, Day 14, Day 21, 
and Day 28 
• 
Relative change from baseline in PASI at Day 7, Day 14, Day 21, and Day 28 
• 
Absolute change from baseline in Physician Global Assessment (PGA) at Day 7, Day 14, Day 21, 
and Day 28 
• 
Relative change from baseline in PGA at Day 7, Day 14, Day 21, and Day 28 
• 
Proportion of subjects achieving a PGA of clear (0) or almost clear (1) at Day 7, Day 14, Day 21, 
and Day 28 
 


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Confidential and proprietary. Permission should be obtained before any reproduction. 
Name of Sponsor/Company:  
Aristea Therapeutics, Inc. 
Name of Investigational 
Product: RIST4721 
Name of Active Ingredient: 
RIST4721 
• 
Proportion of subjects achieving at least a 2-point decrease in PGA at Day 7, Day 14, Day 21, and 
Day 28 
• 
Changes in skin biomarker levels  
• 
Plasma concentration of RIST4721 
Study Design: 
Approximately 30 subjects with moderate to severe PPP, as defined by a PPPASI ≥8, a PPPGA ≥3, and 
a minimum of 8 fresh pustules (fresh pustule count on both right/left palms and soles) at screening and 
20 fresh pustules (fresh pustule count on both right/left palms and soles) at Day –1, will be included in 
this 4-week, multicenter, randomized, double-blind, placebo controlled, Phase 2a study to evaluate the 
efficacy and safety of RIST4721. 
 
All subjects will sign an informed consent and undergo screening for study eligibility. After a screening 
period of no more than 30 days, subjects will be randomized (1:1) at Day –1 to receive oral RIST4721 
300 mg solution or placebo, once daily for 28 days. Subjects will come to the study site at 7 occasions: 
screening; baseline (Day –1); and Days 7, 14, 21, 28, and 42 (follow-up) or early termination (ET) visit. 
Study drug will be dispensed weekly to subjects. 
 
Efficacy will be evaluated using fresh pustule count, total pustule count, PPPASI, PPPGA, PPSI, and 
pain VAS. BSA affected with psoriasis (excluding PPP lesions on palms and soles) will be evaluated to 
assess eligibility. BSA, PGA and PASI will also be evaluated to assess impact on body psoriasis (only 
for subjects who have psoriasis elsewhere on the body at Day -1). Quality of life will be evaluated using 
the DLQI. Safety will be assessed with physical examinations, vital signs, ECG, and clinical laboratory 
tests (hematology, biochemistry, and urinalysis), and by collecting adverse events (AEs). 
 
A total of 6 blood samples will be collected from a subgroup of approximately 20 subjects who consent 
to the procedure for plasma concentration analyses. Samples will be collected within 1 hour prior to 
dosing (pre-dose) and 1 hour ±10 minutes and 2 hours ±10 minutes post-dose on Days 7 and 21. Blood 
sample collection for plasma concentration analyses will be obtained from the same subjects who consent 
to biopsy collection. 
 
A total of three 4.5-mm skin biopsies will be collected from a subgroup of approximately 20 subjects 
who consent to the procedure for reverse transcription polymerase chain reaction (RT-PCR), 
transcriptome profiling, and immunohistochemistry (IHC). Two skin biopsies will be taken at Day –1 
(1 from lesional skin and 1 from adjacent nonlesional skin, either from palm or sole), and one biopsy 
will be taken at Day 28 from lesional skin, preferably from the same anatomical region as for biopsies 
collected on Day –1. Skin biopsy samples will be obtained from the same subjects who consent to blood 
sample collection for plasma concentration analyses. 
 
Medical photographs of PPP areas will be taken at Day –1, Days 28, and 42 from a subgroup of 
approximately 15 subjects who consent to the procedure at selected sites to illustrate the outcome of the 
trial. 
 


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Inclusion/Exclusion Criteria: 
Inclusion criteria: 
In order to be eligible to participate in this study, a subject must meet all of the following criteria at the 
screening and Day –1 visits, unless specified otherwise: 
1. Male or female subject, aged 18–70 years at the time of consent. 
2. Subject has at least a 6-month history of PPP as defined by the presence of pustules on palms 
and/or soles, but without evidence of infection on palms and soles (information obtained from 
medical chart or subject’s physician, or directly from the subject). 
3. Subject has moderate or severe PPP, as defined by PPPASI ≥8 and PPPGA ≥3 at Day –1, and a 
minimum of 8 fresh pustules at screening (fresh pustule count on both right/left palms and soles) 
and 20 fresh pustules at Day –1 (fresh pustule count on both right/left palms and soles). 
4. Subject who wants to use an emollient should agree to use the same emollient, at the same 
frequency of application for 7 days before Day –1 and throughout the study. Note: However, on 
the day of scheduled visits, subjects cannot apply emollient before their scheduled visit time. 
5. For female subject of childbearing potential involved in any sexual intercourse that could lead 
to pregnancy: the subject must agree to use a highly effective contraceptive method, from at least 
4 weeks before Day –1 until at least 4 weeks after the last study drug administration. Highly 
effective contraceptive methods include hormonal contraceptives (combined oral contraceptive, 
patch, vaginal ring, injectable, or implant), intrauterine devices or intrauterine systems, male 
partner(s) vasectomy, tubal ligation, or a double-barrier method of contraception (barrier 
methods include male condom, female condom, cervical cap, diaphragm, and contraceptive 
sponge) in conjunction with spermicide. 
Note: Subjects who are on a hormonal contraceptive must have been on a stable dose for at least 
4 weeks before Day –1. 
Note: The above list of contraceptive methods does not apply to subjects who are abstinent for 
at least 4 weeks before Day –1 and will continue to be abstinent from penile‑vaginal intercourse 
throughout the study. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the participant. 
Note: For countries where double-barrier methods are not accepted as highly effective 
contraception, then this option must not be considered.  
Note: A female of nonchildbearing potential is defined as follows:  
- 
Female who has had surgical sterilization (hysterectomy, bilateral oophorectomy, or 
bilateral salpingectomy). 
- 
Female who has had a cessation of menses for at least 12 months without an alternative 
medical cause, and a follicle-stimulating hormone (FSH) test confirming 
nonchildbearing potential (refer to laboratory reference ranges for confirmatory levels). 
6. Female subject of childbearing potential has a negative serum pregnancy test at screening and 
negative urine pregnancy test at Day –1. 
7. Female subject agrees to not have egg retrieval during the study and for 1 month after the last 
study drug administration. 
8. Male subject agrees to use condom and spermicide from Day –1 until at least 3 months after the 
last study drug administration. 


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Name of Sponsor/Company:  
Aristea Therapeutics, Inc. 
Name of Investigational 
Product: RIST4721 
Name of Active Ingredient: 
RIST4721 
9. Male subject agrees not to donate sperm during the study and for 3 months after the last study 
drug administration. 
10. Subject has negative tuberculosis (TB) infection test. Subject will be evaluated for latent TB 
infection with a purified protein derivative (PPD) test or a QuantiFERON-TB Gold test, if one 
has not been performed in the last 6 months. Subjects who demonstrate evidence of latent TB 
infection (either PPD ≥5 mm of induration or positive QuantiFERON-TB Gold test, irrespective 
of bacille Calmette-Guérin vaccination status) will not be allowed to participate in the study. 
Subjects with documented completed treatment for latent TB will be allowed to participate in 
the study without retesting. 
11. Subject must be capable of giving written informed consent, which must be personally signed 
and dated by the subject and obtained prior to any trial-related activities. 
12. Subject must be willing to comply with all study procedures and must be available for the 
duration of the study. 
Exclusion criteria: 
A subject who meets any of the following criteria at the screening and Day –1 visits, unless specified 
otherwise, will be excluded from participation in this study: 
1. Subject is a female who is breastfeeding, pregnant, or who is planning to become pregnant during 
the study. 
2. In the opinion of the investigator performing the initial examination, the subject should not 
participate in the trial (eg, due to probable noncompliance or inability to understand the nature, 
meaning, and consequences of the trial, and give adequately informed consent). 
3. Subject has evidence of erythrodermic, generalized pustular psoriasis, predominantly guttate 
psoriasis, or drug-induced psoriasis. 
4. Subject has a history of skin disease or presence of skin condition (except psoriasis) that, in the 
opinion of the investigator, would interfere with the study assessments.  
5. Subject has moderate to severe psoriasis, as defined by plaque psoriasis covering ≥10% of 
his/her total BSA at Day –1. 
6. Subject is known to have immune deficiency or is immunocompromised. 
7. Subject has a 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 successfully treated localized carcinoma in situ of the cervix are not to be 
excluded. 
8. Subject had a major surgery within 8 weeks prior to Day –1 or has a major surgery planned 
during the study. 
9. Subject has any clinically significant medical condition or ECG/physical/laboratory/vital signs 
abnormality that would, in the opinion of the investigator, put the subject at undue risk or 
interfere with interpretation of study results. 
10. Subject has positive results for hepatitis B surface antigens (HBsAg), antibodies to hepatitis B 
core antigens (anti-HBc), hepatitis C virus (HCV), or human immunodeficiency virus (HIV). 


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Name of Sponsor/Company:  
Aristea Therapeutics, Inc. 
Name of Investigational 
Product: RIST4721 
Name of Active Ingredient: 
RIST4721 
11. Any clinically significant history of infection (except for localized herpes simplex) within 
4 weeks prior to Day –1. 
12. Subject has absolute neutrophil count 1.8 x 109/L at screening. 
13. Subject has 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, oesophageal varices) at screening. 
14. Subject has a history of clinically significant anemia or hemoglobin (Hgb) value ≤10 g/dL at 
screening. 
15. Subject has a creatinine clearance ≤60 ml/min at screening (calculated with Modification of Diet 
in Renal Disease [MDRD] formula). 
16. Subject has used any topical medication to treat PPP, including corticosteroids, retinoids, 
vitamin D analogues (such as calcipotriol), or tar, within 2 weeks prior to Day –1. 
17. Subject has used topical dapsone within 2 weeks prior to Day –1. 
18. Subject has used any systemic treatment for PPP, including corticosteroids, oral retinoids, biotin, 
immunosuppressive medication, methotrexate, cyclosporine, colchicine or apremilast, within 
4 weeks prior to Day –1. Note: Intranasal corticosteroids and inhaled corticosteroids for stable 
medical conditions are allowed if subject has been on a stable dose for at least 4 weeks prior to 
Day –1 and will agree to maintain the same dose for the duration of the study. Eye drops 
containing corticosteroids are allowed. 
19. Subject has used strong systemic cytochrome P450 3A4/5 inhibitors or inducers within 4 weeks 
or 5 half-lives, whichever is longer, prior to baseline (Day –1). Topical cytochrome P450 3A4/5 
inducers or inhibitors with known limited systemic availability may be permitted. 
20. Subject has received any ultraviolet B (UV-B) phototherapy (including tanning beds) or excimer 
laser within 4 weeks prior to Day –1. 
21. Subject has had psoralen and ultraviolet A (PUVA) treatment within 4 weeks prior to Day –1. 
22. Subject has received any marketed or investigational biological agent within 12 weeks or 
5 half‑lives (whichever is longer) prior to Day –1. 
23. Subject is currently receiving a nonbiological investigational product or investigational device 
or has received one within 4 weeks prior to Day –1. 
24. Subject had excessive sun exposure or has used tanning booths within 4 weeks prior to Day –1, 
or subject is planning a trip where excessive sun exposure is expected or is not willing to 
minimize natural and artificial sunlight exposure during the study. Use of sunscreen products 
and protective apparel are recommended when exposure cannot be avoided. 
25. Subject has a known or suspected allergy to RIST4721 or any component of the study drug. 
26. Subject has a known history of clinically significant drug or alcohol abuse in the last year prior 
to Day –1. 
27. Close affiliation with the investigator (eg, a close relative), including any study staff of the sites 
or persons working at the CRO or subject is an employee of sponsor. 


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Name of Sponsor/Company:  
Aristea Therapeutics, Inc. 
Name of Investigational 
Product: RIST4721 
Name of Active Ingredient: 
RIST4721 
28. Subject is institutionalized because of legal or regulatory order. 
29. For subjects consenting to biopsies only: 
a. Subject has a history of an allergic reaction or significant sensitivity to lidocaine or other 
local anesthetics. 
b. Subject has a history of hypertrophic scarring or keloid formation in scars or suture sites. 
c. Subject has taken anticoagulant medication, such as heparin, low molecular weight 
(LMW) heparin, warfarin, antiplatelets (except low-dose aspirin, which will be 
allowed), within 2 weeks prior to Day –1, or has a contraindication to skin biopsies. 
Nonsteroidal anti-inflammatory drugs (NSAIDs) will not be considered antiplatelets and 
will be allowed. 
 
Statistical methods: 
Continuous variables will be summarized in tables and will include the number of subjects, mean, 
standard deviation (SD), median, interquartile range (IQR), minimum, and maximum. Categorical 
variables will be presented in tables as frequencies and percentages. A statistical analysis plan (SAP) 
will provide additional details on the approach to the analysis and data displays. 
Efficacy Analyses: 
Efficacy analyses will be performed in all subjects who receive at least one dose of study drug, also 
referred to as the modified intent‑to‑treat (mITT) analysis set. All subjects will be analyzed according to 
the treatment group to which they were randomized. 
Mixed model repeated measures (MMRM) analysis will be used for analyzing the relative change from 
baseline in continuous endpoints that are collected in a longitudinal fashion (fresh and total pustule count, 
PPPASI, PPPGA, PPSI, pain VAS, and DLQI). The natural log ratio of the post-dose values to baseline 
will be used as dependent variables in the analysis. The model will include fixed effects for treatment, 
visit and treatment-by-visit interaction, and natural log of baseline value as covariate. Unstructured 
covariance will be used to model the correlation. The treatment effect will be the contrast between 
treatment groups at specified visit(s) (eg, at Day 28) estimated through LS means. The LS mean 
estimates, associated two-sided 90% confidence intervals, and p-values will be reported. In this model, 
the estimates will be back-transformed to the ratio scale and presented as a percent change-from-baseline 
for ease of interpretation. 
An analogous MMRM analysis will be used to analyze the absolute change from baseline. The response 
variable will be the absolute change from baseline at scheduled post‑baseline visits and the baseline 
value as covariate.  
For each post-dose study visit, a Fisher’s exact test will be used to compare the proportion of subjects 
with a 50% or 75% reduction in fresh and total pustule count and the proportion of subjects achieving 
PPPASI-50 and PPPASI-75, for subjects treated with RIST4721 and subjects treated with placebo. 
Statistical testing of the primary and secondary efficacy endpoints will be performed following a 
Gatekeeper strategy over endpoint families and Hochberg procedure within endpoint families. The 
endpoint families are comprised of the primary endpoints (relative change in fresh pustules and relative 
change in total pustules) and the secondary efficacy endpoints (absolute change from baseline in fresh 
pustules, absolute change in total pustules, achieving at least a 50% reduction in fresh pustules, and 


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Confidential and proprietary. Permission should be obtained before any reproduction. 
Name of Sponsor/Company:  
Aristea Therapeutics, Inc. 
Name of Investigational 
Product: RIST4721 
Name of Active Ingredient: 
RIST4721 
achieving at least a 50% reduction in total pustules). This procedure is expected to control the type 1 
error rate at 2-sided α = 10%. 
Safety Analyses: 
The safety analysis set will be defined as all subjects who received at least one dose of study drug. 
Analysis will be done according to the actual treatment they received. Safety data will be summarized 
and presented descriptively by treatment group. Safety data, including AEs and serious adverse events 
(SAEs), laboratory assessments, vital signs, and ECGs will be presented and tabulated. 
Plasma Concentration Analyses: 
The plasma concentration analysis set will include all subjects who received at least one dose of study 
drug and have plasma concentration data. Plasma concentration data will be summarized based on 
nominal timepoints using descriptive statistics, such as mean, SD, median, IQR, minimum and 
maximum. 
Pharmacodynamic Analyses: 
The pharmacodynamic (PD) analysis set will include all subjects who have at least one dose of study 
drug and who have an assessment of PD parameters. Expression levels in lesional and nonlesional PPP 
skin will be compared using RT-PCR, transcriptome profiling, and IHC data. A PD analysis plan will be 
prepared to detail the PD analyses. Results will be presented in a separate report. 
Sample Size Consideration: 
Approximately 30 subjects with moderate to severe PPP will be randomized 1:1 to receive placebo or 
RIST4721. A sample size of 30 (approximately 15 per group) will ensure 85% power to detect a 
statistically significant difference in the relative change from baseline in pustules counts at Day 28 with 
a 2-sided level of significance of 10%. This assumes a log-Normal distribution of the pustules counts, a 
3-fold change (Placebo/RIST4721 at Day 28 relative to Baseline), and a coefficient of variation (CV) in 
the original scale of 150%. This sample size is expected to result in approximately 90% power if the CV 
is 130%. 
 
 
 


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1.2  Study Diagram 
Figure 1: Study Diagram 
 
 
1.3 Schedule of Events 
The screening evaluation will only be performed after the subject has agreed to participate and has 
signed and dated the informed consent form. No treatment or trial-related procedures will be 
initiated before the informed consent is signed. The Day –1 visit must be performed, at the latest, 
30 days after the screening visit. 
 
The screening evaluation will be performed according to the inclusion and exclusion criteria. If 
the subject fulfills all inclusion criteria and no exclusion criteria, he or she may be included in the 
study.  
 
Table 1 provides a description of the procedures to be performed at each visit. 
 
If assessments are scheduled for the same nominal time, then the assessments should occur in the 
following order: 
• Vital signs 
• 12-lead ECG  
• Blood draws for plasma concentration analysis (time window vs administration is detailed 
in the footer of Table 1) 
 






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2 INTRODUCTION 
2.1 Background 
 Palmoplantar Pustulosis 
Palmoplantar pustulosis (PPP) is a chronic inflammatory skin condition characterized by sterile 
pustules with erythema, hyperkeratosis, and scaling on the palms and soles.1,2 A number of reports 
suggest that PPP represents a distinct entity because of its unique genetic and molecular features.2-
4 While few studies have investigated the characteristics, disease burden, and risk factors 
associated with PPP, results indicate that PPP has a mean age at disease onset of 41.6 years and is 
more commonly diagnosed in females than males.4 Reports also indicate that the disease tends to 
affect more frequently the thenar, hypothenar, and central areas of the palms, as well as the 
corresponding areas of the soles, although pustular lesions may also extend to the subject’s wrists 
and heels.2 The clinical manifestations of PPP make it a debilitating condition that puts the afflicted 
subjects at risk of social stigmatism and reduced quality of life.5 
 
While several factors have been shown to induce PPP, such as infections, trauma, stress, and 
various therapeutic agents, the disease pathophysiology remains poorly understood.2 Recent 
studies have begun to highlight the importance of the innate immune system and cytokines in the 
development of PPP.2 In support of these hypotheses, neutrophils were found in high numbers in 
the epidermis of subjects with PPP, with focal accumulations observed at the level of pustules.6 In 
addition, high levels of neutrophil-recruiting chemokines, including interleukins 1 (IL-1) and 8 
(IL-8), were measured in PPP lesions.3,7 
 
The CXC chemokine receptor type 2 (CXCR2) plays important roles in various acute and chronic 
inflammatory processes.8,9 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.10,11 Given the role of neutrophils in inflammation, the blockade of CXCR2 
may represent a novel therapeutic approach for the treatment of neutrophil‑mediated inflammatory 
disorders, such as PPP.11 
 RIST4721  
RIST4721 is a small-molecule CXCR2 antagonist that is proposed to have potential as a novel oral 
treatment for inflammatory diseases, including PPP. RIST4721 is a high-potency antagonist of 
human CXCR2, as validated 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 test systems evaluating RIST4721 selectivity to a number of related receptors, 
RIST4721 demonstrated a 150- and 90-fold greater selectivity for CXCR2 than CXC chemokine 
receptor type 1 (CXCR1) and chemokine motif receptor 2b (CCR2b), respectively.12 
 
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 arthropathy. 


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When the rats were challenged with MSU injection, significant, dose-dependent decreases in 
exudate volume, total white blood cell (WBC) count, and neutrophil infiltration were seen with 
RIST4721 at doses 30, 100, and 300 μmol/kg. 
 
Taken together, the data from both in vitro (cell line) and in vivo animal studies with RIST4721 
provide a rationale for its evaluation for the treatment of neutrophil-mediated inflammatory 
disorders, such as PPP. 
 Study Rationale 
There are currently no treatments approved for PPP.4 Off-label topical therapy typically involves 
corticosteroids with or without occlusion. Other topical agents used for the treatment of PPP 
include calcipotriene, PUVA, and tacrolimus.2 However, topical agents often have limited efficacy 
in PPP, in part due to the lower relative absorptive capacity of the palms and soles compared to 
other body areas.13,14 
 
Off-label systemic treatment options for PPP may involve the use of acitretin, cyclosporine, 
colchicine, and biologic agents, such tumor necrosis factor alpha, IL-23, and IL-17 antagonists.2 
These treatments have limited efficacy and can be associated with significant side effects. The lack 
of approved targeted treatments for PPP warrant development of a more efficacious option. 
 
RIST4721 is an investigational small molecule targeting CXCR2. CXCR2 plays important roles 
in neutrophil recruitment to inflammatory sites and represents a promising therapeutic target for 
the treatment of neutrophil-mediated inflammatory diseases. The utility of antagonizing CXCR2 
was formerly investigated with the use of neutralizing antibodies targeting IL-8, one of several 
CXCR2 ligands.15,16 This study revealed that inhibition of the IL-8/CXCR2 axis causes clinically 
relevant reductions in disease activity in PPP subjects.15 
 
In the present study, the efficacy and safety of RIST4721 will be evaluated in subjects with 
moderate to severe PPP. 
2.2  Risk/Benefit Assessment 
 Known Potential Risks 
The safety of RIST4721 was assessed in a 2-part, Phase 1 study. The first part was a single-blind, 
placebo-controlled, single-ascending dose study with 38 healthy male subjects. Dose escalation 
continued through all planned doses (19 mg, 50 mg, 150 mg, 350 mg, and 730 mg). The second 
part was an open-label, randomized, 2‑way crossover relative bioavailability study comparing a 
single 500 mg dose of orally‑administered RIST4721 in suspension to a single 500 mg dose of 
orally‑administered RIST4721 in solution, conducted in 6 healthy male subjects. The results 
revealed that RIST4721 is generally well tolerated in single ascending doses, up to 730 mg. No 
safety or tolerability concerns were identified. All AEs resolved, and most were considered to be 
mild. There were no clinically significant abnormal clinical laboratory or vital signs results, other 
than the expected reduction in blood neutrophils. Digital ECG and telemetry data revealed no 


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abnormal variations in QT interval by Fredericia (QTcF) values and no trends in mean heart rate, 
QRS, QTcF, or PR intervals in the RIST4721 or placebo groups. No concomitant medication use 
or abnormal physical examination findings were reported.12 
 
The safety of RIST4721 was also assessed in a multiple ascending dose study conducted in 
27 healthy male subjects. RIST4721 was safe and well tolerated in multiple ascending doses 
(75 mg, 225 mg and 500 mg once daily [QD]) for 10 days. Nine of the eighteen subjects dosed 
with RIST4721 reported ≥1 AE, with the most commonly reported AEs being headache and urine 
odor abnormal (n=3 each). No deaths, SAEs, or discontinuation of the study drug were reported, 
and no safety concerns were identified. Treatment with RIST4721 did not lead to clinically 
significant abnormal laboratory results, vital signs, or 12-lead ECG measurements, other than the 
expected reduction in blood neutrophils.12 
 
Reductions in blood neutrophil counts have been seen in humans on treatment with other CXCR2 
antagonists, including SCH527123 and SB656933.17,18 These reductions had a rapid onset, but 
resolved within a few days of treatment discontinuation, suggesting redistribution rather than 
destruction or failure of production of neutrophils. Consistently, in two Phase 1 studies 
investigating the safety and tolerability of RIST4721 in healthy subjects, CXCR2 antagonism 
reduced absolute neutrophil counts. In both studies, this effect resolved in the off-drug follow-up 
period.12 
 
No allergic reactions were seen in human clinical studies conducted with RIST4721; however, as 
with any medication, there may still be risks or side effects that are unforeseeable and not known 
at this time. Symptoms of an allergic reaction includes hives, or swelling of the face, lips, tongue 
and/or throat, which may cause difficulty in breathing or swallowing. This could become 
life‑threatening if it is not treated promptly. Allergic reactions may also be associated with local 
skin anesthesia utilized in the optional biopsy procedure. 
 
As the potential risks of RIST4721 to an unborn fetus are currently unknown, women of 
childbearing potential must agree to use appropriate contraceptive methods as outlined in 
Section 5.1 Inclusion Criteria. 
 
There are several potential risks to participating in study-related procedures. Serious side effects 
from a skin biopsy are rare but may include scarring, infection, tenosynovitis, or nerve damage. 
Plasma concentration blood draws may induce discomfort, bruising, swelling and, in rare 
instances, infection at the site of the needle. In rare cases, a nerve may be hit, which may cause 
pain and temporary tingling in the arm or very rarely permanent nerve damage. Although rare, 
skin irritation is possible after an ECG from the electrodes or gel. Tuberculosis screens may result 
in tenderness, swelling or a rash at the site of the injections. 
 
Further information related to nonclinical and clinical studies is available in the Investigator 
Brochure. The Reference Safety Information for RIST4721 can be found in Section 6.1 of the 
Investigator Brochure. 


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 Known Potential Benefits 
It is anticipated that subjects randomized to the active study drug will see an improvement in their 
PPP condition as a result of participating in this Phase 2a study. Specifically, potential benefits 
may include fewer pustules, less pain, decreased redness and desquamation, smaller involved 
surface areas, and less functional impairment. 
 
It is also anticipated that transcriptional profiling analyses performed on RIST4721- and 
placebo‑treated PPP lesions may help deepen our knowledge of the disease and expand our 
understanding of RIST4721-mediated effects on PPP. 
 
Participation in this study may help generate future benefit for larger groups of subjects with PPP 
if RIST4721 proves to be successful in treating this condition. 
 Assessment of Risks and Benefits 
While there are potential risks associated with the study drug and the study procedures for this 
Phase 2 clinical study, the risk is expected to be minimal. All AEs from previous clinical studies 
were reported as mild or moderate in severity and there were no reported SAEs. The main safety 
consideration for the current study is the expected, mechanism of action-mediated reduction in 
peripheral blood neutrophils, which is to be closely monitored via the procedure outlined in 
Figure 3.   
 
Against these minimal risks stands the benefit of information on the safety and efficacy of a 
promising new substance, which is intended to be used in the treatment of PPP. Despite these 
potential risks, it is expected that subjects randomized to RIST4721 might see an improvement in 
their PPP condition, such as fewer pustules, less pain, decreased redness and desquamation, 
smaller involved surface areas, and less functional impairment. As there are currently no approved 
therapies for PPP, RIST4721 has the potential to improve subjects’ quality of life and daily 
functional mobility. Due to the range of exploratory endpoints, participation in this study will also 
provide useful information about the PPP disease course and correlated quality of life for subjects. 
This may inform future studies of RIST4721 in PPP, with the ultimate goal of providing much 
needed treatment to patients that today do not have effective alternative treatment options. 
 
All quality, pharmacology and toxicology data, and satisfactory safety and tolerability results 
demonstrated in clinical and nonclinical studies are considered sufficient to expect a positive 
benefit/risk ratio for the treatment of PPP with RIST4721, and therefore to initiate this study. 
 
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria, proper 
study design, and close monitoring. 
 
 


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3 OBJECTIVES AND ENDPOINTS 
3.1  Objectives 
Primary: 
• To assess the efficacy of RIST4721 versus placebo in adult subjects with moderate to severe 
PPP using a range of efficacy endpoints 
 
Secondary: 
• To assess the safety of RIST4721 versus placebo in adult subjects with moderate to severe PPP 
 
Exploratory: 
• To evaluate the effects of RIST4721 on skin biomarkers in adult subjects with moderate to 
severe PPP 
• To evaluate the plasma concentration of RIST4721 in adult subjects with moderate to severe 
PPP 
3.2  Endpoints 
Primary Efficacy Endpoints: 
• Relative change from baseline in fresh pustule count at Day 28 
• Relative change from baseline in total pustule count at Day 28 
 
Secondary Efficacy Endpoints: 
• Absolute change from baseline in fresh pustule count at Day 28 
• Absolute change from baseline in total pustule count at Day 28 
• Proportion of subjects achieving at least a 50% reduction in fresh pustule count at Day 28 
• Proportion of subjects achieving at least a 50% reduction in total pustule count at Day 28 
Secondary Safety Endpoints: 
• Incidence of TEAEs 
• Changes in vital signs, ECG, and laboratory tests 
 
Exploratory Endpoints: 
• Absolute change from baseline in fresh pustule count at Day 7, Day 14, and Day 21  
• Relative change from baseline in fresh pustule count at Day 7, Day 14, and Day 21 
• Absolute change from baseline in total pustule count at Day 7, Day 14, and Day 21  
• Relative change from baseline in total pustule count at Day 7, Day 14, and Day 21  


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• Proportion of subjects achieving a 50% reduction in fresh pustule count at Day 7, Day 14, and 
Day 21 
• Proportion of subjects achieving a 75% reduction in fresh pustule count at Day 7, Day 14, 
Day 21, and Day 28  
• Proportion of subjects achieving a 50% reduction in total pustule count at Day 7, Day 14, and 
Day 21 
• Proportion of subjects achieving a 75% reduction in total pustule count at Day 7, Day 14, 
Day 21, and Day 28  
• Absolute change from baseline in PPPASI at Day 7, Day 14, Day 21, and Day 28  
• Relative change from baseline in PPPASI at Day 7, Day 14, Day 21, and Day 28  
• Proportion of subjects achieving a PPPASI-50 at Day 7, Day 14, Day 21, and Day 28  
• Proportion of subjects achieving a PPPASI-75 at Day 7, Day 14, Day 21, and Day 28  
• Absolute change from baseline in PPPGA at Day 7, Day 14, Day 21, and Day 28 
• Relative change from baseline in PPPGA at Day 7, Day 14, Day 21, and Day 28 
• Proportion of subjects achieving a PPPGA of clear (0) or almost clear (1) with a 2-point 
decrease at Day 7, Day 14, Day 21, and Day 28  
• Proportion of subjects achieving at least a 2-point decrease in PPPGA at Day 7, Day 14, 
Day 21, and Day 28  
• Absolute change from baseline in PPSI at Day 7, Day 14, Day 21, and Day 28  
• Proportion of subjects achieving a PPSI-50 at Day 7, Day 14, Day 21, and Day 28  
• Proportion of subjects achieving a PPSI-75 at Day 7, Day 14, Day 21, and Day 28  
• Relative change from baseline in PPSI at Day 7, Day 14, Day 21, and Day 28 
• Absolute change from baseline in pain VAS at Day 7, Day 14, Day 21, and Day 28  
• Relative change from baseline in pain VAS at Day 7, Day 14, Day 21, and Day 28  
• Absolute change from baseline in DLQI at Day 7, Day 14, Day 21, and Day 28 
• Relative change from baseline in DLQI at Day 7, Day 14, Day 21, and Day 28 
• Absolute change from baseline in BSA at Day 7, Day 14, Day 21, and Day 28 
• Relative change from baseline in BSA at Day 7, Day 14, Day 21, and Day 28 
• Absolute change from baseline in PASI at Day 7, Day 14, Day 21, and Day 28 
• Relative change from baseline in PASI at Day 7, Day 14, Day 21, and Day 28 
• Absolute change from baseline in PGA at Day 7, Day 14, Day 21, and Day 28 
• Relative change from baseline in PGA at Day 7, Day 14, Day 21, and Day 28 


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• Proportion of subjects achieving a PGA of clear (0) or almost clear (1) at Day 7, Day 14, 
Day 21, and Day 28 
• Proportion of subjects achieving at least a 2-point decrease in PGA at Day 7, Day 14, Day 21, 
and Day 28 
• Changes in skin biomarker levels  
• Plasma concentration of RIST4721 
4 
STUDY DESIGN  
4.1 Overall Design  
Approximately 30 subjects with moderate to severe PPP, as defined by a PPPASI ≥8, a PPPGA ≥3, 
and a minimum of 8 fresh pustules (fresh pustule count on both right/left palms and soles) at 
screening and 20 fresh pustules (fresh pustule count on both right/left palms and soles) at Day –1, 
will be included in this 4‑week, multicenter, randomized, double‑blind, placebo-controlled, 
Phase 2a study to evaluate the efficacy and safety of RIST4721. 
 
All subjects will sign an informed consent and undergo screening for study eligibility. After a 
screening period of no more than 30 days, subjects will be randomized (1:1) at Day –1 to receive 
oral RIST4721 300 mg solution or placebo, once daily for 28 days. Subjects will come to the study 
site at 7 occasions: screening; baseline (Day –1); and Days 7, 14, 21, 28, and 42 (follow-up) or ET 
visit. Study drug will be dispensed weekly to subjects. 
 
Efficacy will be evaluated using fresh pustule count, total pustule count, PPPASI, PPPGA, PPSI, 
and pain VAS. BSA affected with psoriasis (excluding PPP lesions on palms and soles) will be 
evaluated to assess eligibility. BSA, PGA and PASI will also be evaluated to assess impact on 
body psoriasis (only for subjects who have psoriasis elsewhere on the body at Day -1). Quality of 
life will be evaluated using the DLQI. Safety will be assessed with physical examinations, vital 
signs, ECG, and clinical laboratory tests (hematology, biochemistry, and urinalysis), and by 
collecting AEs. 
 
A total of 6 blood samples will be collected from a subgroup of approximately 20 subjects who 
consent to the procedure for plasma concentration analyses. Samples will be collected within 1 
hour prior to dosing (pre-dose) and 1 hour ±10 minutes and 2 hours ±10 minutes post-dose on 
Days 7 and 21. Blood sample collection for plasma concentration analyses will be obtained from 
the same subjects who consent to biopsy collection. 
 
A total of three 4.5-mm skin biopsies will be collected from a subgroup of approximately 
20 subjects who consent to the procedure for RT-PCR, transcriptome profiling, and IHC. Two skin 
biopsies will be taken at Day –1 (1 from lesional skin and 1 from adjacent nonlesional skin, either 
from palm or sole), and one biopsy will be taken at Day 28 from lesional skin, preferably from the 
same anatomical region as for biopsies collected on Day –1. Skin biopsy samples will be obtained 
from the same subjects who consent to blood sample collection for plasma concentration analyses. 


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Medical photographs of PPP areas will be taken at Day –1, Days 28, and 42 from a subgroup of 
approximately 15 subjects who consent to the procedure at selected sites to illustrate the outcome 
of the trial. 
4.2 Scientific Rationale for Study Design  
The proposed design is considered appropriate for assessing the efficacy, safety, and plasma 
concentration of RIST4721 compared to placebo in subjects with moderate to severe PPP. 
 
This Phase 2a study is an intervention-based study. To provide the highest possible evidence of 
causation, this study will have a randomized, double‑blind, placebo-controlled study design, the 
gold standard approach for intervention-based trials. The study will be randomized and double 
blind to ensure a random allocation of subjects to each treatment arm and minimize bias introduced 
by known and unknown confounding factors. In addition, the study will be placebo controlled to 
establish a cause-effect relationship between treatment and outcome, and differentiate any 
uncovered relationship from the act of treating the condition.19 
4.3 Justification for Dose 
RIST4721 has been tested in Phase 1 Single Ascending Dose (SAD) and Multiple Ascending Dose 
(MAD) studies and has been shown to have an acceptable safety and tolerability profile. To date, 
RIST4721 has not been tested in PPP patients. As this is a proof-of-concept study designed to 
assess the safety and efficacy of RIST4721 in adult subjects with moderate to severe PPP, the goal 
is to maximize potential efficacy by testing the highest dose that is expected to be safe and tolerable 
in humans based on existing animal toxicology and human safety and tolerability data.   
 
RIST4721 has been tested and yielded an acceptable toxicological profile in animal toxicology 
studies of up to 28 days duration, which supports the 28-day dosing regimen for this clinical study.  
There are, however, no validated animal models of PPP. The anti-inflammatory potency of 
RIST4721 has been evaluated in 4 studies in a rat air pouch MSU crystal-induced arthropathy with 
significant, dose-dependent decreases in exudate volume, total WBC count, and neutrophil 
infiltration being observed, which provides support for the evaluation of RIST4721 in 
inflammatory conditions. It is, however, challenging to extrapolate the doses used in these animal 
studies to PPP disease and patients.  
   
The results of the two Phase 1 clinical studies investigating the safety and tolerability of RIST4721 
in 64 healthy human male subjects show that RIST4721 was generally safe and well tolerated in 
single ascending doses, up to 730 mg and multiple ascending doses, up to 500 mg for 10 days.  
 
In the first study, where subjects received a single dose of RIST4721 between 19 and 730 mg, no 
safety or tolerability concerns were identified. A similar proportion of subjects reported AEs across 
all RIST4721 dose groups and placebo. The AEs were mostly considered to be mild and all the 
AEs resolved by the end of the study. No deaths, SAEs or AEs that led to subjects discontinuing 
from the study were reported. A number of subjects who received RIST4721 showed temporary 
reductions of peripheral blood neutrophils, as expected, based on the mechanism of action. All 


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neutrophil reductions returned to normal by the end of the study and no serious infections were 
noted. 
 
In the second study, where subjects received 10 daily doses of RIST4721 at either 75 mg, 225 mg 
or 500 mg, no safety or tolerability concerns were identified. A similar proportion of subjects 
reported AEs across all RIST4721 dose groups and placebo. The AEs were mostly considered to 
be mild and all but 2 of the AEs resolved by the end of the study. No deaths, SAEs or AEs that led 
to subjects discontinuing from the study were reported. RIST4721 dosed QD for 10 days reduced 
absolute peripheral blood neutrophil counts, as expected, based on mechanism of action, with the 
largest effect observed at the 500 mg dose level. Seven subjects had mild reductions in neutrophil 
counts at the end of the study, but these all resolved in the off-drug, follow-up period. None of 
these reductions were reported as AEs and no serious infections were noted.    
 
The main safety consideration for the current study is the expected, mechanism of action-mediated 
reduction in peripheral blood neutrophils. Modelling of the data from the SAD and MAD studies 
suggests that, within a 95% confidence interval, patients dosed QD with RIST4721 at 300 mg are 
not expected to experience peripheral blood neutrophil counts of <1.0 X 109/L.        
 
In summary, based on the existing animal toxicology data and human experience from Phase 1 
SAD and MAD studies, a 300-mg once-daily dose of RIST4721 is expected to be safe, tolerable, 
and unlikely to result in clinically significant neutropenia whilst providing the best opportunity to 
establish the efficacy of RIST4721 in PPP patients. 
4.4 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 Schedule of Events, 
Table 1. For subjects undergoing the early termination visit, their study participation is considered 
completed when the early termination assessments are completed and they are no longer being 
examined. 
 
The end of the study is defined as completion of the last visit or procedure shown in the schedule 
of events for the last enrolled subject in the trial globally for all sites. 
5 STUDY POPULATION  
5.1 Inclusion Criteria 
In order to be eligible to participate in this study, a subject must meet all of the following criteria 
at the screening and Day –1 visits, unless specified otherwise: 
1. Male or female subject, aged 18–70 years at the time of consent. 
2. Subject has at least a 6-month history of PPP as defined by the presence of pustules on 
palms and/or soles, but without evidence of infection on palms and soles (information 
obtained from medical chart or subject’s physician, or directly from the subject). 


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3. Subject has moderate or severe PPP, as defined by PPPASI ≥8 and PPPGA ≥3 at Day –1, 
and a minimum of 8 fresh pustules at screening (fresh pustule count on both right/left palms 
and soles) and 20 fresh pustules at Day –1 (fresh pustule count on both right/left palms and 
soles). 
4. Subject who wants to use an emollient should agree to use the same emollient, at the same 
frequency of application for 7 days before Day –1 and throughout the study. Note: 
However, on the day of scheduled visits, subjects cannot apply emollient before their 
scheduled visit time. 
5. For female subject of childbearing potential involved in any sexual intercourse that could 
lead to pregnancy: the subject must agree to use a highly effective contraceptive method, 
from at least 4 weeks before Day –1 until at least 4 weeks after the last study drug 
administration. Highly effective contraceptive methods include hormonal contraceptives 
(combined oral contraceptive, patch, vaginal ring, injectable, or implant), intrauterine 
devices or intrauterine systems, male partner(s) vasectomy, tubal ligation, or a 
double‑barrier method of contraception (barrier methods include male condom, female 
condom, cervical cap, diaphragm, and contraceptive sponge) in conjunction with 
spermicide.  
Note: Subjects who are on hormonal contraceptive must have been on a stable dose for at 
least 4 weeks before Day –1. 
Note: The above list of contraceptive methods does not apply to subjects who are abstinent 
for at least 4 weeks before Day –1 and will continue to be abstinent from penile‑vaginal 
intercourse throughout the study. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the clinical trial and the preferred and usual lifestyle of the 
participant. 
Note: For countries where double-barrier methods are not accepted as highly effective 
contraception, then this option must not be considered. 
Note: A female of nonchildbearing potential is defined as follows:  
− Female who has had surgical sterilization (hysterectomy, bilateral oophorectomy, 
or bilateral salpingectomy). 
− Female who has had a cessation of menses for at least 12 months without an 
alternative medical cause, and a FSH test confirming nonchildbearing potential 
(refer to laboratory reference ranges for confirmatory levels). 
6. Female subject of childbearing potential has a negative serum pregnancy test at screening 
and negative urine pregnancy test at Day –1. 
7. Female subject agrees to not have egg retrieval during the study and for 1 month after the 
last study drug administration. 
8. Male subject agrees to use condom and spermicide from Day –1 until at least 3 months 
after the last study drug administration. 
9. Male subject agrees not to donate sperm during the study and for 3 months after the last 
study drug administration. 


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10. Subject has negative TB infection test. Subject will be evaluated for latent TB infection 
with a PPD test or a QuantiFERON-TB Gold test, if one has not been performed in the last 
6 months. Subjects who demonstrate evidence of latent TB infection (either PPD ≥5 mm 
of induration or positive QuantiFERON-TB Gold test, irrespective of bacille Calmette-
Guérin vaccination status) will not be allowed to participate in the study. Subjects with 
documented completed treatment for latent TB will be allowed to participate in the study 
without retesting. 
11. Subject must be capable of giving written informed consent, which must be personally 
signed and dated by the subject and obtained prior to any trial-related activities. 
12. Subject must be willing to comply with all study procedures and must be available for the 
duration of the study. 
5.2 Exclusion Criteria 
A subject who meets any of the following criteria at the screening and Day –1 visits, unless 
specified otherwise, will be excluded from participation in this study: 
1. Subject is a female who is breastfeeding, pregnant, or who is planning to become pregnant 
during the study. 
2. In the opinion of the investigator performing the initial examination, the subject should not 
participate in the trial (eg, due to probable noncompliance or inability to understand nature, 
meaning, and consequences of the trial, and give adequately informed consent). 
3. Subject has evidence of erythrodermic, generalized pustular psoriasis, predominantly 
guttate psoriasis, or drug-induced psoriasis. 
4. Subject has a history of skin disease or presence of skin condition (except psoriasis) that, 
in the opinion of the investigator, would interfere with the study assessments.  
5. Subject has moderate to severe psoriasis, as defined by plaque psoriasis covering ≥10% of 
his/her total BSA at Day –1. 
6. Subject is known to have immune deficiency or is immunocompromised. 
7. Subject has a 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 successfully treated localized carcinoma in situ of the cervix are not 
to be excluded. 
8. Subject had a major surgery within 8 weeks prior to Day –1 or has a major surgery planned 
during the study. 
9. Subject has any clinically significant medical condition or ECG/physical/laboratory/vital 
signs abnormality that would, in the opinion of the investigator, put the subject at undue 
risk or interfere with interpretation of study results. 
10. Subject has positive results for HBsAg, antibodies to anti-HBc, HCV, or HIV. 
11. Any clinically significant history of infection (except for localized herpes simplex) within 
4 weeks prior to Day –1. 


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12. Subject has absolute neutrophil count 1.8 x 109/L at screening. 
13. Subject has ALT, AST or total bilirubin values ≥2 times the ULN, or other clinical 
evidence of significant hepatic impairment (eg, ascites, peri-umbilical veins, oesophageal 
varices) at screening. 
14. Subject has a history of clinically significant anemia or Hgb value ≤10 g/dL at screening. 
15. Subject has a creatinine clearance ≤60 ml/min at screening (calculated with MDRD 
formula). 
16. Subject has used any topical medication to treat PPP, including corticosteroids, retinoids, 
vitamin D analogues (such as calcipotriol), or tar within 2 weeks prior to Day –1. 
17. Subject has used topical dapsone within 2 weeks prior to Day –1. 
18. Subject has used any systemic treatment for PPP, including corticosteroids, oral retinoids, 
biotin, immunosuppressive medication, methotrexate, cyclosporine, colchicine or 
apremilast, within 4 weeks prior to Day –1. Note: Intranasal corticosteroids and inhaled 
corticosteroids for stable medical conditions are allowed if subject has been on a stable 
dose for at least 4 weeks prior to Day –1 and will agree to maintain the same dose for the 
duration of the study. Eye drops containing corticosteroids are allowed. 
19. Subject has used strong systemic cytochrome P450 3A4/5 inhibitors or inducers within 
4 weeks or 5 half-lives, whichever is longer, prior to baseline (Day –1) (topical cytochrome 
P450 3A4/5 inducers or inhibitors with known limited systemic availability may be 
permitted). Examples of strong systemic cytochrome P450 3A4/5 inhibitors or inducers are 
provided in Table 3. 
20. Subject has received any UV-B phototherapy (including tanning beds) or excimer laser 
within 4 weeks prior to Day –1. 
21. Subject has had PUVA treatment within 4 weeks prior to Day –1. 
22. Subject has received any marketed or investigational biological agent within 12 weeks or 
5 half-lives (whichever is longer) prior to Day –1. 
23. Subject is currently receiving a nonbiological investigational product or investigational 
device or has received one within 4 weeks prior to Day –1. 
24. Subject had excessive sun exposure or has used tanning booths within 4 weeks prior to 
Day –1, or subject is planning a trip where excessive sun exposure is expected, or is not 
willing to minimize natural and artificial sunlight exposure during the study. Use of 
sunscreen products and protective apparel are recommended when exposure cannot be 
avoided. 
25. Subject has a known or suspected allergy to RIST4721 or any component of the study drug. 
26. Subject has a known history of clinically significant drug or alcohol abuse in the last year 
prior to Day –1. 
27. Close affiliation with the investigator (eg, a close relative), including any study staff of the 
sites or persons working at the CRO or subject is an employee of sponsor. 
28. Subject is institutionalized because of legal or regulatory order. 


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29. For subjects consenting to biopsies only: 
– 
Subject has a history of an allergic reaction or significant sensitivity to lidocaine or 
other local anesthetics. 
– 
Subject has a history of hypertrophic scarring or keloid formation in scars or suture 
sites. 
– 
Subject has taken anticoagulant medication, such as heparin, LMW heparin, 
warfarin, antiplatelets (except low-dose aspirin, which will be allowed), within 
2 weeks prior to Day –1, or has a contraindication to skin biopsies. NSAIDs will 
not be considered antiplatelets and will be allowed. 
5.3 Lifestyle Considerations 
Subjects will be instructed to avoid food or beverages containing grapefruit within 7 days prior to 
Day –1 and during the study. 
5.4 Screen Failures 
Screen failures are defined as individuals who consent to participate in the clinical trial 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. 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) may be 
rescreened, if deemed acceptable by the investigator. Rescreened subjects should be assigned a 
different subject number than the initial screening. All procedures planned at the screening visit, 
including signature of a new consent form, will be performed. 
 
 




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More details on the administration methods are described in the study manual. 
 Accountability  
The investigator is responsible for maintaining accurate records of the study drug received initially 
and of the study drug dispensed/used. At the conclusion of the study, all used and unused 
investigational products and all medication containers will be returned to the sponsor unless other 
arrangements have been approved. Any study drug accidentally or deliberately destroyed or 
returned to the sponsor or designee will be accounted for. Any discrepancies between amounts 
dispensed and returned will be explained. 
 
All study drug accountability forms and treatment logs must be retained in the investigator’s study 
files. Product inventory and accountability records will be maintained as per ICH 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 drug are provided in the study 
manual.  
6.3 Randomization 
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). 
 
Approximately 30 subjects will be randomized (1:1) to receive RIST4721 or placebo. 
 
Randomization will occur prior to first dosing, at the Day –1 visit. The randomization list will be 
generated using a validated software. Randomization will be stratified by consent to biopsy 
collection. The master randomization list will be kept secured until the study blind is broken at the 
end of study. This list will be uploaded into an Interactive Web Response System (IWRS). The 
investigator or designee will be able to acquire a randomization number for eligible subjects by 
connecting to the IWRS. 
 
Further guidance and information can be obtained in the study manual. 
 Blinding 
This study will be double-blinded. At all times, treatment and randomization information will be 
kept confidential and will not be released to the investigator, the study staff, the contract research 
organization (CRO), or the sponsor’s study team until after the conclusion of the study. 


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Blinding codes should only be broken in emergency situations for reasons of subject safety. When 
the blind for a subject has been broken, the reason must be fully documented in the source 
document and eCRF. Whenever possible, the investigator should contact the sponsor or its 
designee before breaking the blind. If the blind is broken, the investigator should promptly inform 
the medical monitor. Documentation of breaking the blind should be recorded with the date/time 
and reason why the blind was broken, and the names of the personnel involved. 
 
The subject for whom the blind has been broken will be discontinued from the study and undergo 
the ET procedures. The primary reason for discontinuation (the event or condition which led to the 
unblinding) will be recorded. 
 
In order to reduce risk of breaking the blind, investigators, the study staff, the CRO, and the 
sponsor’s study team will not receive absolute and relative neutrophil and WBC count results, 
starting on Day 7. 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 be disclosed to the respective 
investigators if absolute neutrophil counts reach values <1.8 x 109/L, in which case immediate 
actions will be taken, as described in Figure 3. Retest results will be communicated to the 
investigators who will follow up on neutropenia and the incidence of infections with patients 
having absolute neutrophil count results 1.0 x 109/L. Neutropenia will be followed up through 
resolution. Absolute and relative neutrophil and WBC count results will also be disclosed if the 
values are higher than the ULN. 
 Study Treatment Compliance 
Study treatment compliance will be monitored at each visit. Adherence to treatment will be 
assessed by direct questioning, review of the subject’s dosing diary, and by maintaining adequate 
study drug dispensing and return records. Any deviation from the prescribed dosage regimen will 
be recorded in the source document and eCRF. 
 
Subjects who are significantly noncompliant with treatment 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 drug, as judged by the 
investigator. 
6.4 Concomitant Therapy 
All medications, including over-the-counter drugs, vitamins, herbal/natural products, and antacids 
taken within 4 weeks prior to screening and throughout the study must be recorded. In addition, 
the use of any prohibited medications within the prespecified timeframe described in the exclusion 
criteria should be documented. 
 






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7.1 Discontinuation 
Subjects who discontinue the study after the first dose will be asked, if they agree, to come for a 
last assessment (ET visit). Subjects who are discontinued for safety reasons may be asked to come 
for additional follow-up visits, at the investigator’s discretion, after the ET visit to ensure 
appropriate medical care and AEs follow-up. 
 
Subjects who discontinue will not be replaced. 
 
Reasons for discontinuation include the following: 
• 
The investigator decides that the subject should be withdrawn. If this decision is made because 
of a SAE, the study drug is to be discontinued in that subject immediately and appropriate 
measures are to be taken. The investigator will notify the sponsor immediately. 
• 
The attending physician requests that the subject be withdrawn from the study. 
• 
The subject, for any reason, requires treatment with another therapeutic agent that has been 
demonstrated to be effective for treatment of the study indication. In this case, discontinuation 
from the study occurs immediately upon introduction of the new agent. 
• 
The subject is lost to follow-up. In this case, a reasonable attempt to contact the subject and 
ascertain his or her status must be made, and these attempts must be documented. 
• 
The subject becomes pregnant at any time during the study. 
• 
The subject has neutrophil counts below 1.0 x 109/L. Refer to Figure 3 for more details. 
• 
The subject may withdraw from the study for any other reason, including withdrawal of 
consent. 
• 
The sponsor or regulatory authorities, for any reason, stop the study. In this case, all subjects 
will be discontinued from the study. The investigator will immediately, on discontinuance of 
the study by the sponsor, in its entirety or at a clinical trial site, inform both the subjects and 
the IRB/REB/EC of the discontinuance, provide them with the reasons for the discontinuance 
and advise them in writing of any potential risks to the health of subjects or other persons. 
7.2 Lost to Follow-Up 
A subject will be considered lost to follow-up if he or she fails to return for scheduled visits and is 
unable to be contacted by the study site staff.  
 
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. 
• 
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.  


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• 
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. 
8 STUDY ASSESSMENTS AND PROCEDURES 
8.1 Efficacy Assessments 
Clinical evaluations of PPP will be performed by an experienced and qualified dermatologist 
(board certified or eligible) or other suitably qualified and experienced designee. To assure 
consistency and reduce variability, the same assessor should perform all assessments on a given 
subject whenever possible. 
 Fresh and Total Pustule Count 
The number of fresh and total pustules will be counted on each palm and sole at the visits specified 
in Table 1. Fresh pustules are defined as macroscopically visible pustules that are white/yellow in 
color with no brown color, with or without crust, and present on the glabrous skin of the palms 
and/or soles. The pustule count will refer to the sum of pustules counted on all palms and soles. 
To be eligible to enroll in this study, subjects should have a minimum of 8 fresh pustules (fresh 
pustule count on both right/left palms and soles) at screening and 20 fresh pustules (fresh pustule 
count on both right/left palms and soles) at Day –1. 
 Palmoplantar Pustulosis Psoriasis Area Severity Index 
The PPPASI will be evaluated at the visits specified in Table 1. The PPPASI is a scale from 0 to 
72 that is used to evaluate the severity of PPP on palms and soles.20 
 
Refer to APPENDIX A for a complete description of this scale. To be eligible to enroll in this 
study, subjects must have a PPPASI score ≥8 at Day –1. 
 Palmoplantar Pustulosis Physician Global Assessment 
The PPPGA will be assessed at the visits specified in Table 1. The PPPGA is a 5-point scale that 
evaluates the severity of PPP.21,22 A detailed description of PPPGA score calculation is provided 
in Table 4. To be eligible to enroll in this study, subjects must have a PPPGA score ≥3 at Day –1. 
 






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8.3 Safety and Other Assessments 
 Vital Signs 
The following vital signs will be recorded at the visits specified in Table 1 with the subject in a 
seated position, after having sat calmly for at least 5 minutes: systolic and diastolic blood pressure 
(mmHg), pulse (bpm), body temperature (°C), and respiratory rate (breaths/min). 
 
Weight (kg) and height (cm) will be collected at screening, and weight measured on Day 42 
(follow-up) or ET. 
 
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. 
 Physical Examination 
The following sites/systems will at least be included in the physical examination, which will be 
performed at the visits specified in Table 1: 
 
• General appearance 
• Dermatological (except PPP) 
• Head, eyes, ears, nose, throat (HEENT) 
• Respiratory 
• Cardiovascular 
• Abdominal 
• Neurological 
• Musculoskeletal 
• Lymphatic  
 
Information for all physical examinations must be included in the source document. 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. 
 
A symptom-oriented physical examination may be performed during the study, if deemed 
necessary by the investigator. 
 Brief Physical Examination 
The following sites/systems will at least be included in the brief physical examination that will be 
performed on Day 14, as specified in Table 1: 
 
• General appearance 


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• Dermatological (except PPP) 
• Respiratory 
• Cardiovascular 
• Abdominal 
 
Information for all physical examinations must be included in the source document. 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. 
 
If deemed appropriate by the investigator based on the subject’s condition, a complete physical 
examination, as described in Section 8.3.2 can be performed instead of a brief/symptom-oriented 
examination. 
 Clinical Laboratory Tests 
Laboratory tests will be performed at the visits specified in Table 1. The tests will include 
urinalysis, hematology with differential and coagulation testing, a standard biochemistry panel 
(including liver function tests and cholesterol), and serum pregnancy test (screening) for women 
of childbearing potential (WOCBP). At the visit specified in Table 1, a urine pregnancy test will 
be performed for WOCBP (conducted at the investigator site). The specific tests in these panels 
are listed in Table 6. 
 




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having absolute neutrophil count results 1.0 x 109/L. Neutropenia will be followed up through 
resolution. Absolute and relative neutrophil and WBC count results will also be disclosed if the 
values are higher than the ULN. 
 
Figure 3: Diagram for Addressing Neutrophil Counts 
 
 
 Electrocardiogram  
Twelve-lead ECGs will be performed as a safety assessment at the visits specified in Table 1. 
Clinically significant findings in the ECG should exclude a subject from study participation (as 
deemed appropriate by the investigator). Any clinically significant change will be reported as an 
AE. 
 Plasma Concentration Assessment in Blood 
Blood samples will be collected for analysis of RIST4721 plasma concentration on visits and time 
points indicated in the schedule of events in Table 1. 
 
The actual date and time of each blood sample collection, as well as the time of last meal prior to 
dosing will be recorded. 
 


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Details about the collection, processing, handling, storage and shipping of blood samples will be 
provided in the laboratory manual. 
 Pharmacodynamic Assessments in Skin Biopsies 
Approximately 20 subjects who consent to biopsy collection will have three 4.5‑mm skin biopsies 
at the visits specified in Table 1: two biopsies will be taken at Day –1 (1 from lesional skin and 1 
from adjacent nonlesional skin, either from palm or sole) and one biopsy will be taken at Day 28 
from lesional skin, preferably from the same anatomical region as for biopsies collected on Day ‑1. 
For comparison of expression levels of lesional and nonlesional PPP skin, RT-PCR, transcriptome 
profiling, and IHC data will be performed. 
 
The skin will be cleaned, disinfected, and anesthetized before skin biopsies are performed. Sterile 
gauze will be used to absorb any bleeding. The biopsy sites will be sutured, if necessary. 
 
Details about the collection, processing, handling, storage and shipping of biopsy samples will be 
provided in the laboratory manual. 
 
Pharmacodynamic results will be presented in a separate report. 
 Medical Photography 
Medical photographs of PPP areas will be performed on a subgroup of approximately 15 subjects 
at the visits specified in Table 1. Care will be taken to use the same camera, the same magnification, 
and the same settings for each photograph at each visit in order to obtain comparable pictures. 
Medical photographs will be taken using a blue background. 
 
Photographs will be identified and stored as instructed in the study reference manual. 


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8.4 Adverse Events and Serious Adverse Events 
 Definition of Adverse Event  
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and that does not necessarily have a causal relationship with this treatment. An AE can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the study drug. 
 Definition of Treatment-Emergent Adverse Event 
A TEAE is any condition that was not present prior to treatment with the study product but 
appeared following treatment, was present at treatment initiation but worsened during treatment, 
or was present at treatment initiation but resolved and then reappeared while the individual was on 
treatment (regardless of the intensity of the AE when the treatment was initiated). 
 Definition of Serious Adverse Event  
A SAE or reaction is any untoward medical occurrence that, at any dose has any of the following 
consequences: 
• 
Results in death 
• 
Is life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
 
The term “life-threatening” in the definition of “serious” refers to an event in which the subject 
was at risk of death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if it were more severe. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life‑threatening or result in death or hospitalization, but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should also 
usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 


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 Classification of an Adverse Event 
8.4.4.1 Relationship to Study Treatment 
 
The investigator will establish causality of the AE to the study drug. The investigator should 
consider the subject’s history, most recent physical examination findings, and concomitant 
medications.  
 
The following definitions will be used to determine causality of an AE: 
• 
Not related: Temporal relationship of the onset of the AE, relative to the study drug, is not 
reasonable, or another cause can explain the occurrence of the AE. 
• 
Related: Temporal relationship of the onset of the AE, relative to the study drug, is 
reasonable, follows a known response pattern to the treatment, and an alternative cause is 
unlikely. 
8.4.4.2 Adverse Event Severity 
 
The intensity of an AE is an estimate of the relative severity of the event made by the investigator 
based on his or her clinical experience and familiarity with the literature. The following definitions 
are to be used to rate the severity of an AE: 
• 
Mild: The symptom is barely noticeable to the subject and does not influence performance 
of daily activities. Treatment is not ordinarily indicated. 
• 
Moderate: The symptom is sufficiently severe to make the subject uncomfortable, and 
performance of daily activities is influenced. Treatment may be necessary. 
• 
Severe: The symptom causes severe discomfort, and daily activities are significantly 
impaired or prevented. Treatment may be necessary. 
8.4.4.3 Expectedness 
 
 in consultation with the medical monitor, if need be, will assess the 
expectedness of each SAE in relation to the study drug. 
 Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits 
and interviews of a study subject presenting for medical care, or upon review by a study monitor. 
 
All AEs, including local and systemic reactions, will be captured on the appropriate eCRF. 
Information to be collected includes event description, date of onset, clinician’s assessment of 
severity, relationship to study drug (assessed only by those with the training and authority to make 


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a diagnosis), and date of resolution/stabilization of the event. All AEs occurring while on study 
must be documented appropriately regardless of relationship.  
 
Before subject enrollment, study site personnel will note the occurrence and nature of each 
subject’s medical condition(s) in the appropriate section of the source document and eCRF. During 
the study, site personnel will note any change in the condition(s) and the occurrence and nature of 
any AE.  
 
Any medical condition that is present prior to informed consent signature will be considered as 
part of medical history and not reported as an AE. However, if the study subject’s condition 
deteriorates after the consent signature, it will be recorded as an AE. 
 
If a subject experiences an AE at any time after the informed consent signature until the end of 
participation in the study, the event will be recorded as an AE in the source document and eCRF. 
Any SAE related to the study participation will be recorded in the source document and eCRF 
from the time a subject consents to participate in the study until the end of participation in the 
study. 
 
The investigator is responsible for appropriate medical care of subjects during the study. The 
investigator also remains responsible for following through with an appropriate health care option 
for all AEs that are ongoing at the end of the study. The subject should be followed until the event 
is resolved or stable. If an AE is ongoing at the end of study, the follow-up duration is left to the 
discretion of the investigator, except for subjects with neutropenia who will be followed until 
resolution. Follow-up frequency will be performed at the discretion of the investigator.  
 
Whenever possible, clinically significant abnormal laboratory results are to be reported using the 
diagnosis that resulted in the clinically significant abnormal laboratory results and not the actual 
abnormal test. 
 Adverse Event Reporting 
Investigators are responsible for monitoring the safety of subjects who are participating in this 
study and for alerting the sponsor (via the medical monitor) to any event that seems unusual, even 
if this event may be considered an unanticipated benefit to the subject. 
 Serious Adverse Event Reporting 
will be the pharmacovigilance unit responsible for the overall pharmacovigilance process for 
this study. All SAEs, related to the study drug or not, occurring during the course of the study must 
be reported on an SAE form to the pharmacovigilance unit (see below contact information) within 
24 hours of the knowledge of the occurrence. The SAE reporting period ends at the end of the 
follow-up period or if the subject begins an alternative therapy, except for subjects with 
neutropenia who will be followed until resolution.  
 


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Reporting should be done by sending the completed SAE form to the following email address 
(faxing can also be done as a second option in case e-mailing is not possible).  
 
Safety Contact Information: 
 
E-mail
 
Fax: 
 
 
The pharmacovigilance unit will inform the medical monitor, the sponsor, and CRO within 1 
business day of awareness of a new SAE. The pharmacovigilance unit will process and the medical 
monitor will evaluate all SAEs as soon as the reports are received. For each SAE received, the 
pharmacovigilance unit, in consultation with the medical monitor, if needed, will determine 
whether the criteria for expedited reporting to relevant regulatory authorities have been met. The 
pharmacovigilance unit will manage the expedited reporting of relevant safety information, in 
accordance with local laws and regulations. SAEs will be reported to the REB/IRB/EC as per local 
REB/IRB/EC requirements. 
 Suspected Unexpected Serious Adverse Reactions Reporting 
The sponsor will ensure that all relevant information about suspected unexpected serious adverse 
reactions (SUSAR) that are fatal or life-threatening is recorded and reported as soon as possible to 
the competent authorities in all the member states concerned, to the IRB/REB/EC as per local 
REB/IRB/EC requirements, and to all investigators in any case no later than seven days after 
knowledge by the sponsor of such an event. Finally, any additional relevant follow-up information 
is subsequently communicated to the competent authorities, the IRB/REB/EC as per local 
REB/IRB/EC requirements, and all investigators within an additional eight days.  
 
All other SUSARs (ie, not fatal or life-threatening) shall be reported to the competent authorities 
concerned, to the IRB/REB/EC as per local REB/IRB/EC requirements, and all investigators 
concerned as soon as possible but within a maximum of fifteen days of first knowledge by the 
sponsor. 


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 Pregnancy Reporting 
If a female subject or a female partner of a male subject becomes pregnant during the study, the 
subject should inform the study site as soon as possible. Upon confirmation of the pregnancy, the 
female subject will be discontinued from the study. The investigator must complete a study specific 
pregnancy form upon confirmation of a pregnancy and send it to the pharmacovigilance unit within 
24 hours of confirmation of the pregnancy (contact information to be used is the same as for SAE 
reporting). The pharmacovigilance unit will report all cases of pregnancy to the medical monitor, 
the sponsor, and CRO in a timely manner. Post-treatment follow-up should be done to ensure the 
safety of the pregnant subject and her fetus. Pregnancy is not itself an AE or SAE; however, 
maternal/fetal complications or abnormalities will be recorded as AEs or SAEs, as appropriate. 
The investigator will follow the pregnancy until completion or until pregnancy termination and, in 
the case of a live-born offspring, to 1 month of age in that infant. The investigator will notify the 
pharmacovigilance unit and CRO of the outcome as a follow-up to the initial pregnancy form. All 
pregnancies should be reported to the sponsor and, when applicable, to the ethics committee. 
 Overdose 
Study drug overdose is defined as any accidental or intentional use of study drug in an amount 
higher than the dose indicated per protocol for a given subject. Study drug compliance (see 
Section 6.3.2) should be reviewed to detect potential instances of overdose (intentional or 
accidental). 
 
Any study drug overdose during the study should be recorded on the source document and eCRF. 
In the event of overdose, the subject should be closely monitored for any potential AEs. All AEs 
associated with an overdose should be entered on the Adverse Event eCRF and reported using the 
procedures detailed in Section 8.4.7, Serious Adverse Events Reporting, even if the events do not 
meet seriousness criteria. 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 Adverse Event eCRF. The excess quantity and duration 
of the overdose should be recorded. 
9 STATISTICAL CONSIDERATIONS  
9.1 Sample Size Determination 
This trial is a proof-of-concept trial aimed at exploring preliminary indications of efficacy and 
safety of RIST4721 in PPP, with the aim of informing a decision about proceeding into full 
development. The exploratory nature of this study necessitates a minimum number of subjects to 
be exposed to the drug, yet without losing the possibility of inferring meaningful conclusions. 
 
Approximately 30 subjects with moderate to severe PPP will be randomized 1:1 to receive placebo 
or RIST4721. A sample size of 30 (approximately 15 per group) will ensure 85 % power to detect 
a statistically significant difference in the relative change from baseline in pustules counts at 


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Day 28 with a 2-sided level of significance of 10%. This assumes a log-Normal distribution of the 
pustules counts, a 3-fold change (Placebo/RIST4721 at Day 28 relative to Baseline), and a 
coefficient of variation (CV) in the original scale of 150%. This sample size is expected to result 
in approximately 90% power if the CV is 130%. 
9.2 Populations for Analyses 
mITT analysis set: This analysis set will include all subjects who received at least one dose of the 
study drug. All subjects will be analyzed according to the treatment group to which they were 
randomized. The mITT analysis set will be used as the primary analysis set for efficacy. 
 
Safety analysis set: This analysis set will include all subjects who received at least one dose of the 
study drug. All subjects will be analyzed according to the treatment that they actually received. 
 
Plasma concentration analysis set: This analysis set will include all subjects who received at least 
one dose of study drug and have plasma concentration data. 
 
PD analysis set: This analysis set will include all subjects who have at least one dose of study drug 
and who have an assessment of PD parameters. 
9.3 Statistical Analyses 
 General Approach 
Continuous variables will be summarized in tables and will include the number of subjects, mean, 
SD, median, IQR, minimum, and maximum. Categorical variables will be presented in tables as 
frequencies and percentages. 
 
All details regarding the efficacy and safety variable definitions, analyses strategy, statistical 
justification, and techniques for handling missing values will be detailed in a separate SAP that 
will be prepared before the database is locked and any analyses are undertaken.  
The two primary efficacy endpoints (relative change in fresh pustules and relative change in total 
pustules) and the secondary efficacy endpoints (absolute change from baseline in fresh pustules, 
absolute change in total pustules, achieving at least a 50% reduction in fresh pustules, and 
achieving at least a 50% reduction in total pustules) will be tested using a Gatekeeper strategy and 
the Hochberg’s method. The primary endpoints will first be tested at alpha of 10% (2-sided). If the 
larger p-value is less than 10% (2-sided), both primary endpoints will be declared statistically 
significant. If the larger p-value is greater than 10%, but the smaller p-value is less than 5% 
(2‑sided), then the primary endpoint with the smaller p-value will be declared statistically 
significant. 
With Hochberg’s method, the study will be considered positive in terms of efficacy, if at least one 
of the primary endpoints is declared statistically significant. 


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The secondary efficacy endpoints (absolute change from baseline in fresh pustules, absolute 
change in total pustules, achieving at least a 50% reduction in fresh pustules, and achieving at least 
a 50% reduction in total pustules) will be tested using the same approach described above using 
Hochberg’s method, only if both primary endpoints are considered statistically significant. 
Exploratory endpoints will be tested at nominal alpha = 10% with no adjustment for multiplicity 
for exploratory purposes. 
 Efficacy Analyses 
Efficacy analyses will be based on the mITT analysis set. 
 
A MMRM model will be used for analyzing the relative change from baseline in continuous 
endpoints that are collected in a longitudinal fashion (fresh and total pustule count, PPPASI, 
PPPGA, PPSI, pain VAS, and DLQI). The natural log ratio of the post-dose values to baseline will 
be used as dependent variables in the analysis. The model will include fixed effects for treatment, 
visit and treatment-by-visit interaction, and natural log of baseline value as covariate. Unstructured 
covariance will be used to model the correlation. The treatment effect will be the contrast between 
treatment groups at specified visit(s) (eg, at Day 28) estimated through LS means. The LS mean 
estimates, associated two-sided 90% confidence intervals, and p-values will be reported. In this 
model, the estimates will be back-transformed to the ratio scale and presented as a percent change-
from-baseline for ease of interpretation. 
 
An analogous MMRM analysis will be used to analyze the absolute change from baseline. The 
response variable will be the absolute change from baseline at scheduled post‑baseline visits and 
the baseline value as covariate.  
 
For each post-dose study visit, a Fisher’s exact test will be used to compare the proportion of 
subjects with a 50% or 75% reduction in fresh and total pustule count and the proportion of subjects 
achieving PPPASI-50 and PPPASI-75, for subjects treated with RIST4721 and subjects treated 
with placebo. 
 Safety Analyses 
Safety analyses will be based on the Safety analysis set. 
 
AEs will be presented and tabulated according to Medical Dictionary for Regulatory Activities 
(MedDRA) classification. Descriptions of AEs will include the start date, the stop date (if it 
resolved), the severity and seriousness of the AE, the causality of the AE to study drug, and the 
outcome. The focus in this protocol will be the prevalence of TEAEs. 
 
Reported TEAEs will be summarized by the number of subjects reporting the events, as well as by 
System Organ Class, Preferred Term, severity, seriousness, and relationship to study drug. For the 
summary of AEs by severity, each subject will be counted only once within a System Organ Class 
or a Preferred Term by using the AEs with the highest intensity within each category for each 


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analysis. For the summary of AEs by relationship to study drug, each subject will be counted only 
once within a System Organ Class or a Preferred Term by using the AEs with the greatest reported 
relationship within each category. For the summary of AEs by relationship to study drug and 
severity, each subject will be counted only once within a System Organ Class or a Preferred Term 
by using (1) the greatest reported relationship followed by (2) the highest reported intensity. 
 
Information pertaining to AEs noted during the study will be listed by subject, detailing verbatim, 
System Organ Class, Preferred Term, start date, stop date, intensity, outcome, and relationship to 
study drug. The AE onset will also be shown relative (in number of days) to the first day of study 
drug administration. Serious adverse events will be tabulated by treatment group, relationship to 
the study drug, and a reference to the occurrence of the SAEs to the relative day of dosing. 
 
Results from laboratory analyses, vital signs, and ECGs will be tabulated by treatment and visit 
using descriptive statistics. The value at each visit as well as the change from baseline will be 
presented descriptively.  
 
Concomitant medications will be coded with the World Health Organization-Drug Dictionary 
(WHO-DD) and listed by subject. Summary of medication classes will also be tabulated.  
 
No inferential statistics will be done on safety variables. 
 Plasma Concentration Analyses 
RIST4721 plasma concentration data will be listed per subject and summarized descriptively. 
 Pharmacodynamic Analyses 
Expression levels in lesional and nonlesional PPP skin will be compared using RT-PCR, 
transcriptome profiling, and IHC data. A PD analysis plan will be prepared to detail the PD 
analyses. Results will be presented in a separate report. 
 Other Analyses 
Descriptive summaries of baseline characteristics, including demographic data, prior concomitant 
therapy, and subject disposition will be presented.  
 
Protocol deviations will be summarized by treatment and category. 
 Planned Interim Analyses 
No interim analysis is planned in this study. 


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10 REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
10.1  Local Regulations/Declaration of Helsinki 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and that are consistent with ICH E6 (R2) Tripartite Guideline for GCP and 
the applicable laws (eg, German Drug Law [AMG] §40 and §41) and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the individual. 
10.2  Ethical Review 
It is the understanding of the sponsor that this protocol (and any amendments) as well as 
appropriate consent procedures, will be reviewed and approved by a IRB/REB/EC. This board 
must operate in accordance with the current federal regulations. For sites with a local ethics 
committee, a letter or certification of approval will be sent by the investigator to the sponsor or 
CRO before initiation of the study and also whenever subsequent modifications to the protocol are 
made. 
10.3  Informed Consent Process 
An Informed Consent Form describing in detail the study treatment, study procedures, and risks 
will be given to the subject, along with an assent form when required.  
 
It is the responsibility of the investigator, or a person designated by the investigator (if acceptable 
by local regulation), to obtain written informed consent from each individual participating in this 
study, after adequate explanation of the aims, methods, objectives, and potential hazards of the 
study. Should a subject be unable to understand the trial and give informed consent adequately in 
the opinion of the investigator, the subject will not be included in the trial. 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be 
IRB/REB/EC approved, and the subject will be asked to read and review the document. The 
investigator will explain the research study to the subject and answer any questions that may arise. 
A verbal explanation will be provided in terms suited to the subject’s comprehension of the 
purposes, procedures, and potential risks of the study and of his or her rights as a research subject. 
Subjects will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The subjects should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. 
 
Subjects must be informed that participation is voluntary and that they may withdraw from the 
study at any time for any reason, without prejudice. A copy of the signed informed consent 
document will be given to the subjects for their records. The informed consent process will be 
conducted and documented in the source document (including the date), and the form signed, 
before the subject undergoes any study-specific procedures. 
 


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The rights and welfare of the subjects will be protected by emphasizing to them that the quality of 
their medical care will not be adversely affected if they decline to participate in this study. 
 
If new safety information results in significant changes in the risk/benefit assessment, or if any 
new information becomes available that may affect the willingness of a subject to continue to 
participate, the consent form should, if necessary, be reviewed and updated by the IRB/REB/EC. 
All subjects (including those already being treated) should be informed of the new information, 
given a copy of the revised form, and asked to give their consent to continue in the study. 
10.4  Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study subjects, 
investigators, the sponsor, and regulatory authorities. If the study is prematurely terminated or 
suspended, the principal investigators will promptly inform study subjects and the IRB/REB/EC, 
and will provide the reason(s) for the termination or suspension. Study subjects will be contacted, 
as applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension of the study include, but are not limited 
to the following: 
• 
Determination of unexpected, significant, or unacceptable risk to subjects 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete or evaluable 
• 
Scientific or administrative reasons 
 
The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed and satisfy the sponsor, IRB/REB/EC, and Health Authorities. 
10.5  Confidentiality and Privacy  
Subject confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor. This confidentiality is extended to cover testing of biological samples in 
addition to the clinical information relating to subjects. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence.  
 
The investigator must assure that the subjects’ anonymity will be maintained and that subjects’ 
identities are protected from unauthorized parties. On case report forms or other documents 
submitted to the sponsor, subjects should not be identified by their names, but by an identification 
code. The investigator should keep a subject enrollment log relating codes with the names of 
subjects. The investigator should maintain in strict confidence documents not for submission to 
Aristea Therapeutics, Inc. (eg, subjects’ written consent forms). 
 
All research activities will be conducted in a setting as private as possible. 
 


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The study monitor, other authorized representatives of the sponsor, and representatives of the 
IRB/REB/EC, regulatory agencies, or pharmaceutical company supplying study drug may inspect 
all documents and records required to be maintained by the investigator, including but not limited 
to, medical records (office, clinic, or hospital) and pharmacy records for the subjects in this study. 
The clinical study site will permit access to such records. 
 
The study subject’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the applicable legal or regulatory requirements, the reviewing 
IRB/REB/EC, institutional policies, or sponsor requirements. 
10.6  Clinical Monitoring 
Clinical site monitoring will be conducted to ensure that the rights and well-being of trial subjects 
are protected; that the reported trial data are accurate, complete, and verifiable; and that the conduct 
of the trial is compliant with the currently approved protocol/amendment(s), ICH GCP guidelines, 
and with applicable regulatory requirement(s). Details of clinical site monitoring will be 
documented in a Monitoring Plan. 
10.7  Quality Assurance and Quality Control 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation, and completion. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system, and 
data QC checks, which will be run on the database, will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
 
During the study, the sponsor or its representative will conduct monitoring visits at regular 
intervals. The monitoring visits will be conducted to ensure protocol adherence, quality of data, 
accuracy of entries on the eCRFs, study drug accountability, compliance with regulatory 
requirements, and continued adequacy of the study site and its facilities.  
 
The site may be audited, monitored, or inspected by a quality assurance officer named by the 
sponsor, by the IRB/REB/EC, and/or by the regulatory authorities. The investigator will be 
expected to cooperate with any audit and provide direct access to all trial-related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor and 
inspection by local and regulatory authorities. 
10.8  Data Handling and Record Keeping 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should be 


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classified into two separate categories: investigator’s study files and subject clinical source 
documents. 
 
The investigator must maintain source documents for each subject in the study. These source 
documents will consist of case and visit notes (clinical medical records) containing demographic 
and medical information and the results of any tests or assessments. All information on the eCRFs 
must be traceable to the source documents in the subject’s file. Data not requiring a written or 
electronic record will be defined before study start and will be recorded directly on the eCRFs, 
which will be documented as being the source data. 
The records should be retained by the investigator according to ICH guidelines, local regulations, 
or as specified in the Clinical Trial Agreement, whichever retention period is longer.  
 
Subject data will be entered by site personnel using 
, a web-based electronic data capture 
(EDC) and reporting system. This application will be set up for remote entry. The EDC software 
has been fully validated and conforms to Title 21 of the Code of Federal Regulations, Part 11 
requirements. Investigator site staff will not be given access to the EDC system until they have 
been fully trained. Designated investigator staff will enter the data required by the protocol into 
the eCRFs using this web-based application. Automatic validation programs check for data 
discrepancies in the eCRFs and, by generating appropriate error messages, allow modification or 
verification of the entered data by the investigator staff before confirming the data. The 
investigator must certify that the data are complete and accurate by applying an electronic signature 
to the eCRFs.  
 
The data collected will be encoded and stored electronically in a database system. Validated data 
may subsequently be transferred to the sponsor. 
10.9  Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol requirements. The 
noncompliance may be either on the part of the subject, the investigator, or the study site staff. As 
a result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
Protocol deviations must be sent to the reviewing IRB/REB/EC per their policies. The investigator 
is responsible for knowing and adhering to the reviewing IRB/REB/EC requirements.  
10.10  Publication Policy 
The publication policy will be addressed in the Research and Financial Agreement, and all details 
outlined in the agreement will apply to this protocol.  
 
 


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Confidential and proprietary. Permission should be obtained before any reproduction. 
11 REFERENCES 
1. 
Dermatologists BAo. Palmoplantar Pustulosis.  04/2018 2018. 
2. 
Benjegerdes KE, Hyde K, Kivelevitch D, Mansouri B. Pustular psoriasis: pathophysiology 
and current treatment perspectives. Psoriasis (Auckl). 2016;6:131-144. 
3. 
Bissonnette R, Suarez-Farinas M, Li X, et al. Based on Molecular Profiling of Gene 
Expression, Palmoplantar Pustulosis and Palmoplantar Pustular Psoriasis Are Highly 
Related Diseases that Appear to Be Distinct from Psoriasis Vulgaris. PLoS One. 
2016;11(5):e0155215. 
4. 
Wilsmann-Theis D, Jacobi A, Frambach Y, et al. Palmoplantar pustulosis - a cross-
sectional analysis in Germany. Dermatol Online J. 2017;23(4). 
5. 
Stanford CW, Kollipara R, Melookaran AM, Hall JC. Palmoplantar pustular psoriasis 
following initiation of a beta-blocker: disease control with low-dose methotrexate. Cutis. 
2014;94(3):153-155. 
6. 
Bissonnette R, Fuentes-Duculan J, Mashiko S, et al. Palmoplantar pustular psoriasis 
(PPPP) is characterized by activation of the IL-17A pathway. J Dermatol Sci. 
2017;85(1):20-26. 
7. 
Kim DY, Kim JY, Kim TG, et al. A comparison of inflammatory mediator expression 
between palmoplantar pustulosis and pompholyx. J Eur Acad Dermatol Venereol. 
2013;27(12):1559-1565. 
8. 
Dyer DP, Pallas K, Ruiz LM, Schuette F, Wilson GJ, Graham GJ. CXCR2 deficient mice 
display macrophage-dependent exaggerated acute inflammatory responses. Sci Rep. 
2017;7:42681. 
9. 
Jamieson T, Clarke M, Steele CW, et al. Inhibition of CXCR2 profoundly suppresses 
inflammation-driven and spontaneous tumorigenesis. J Clin Invest. 2012;122(9):3127-
3144. 
10. 
Eash KJ, Greenbaum AM, Gopalan PK, Link DC. CXCR2 and CXCR4 antagonistically 
regulate neutrophil trafficking from murine bone marrow. J Clin Invest. 2010;120(7):2423-
2431. 
11. 
Boppana NB, Devarajan A, Gopal K, et al. Blockade of CXCR2 signalling: a potential 
therapeutic target for preventing neutrophil-mediated inflammatory diseases. Exp Biol Med 
(Maywood). 2014;239(5):509-518. 
12. 
Aristea Therapeutics I. Investigator's Brochure.  30 August 2018 2018. 
13. 
Greaves Malcolm W. SS. Pharmacology of the Skin II. 1 ed: Springer-Verlag Berlin 
Heidelberg; 1989. 
14. 
Kumar B, Sandhu K, Kaur I. Topical 0.25% methotrexate gel in a hydrogel base for 
palmoplantar psoriasis. J Dermatol. 2004;31(10):798-801. 
15. 
Skov L, Beurskens FJ, Zachariae CO, et al. IL-8 as antibody therapeutic target in 
inflammatory diseases: reduction of clinical activity in palmoplantar pustulosis. J Immunol. 
2008;181(1):669-679. 
16. 
Veenstra M, Ransohoff RM. Chemokine receptor CXCR2: physiology regulator and 
neuroinflammation controller? J Neuroimmunol. 2012;246(1-2):1-9. 
17. 
Lazaar AL, Sweeney LE, MacDonald AJ, Alexis NE, Chen C, Tal-Singer R. SB-656933, 
a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone-
induced airway inflammation in humans. Br J Clin Pharmacol. 2011;72(2):282-293. 


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Protocol version 3.0_DE: 22 March 2019 
 
 
 
 
 
 
Confidential and proprietary. Permission should be obtained before any reproduction. 
18. 
Nair P, Gaga M, Zervas E, et al. Safety and efficacy of a CXCR2 antagonist in patients 
with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial. 
Clin Exp Allergy. 2012;42(7):1097-1103. 
19. 
Misra S. Randomized double blind placebo control studies, the "Gold Standard" in 
intervention based studies. Indian J Sex Transm Dis AIDS. 2012;33(2):131-134. 
20. 
Bhushan M, Burden AD, McElhone K, James R, Vanhoutte FP, Griffiths CE. Oral liarozole 
in the treatment of palmoplantar pustular psoriasis: a randomized, double-blind, placebo-
controlled study. Br J Dermatol. 2001;145(4):546-553. 
21. 
Trust GsaSTNF. Treatment of Pustular Psoriasis with the IL-1 receptor antagonist 
anakinra: a randomised, placebo controlled trial and associated mechanistic studies. 
Guy’s and St. Thomas’ NHS Foundation Trust 1st November 2017 2017. 
22. 
Cornelius V, Wilson R, Cro S, et al. A small population, randomised, placebo-controlled 
trial to determine the efficacy of anakinra in the treatment of pustular psoriasis: study 
protocol for the APRICOT trial. Trials. 2018;19(1):465. 
23. 
Terui T, Kobayashi S, Okubo Y, Murakami M, Hirose K, Kubo H. Efficacy and Safety of 
Guselkumab, an Anti-interleukin 23 Monoclonal Antibody, for Palmoplantar Pustulosis: 
A Randomized Clinical Trial. JAMA Dermatol. 2018;154(3):309-316. 
24. 
Hawker GA, Mian S, Kendzerska T, French M. Measures of adult pain: Visual Analog 
Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain 
Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain 
Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of 
Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken). 
2011;63 Suppl 11:S240-252. 
25. 
Assessing Psoriasis in the Clinic: PGA and BSA: Group for Research and Assessment of 
Psoriasis and Psoriatic Arthritis; 2017. 
26. 
Fredriksson T, Pettersson U. Severe psoriasis--oral therapy with a new retinoid. 
Dermatologica. 1978;157(4):238-244. 
27. 
Marks R, Barton SP, Shuttleworth D, Finlay AY. Assessment of disease progress in 
psoriasis. Archives of dermatology. 1989;125(2):235-240. 
28. 
Langley RG, Feldman SR, Nyirady J, van de Kerkhof P, Papavassilis C. The 5-point 
Investigator's Global Assessment (IGA) Scale: A modified tool for evaluating plaque 
psoriasis severity in clinical trials. J Dermatolog Treat. 2015;26(1):23-31. 
29. 
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical measure 
for routine clinical use. Clin Exp Dermatol. 1994;19(3):210-216. 
 


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


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APPENDIX B: Palmoplantar Pustulosis Severity Index 
 
PPSI Scoring 
 
The severity of PPP lesions on palms and soles is assessed based on three target symptoms; 
erythema, desquamation (scaling), and pustules or vesicles, as seen on the day of the examination.  
 
The severity of each sign is assessed using a 5-point scale: 
• 0 = not present 
• 1 = minimal  
• 2 = mild 
• 3 = moderate 
• 4 = severe 
 
The PPSI score can vary from 0 (absence of disease) to 12 (most severe PPP possible), and is 
obtained by using the formula below: 
 
PPSI = E + D + P 
 
Where E, D, and P denote erythema, desquamation (scaling), and pustules or vesicles, respectively. 
 
 


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APPENDIX C: Psoriasis Area Severity Index 
PASI Scoring  
 
Four anatomic sites – head, upper extremities, trunk and lower extremities – are assessed for 
erythema, induration (plaque thickness), and desquamation (scaling) as seen on the day of the 
examination. The severity of each sign is assessed using the 5-point scale below: 
 
•  0 = No symptoms  
•  1 = Slight  
•  2 = Moderate  
•  3 = Marked  
•  4 = Very marked  
  
The area affected by psoriasis within a given anatomic site is estimated as a percentage of the 
total area of that anatomic site and assigned a numerical value according to the degree of 
psoriatic involvement as follows:  
 
•  0 = no involvement  
•  1 = < 10 %  
•  2 = 10 to < 30%  
•  3 = 30 to < 50%  
•  4 = 50 to < 70%  
•  5 = 70 to < 90%  
•  6 = 90 to 100 %  
  
  
Assignments for the following body regions are as follows: 
 
•  Neck: include with the head 
•  Buttocks: include with the lower extremities  
•  Axillae: include with the trunk  
•  Genitals: include with the trunk  
•  The inguinal canal separates the trunk and legs anteriorly  
  
The PASI score for each body region is obtained by using the formula  
  
PASI = 0.1 (Eh + Ih + Dh) Ah + 0.2 (Eu + Iu + Du) Au + 0.3 (Et + It + Dt) At + 0.4 (El + Il + Dl) Al  
  
Where E, I, D, and A denote erythema, induration, desquamation, and area, respectively, and h, 
u, t, and l denote head, upper extremities, trunk, and lower extremities, respectively.  


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APPENDIX D: Dermatology Life Quality Index 
 
Subject ID #: ___ ___ - ___ ___ ___  
 
 
 
Visit Day: ___________ 
 
Visit Date (dd-mmm-yyyy): ______________ 
The aim of this questionnaire is to measure how much your skin problem has affected your 
life OVER THE LAST WEEK. Please check one box for each question. 
 
1. Over the last week, how itchy, sore, painful or 
stinging has your skin been? 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
2. Over the last week, how embarrassed or 
self conscious have you been because of your skin? 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
3. Over the last week, how much has your skin 
interfered with you going shopping or looking after 
your home or garden? 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant  
4. Over the last week, how much has your skin 
influenced the clothes you wear? 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant  
5. Over the last week, how much has your skin 
affected any social or leisure activities? 
 
 
 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant  
6. Over the last week, how much has your skin made 
it difficult for you to do any sport? 
 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant  
7. Over the last week, has your skin prevented you from 
working or studying? 
Yes 
No 
 
 
 
 
Not relevant  
If “No,” over the last week how much has your skin 
been a problem at work or studying? 
A lot 
A little 
Not at all  
 
 
 
 
 
 


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8. Over the last week, how much has your skin created 
problems with your partner or any of your close 
friends or relatives?   
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant  
9. Over the last week, how much has your  
skin 
caused any sexual difficulties? 
 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant  
10 Over the last week, how much of a problem has the 
treatment for your skin been, for example by 
making your home messy, or by taking up time? 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant  
©AY Finlay, GK Khan, April 1992 www.dermatology.org.uk. 
 
Please check you have answered EVERY question. Thank you. 
 
If two or more questions are left unanswered the questionnaire is not scored. If two or more 
response options are ticked, the response option with the highest score should be recorded. 
If there is a response between two tick boxes, the lower of the two score options should be 
recorded. 
 

SAP_001.pdf: 


 
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STATISTICAL ANALYSIS PLAN REVISION SUMMARY 
Version 
Version Date 
Author 
Summary of Changes  
Final v1.0 
20-Dec-2019 
 
Initial version 
 
 




 
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TABLE OF CONTENT 
1 
INTRODUCTION.................................................................................................................... 7 
2 
STUDY OBJECTIVES AND ENDPOINTS .......................................................................... 7 
2.1 
Objectives .......................................................................................................................... 7 
2.2 
Endpoints .......................................................................................................................... 8 
3 
STUDY DESIGN .................................................................................................................... 10 
3.1 
Overall Design ................................................................................................................ 10 
3.2 
Schedule of Events ......................................................................................................... 11 
3.3 
Treatment ....................................................................................................................... 14 
3.4 
Randomization, Replacement, and Unblinding Procedures ...................................... 14 
3.5 
Changes to the Analysis from the Protocol .................................................................. 15 
4 
POPULATIONS FOR ANALYSIS ...................................................................................... 16 
4.1 
All Screened Subjects Analysis Set ............................................................................... 16 
4.2 
Modified Intent-to-Treat Analysis Set ......................................................................... 16 
4.3 
Safety Analysis Set ......................................................................................................... 16 
5 
GENERAL CONSIDERATIONS ........................................................................................ 16 
5.1 
Sample Size ..................................................................................................................... 16 
5.2 
Baseline ........................................................................................................................... 17 
5.3 
Reference Start Date and Analysis Day ....................................................................... 17 
5.4 
Windowing Conventions ................................................................................................ 17 
5.5 
Descriptive Statistics ...................................................................................................... 17 
5.6 
Statistical Tests ............................................................................................................... 18 
5.7 
Handling of Retests, Repeats, Unscheduled Visits, and Early Termination 
Data ................................................................................................................................. 18 
5.8 
Software Version ............................................................................................................ 18 
6 
STATISTICAL CONSIDERATIONS ................................................................................. 18 
6.1 
Adjustments for Covariates .......................................................................................... 18 
6.2 
Handling of Dropouts or Missing data ......................................................................... 19 
6.3 
Interim Analysis and Data Monitoring ........................................................................ 19 
6.4 
Multicenter Studies ........................................................................................................ 19 
6.5 
Multiple Comparisons/Multiplicity .............................................................................. 19 
6.6 
Examination of Subgroups ............................................................................................ 20 
7 
STUDY SUBJECTS ............................................................................................................... 20 
7.1 
Disposition of Subjects ................................................................................................... 20 
7.2 
Protocol Deviations ........................................................................................................ 20 


 
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8 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................ 21 
9 
SURGICAL AND MEDICAL HISTORY ........................................................................... 22 
10 
PRIOR AND CONCOMITANT MEDICATIONS ............................................................. 22 
11 
STUDY TREATMENT EXPOSURE AND TREATMENT COMPLIANCE ................. 23 
12 
EFFICACY ANALYSIS ........................................................................................................ 23 
12.1 
Primary Efficacy Endpoints .......................................................................................... 23 
12.2 
Secondary Efficacy Endpoints ...................................................................................... 25 
12.3 
Exploratory Efficacy Endpoints ................................................................................... 25 
12.3.1 
Exploratory Efficacy Endpoint Variables ......................................27 
12.3.2 
Exploratory Efficacy Endpoints Analyses .....................................31 
12.4 
Additional Exploratory Endpoint ................................................................................. 33 
13 
SAFETY ANALYSIS............................................................................................................. 34 
13.1 
Adverse Events ............................................................................................................... 34 
13.2 
Clinical Laboratory ........................................................................................................ 35 
13.3 
Vital Signs ....................................................................................................................... 36 
13.4 
Electrocardiogram (ECG) ............................................................................................. 36 
14 
REFERENCE ......................................................................................................................... 37 
15 
APPENDICES ........................................................................................................................ 38 
 
 


 
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ABBREVIATIONS 
AE 
adverse event 
ATC 
anatomical therapeutic chemical 
BSA 
body surface area 
CI 
confidence interval 
CRO 
contract research organization 
CV 
coefficient of variation 
DLQI 
Dermatology Life Quality Index 
ECG 
electrocardiogram 
eCRF  
electronic case report form  
ET 
early termination 
IQR 
interquartile range 
IWRS 
Interactive Web Response System 
LS 
least squares 
MedDRA  
Medical Dictionary for Regulatory Activities  
mITT 
modified intent-to-treat 
MMRM 
mixed model repeated measures 
n 
number of subjects with non-missing data 
PASI 
Psoriasis Area Severity Index 
PD 
pharmacodynamic 
PGA 
Physician Global Assessment 
PPP 
palmoplantar pustulosis 
PPPASI 
Palmoplantar Pustulosis Psoriasis Area and Severity Index 
PPPASI-50 
50% reduction in PPPASI 
PPPASI-75 
75% reduction in PPPASI 
PPPGA 
Palmoplantar Pustulosis Physician Global Assessment 
PPSI 
Palmoplantar Pustulosis Severity Index 
PPSI-50 
50% reduction in PPSI 
PPSI-75 
75% reduction in PPSI 
PT 
preferred term 
QT 
QT interval 
SAE  
serious adverse event  
SAP  
Statistical Analysis Plan  
SAS 
Statistical Analysis System® 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event  
TLF 
tables, listings, and figures 
VAS 
visual analog scale 
WHO-DD  
World Health Organization Drug Dictionary  
 
 


 
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1 INTRODUCTION 
This statistical analysis plan (SAP) describes the planned analysis and reporting for Aristea 
Therapeutics clinical protocol RIST4721-201. The analyses described in the SAP are based upon 
the protocol version 3.0 dated 22-Mar-2019 (version available in Canada and Germany). 
This SAP has been developed prior to database lock, final unblinding, and final analyses. All final 
analyses will be performed after the clinical trial data are entered into the database, any 
discrepancies in the data are resolved, the lock of the database, and following the signature of the 
SAP. 
Analyses related to pharmacodynamic assessments (i.e. skin biomarkers) and plasma 
concentrations of RIST4721 are not covered in this SAP and will be described in separate 
documents. 
2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 Objectives 
Primary 
• To assess the efficacy of RIST4721 versus placebo in adult subjects with moderate to 
severe palmoplantar pustulosis (PPP) using a range of efficacy endpoints 
Secondary 
• To assess the safety of RIST4721 versus placebo in adult subjects with moderate to severe 
PPP 
Exploratory 
• To evaluate the effects of RIST4721 on skin biomarkers in adult subjects with moderate to 
severe PPP 
• To evaluate the plasma concentration of RIST4721 in adult subjects with moderate to 
severe PPP 


 
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2.2 Endpoints 
Primary Efficacy Endpoints 
• Relative change from baseline in fresh pustule count at Day 28 
• Relative change from baseline in total pustule count at Day 28 
Secondary Efficacy Endpoints 
• Absolute change from baseline in fresh pustule count at Day 28 
• Absolute change from baseline in total pustule count at Day 28 
• Proportion of subjects achieving at least a 50% reduction in fresh pustule count at Day 28 
• Proportion of subjects achieving at least a 50% reduction in total pustule count at Day 28 
Secondary Safety Endpoints 
• Incidence of treatment-emergent adverse events (TEAEs) 
• Changes in vital signs, electrocardiogram (ECG), and laboratory tests 
Exploratory Endpoints 
• Absolute change from baseline in fresh pustule count at Day 7, Day 14, and Day 21  
• Relative change from baseline in fresh pustule count at Day 7, Day 14, and Day 21 
• Absolute change from baseline in total pustule count at Day 7, Day 14, and Day 21  
• Relative change from baseline in total pustule count at Day 7, Day 14, and Day 21  
• Proportion of subjects achieving a 50% reduction in fresh pustule count at Day 7, Day 14, 
and Day 21 
• Proportion of subjects achieving a 75% reduction in fresh pustule count at Day 7, Day 14, 
Day 21, and Day 28  
• Proportion of subjects achieving a 50% reduction in total pustule count at Day 7, Day 14, 
and Day 21 
• Proportion of subjects achieving a 75% reduction in total pustule count at Day 7, Day 14, 
Day 21, and Day 28  
• Absolute change from baseline in Palmoplantar Pustulosis Psoriasis Area and Severity 
Index (PPPASI) at Day 7, Day 14, Day 21, and Day 28  
• Relative change from baseline in PPPASI at Day 7, Day 14, Day 21, and Day 28  
• Proportion of subjects achieving a 50% reduction in PPPASI (PPPASI-50) at Day 7, Day 
14, Day 21, and Day 28  
• Proportion of subjects achieving a 75% reduction in PPPASI (PPPASI-75) at Day 7, Day 
14, Day 21, and Day 28 


 
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• Absolute change from baseline in Palmoplantar Pustulosis Physician Global Assessment 
(PPPGA) at Day 7, Day 14, Day 21, and Day 28 
• Relative change from baseline in PPPGA at Day 7, Day 14, Day 21, and Day 28 
• Proportion of subjects achieving a PPPGA of clear (0) or almost clear (1) with a 2-point 
decrease at Day 7, Day 14, Day 21, and Day 28  
• Proportion of subjects achieving at least a 2-point decrease in PPPGA at Day 7, Day 14, 
Day 21, and Day 28  
• Absolute change from baseline in palmoplantar pustulosis severity index (PPSI) at Day 7, 
Day 14, Day 21, and Day 28 
• Proportion of subjects achieving a 50% reduction in PPSI (PPSI-50) at Day 7, Day 14, 
Day 21, and Day 28  
• Proportion of subjects achieving a 75% reduction in PPSI (PPSI-75) at Day 7, Day 14, 
Day 21, and Day 28 
• Relative change from baseline in PPSI at Day 7, Day 14, Day 21, and Day 28 
• Absolute change from baseline in pain visual analog scale (VAS) at Day 7, Day 14, Day 
21, and Day 28  
• Relative change from baseline in pain VAS at Day 7, Day 14, Day 21, and Day 28  
• Absolute change from baseline in Dermatology Life Quality Index (DLQI) at Day 7, Day 
14, Day 21, and Day 28 
• Relative change from baseline in DLQI at Day 7, Day 14, Day 21, and Day 28 
• Absolute change from baseline in body surface area (BSA) at Day 7, Day 14, Day 21, and 
Day 28 
• Relative change from baseline in BSA at Day 7, Day 14, Day 21, and Day 28 
• Absolute change from baseline in Psoriasis Area Severity Index (PASI) at Day 7, Day 14, 
Day 21, and Day 28 
• Relative change from baseline in PASI at Day 7, Day 14, Day 21, and Day 28 
• Absolute change from baseline in Physician Global Assessment (PGA) at Day 7, Day 14, 
Day 21, and Day 28 
• Relative change from baseline in PGA at Day 7, Day 14, Day 21, and Day 28 
• Proportion of subjects achieving a PGA of clear (0) or almost clear (1) at Day 7, Day 14, 
Day 21, and Day 28 
• Proportion of subjects achieving at least a 2-point decrease in PGA at Day 7, Day 14, 
Day 21, and Day 28 
• Changes in skin biomarker levels  
• Plasma concentration of RIST4721 


 
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3 STUDY DESIGN 
3.1 Overall Design 
Approximately 30 subjects with moderate to severe PPP, as defined by a PPPASI ≥8, a PPPGA 
≥3, and a minimum of 8 fresh pustules (fresh pustule count on both right/left palms and soles) at 
screening and 20 fresh pustules (fresh pustule count on both right/left palms and soles) at Day –1, 
will be included in this 4-week, multicenter, randomized, double-blind, placebo controlled, 
Phase2a study to evaluate the efficacy and safety of RIST4721. 
All subjects will sign an informed consent and undergo screening for study eligibility. After a 
screening period of no more than 30 days, subjects will be randomized (1:1) at Day -1 to receive 
oral RIST4721 300 mg solution or placebo, once daily for 28 days. Subjects will come to the study 
site at 7 occasions: screening; baseline (Day -1); and Days 7, 14, 21, 28, and 42 (follow-up) or 
early termination (ET) visit. Study drug will be dispensed weekly to subjects. 
Efficacy will be evaluated using fresh pustule count, total pustule count, PPPASI, PPPGA, PPSI, 
and pain VAS. BSA affected with psoriasis (excluding PPP lesions on palms and soles) will be 
evaluated to assess eligibility. BSA, PGA and PASI will also be evaluated to assess impact on 
body psoriasis (only for subjects who have psoriasis elsewhere on the body at Day -1). Quality of 
life will be evaluated using the DLQI. Safety will be assessed with physical examinations, vital 
signs, ECG, and clinical laboratory tests (hematology, biochemistry, and urinalysis), and by 
collecting adverse events (AEs). 
A total of 6 blood samples will be collected from a subgroup of up to 20 subjects who consent to 
the procedure for plasma concentration analyses. Samples will be collected within 1 hour prior to 
dosing (pre-dose) and 1 hour ±10 minutes and 2 hours ±10 minutes post-dose on Days 7 and 21. 
A total of three 4.5-mm skin biopsies will be collected from a subgroup of approximately 20 
subjects who consent to the procedure for reverse transcription polymerase chain reaction (RT-
PCR), transcriptome profiling, and immunohistochemistry (IHC). Two skin biopsies will be taken 
at Day -1 (1 from lesional skin and 1 from adjacent nonlesional skin, either from palm or sole), 
and one biopsy will be taken at Day 28 from lesional skin, preferably from the same anatomical 
region as for biopsies collected on Day –1.  
Medical photographs of PPP areas will be taken at Day -1, Days 28, and 42 from a subgroup of 
approximately 15 subjects who consent to the procedure at selected sites to illustrate the outcome 
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3.3 Treatment 
The treatment groups are: 
• Treatment group A: RIST4721 300 mg solution once daily for 28 days 
• Treatment group B: Placebo solution once daily for 28 days 
3.4 Randomization, Replacement, and Unblinding Procedures 
At the study site, each screened subject will be assigned a subject identifier number during 
screening that will be used on all subject documentation.  
Approximately 30 subjects will be randomized (1:1) to receive RIST4721 or placebo. 
Randomization will occur prior to first dosing, at the Day –1 visit. The randomization list will be 
generated using a validated software. Randomization will be stratified by consent to biopsy 
collection. The master randomization list will be kept secured until the study blind is broken at the 
end of study. This list will be uploaded into an Interactive Web Response System (IWRS). The 
investigator or designee will be able to acquire a randomization number for eligible subjects by 
connecting to the IWRS. 
This study will be double-blinded. At all times, treatment and randomization information will be 
kept confidential and will not be released to the investigator, the study staff, the contract research 
organization (CRO), or the sponsor’s study team until after the conclusion of the study. 
Blinding codes should only be broken in emergency situations for reasons of subject safety. When 
the blind for a subject has been broken, the reason must be fully documented in the source 
document and electronic case report form (eCRF). Whenever possible, the investigator should 
contact the sponsor or its designee before breaking the blind. If the blind is broken, the investigator 
should promptly inform the medical monitor. Documentation of breaking the blind should be 
recorded with the date/time and reason why the blind was broken, and the names of the personnel 
involved. 
The subject for whom the blind has been broken will be discontinued from the study and undergo 
the ET procedures. The primary reason for discontinuation (the event or condition which led to the 
unblinding) will be recorded. 
In order to reduce risk of breaking the blind, investigators, the study staff, the CRO, and the 
sponsor’s study team will not receive absolute and relative neutrophil and WBC count results, 
starting on Day 7. A medical monitor will review the blinded data and ensure that the safety of all 
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Subjects who discontinue will not be replaced. 
3.5 Changes to the Analysis from the Protocol 
The definition of the modified Intent-to-Treat (mITT) analysis set has been clarified so that only 
randomized subjects who received at least one dose of study drug be included in that population. 
Due to emerging fresh and total pustule count data of 0, the planned MMRM analysis with the 
natural log ratio of the post-dose values to baseline as dependent variable has been revised to a 
MMRM analysis with the ratio of the post-baseline values to baseline transformed as per McCune 
and Grace (2002) as dependent variable.  Refer to Section 12.1 for more details. 
Since this is a Phase 2 study, the secondary efficacy endpoints will not be formally tested and no 
adjustment to the overall alpha level will be done for these endpoints.  Hence, only nominal p-
values will be presented for the secondary efficacy endpoints. 
Due to emerging data, the following exploratory endpoints will not be summarized and analyzed: 
• Proportion of subjects achieving a 75% reduction in total pustule count at Day 7, Day 14, 
Day 21, and Day 28 
• Proportion of subjects achieving a 75% reduction in PPPASI (PPPASI-75) at Day 7, Day 
14, Day 21, and Day 28 
• Proportion of subjects achieving a PPPGA of clear (0) or almost clear (1) with a 2-point 
decrease at Day 7, Day 14, Day 21, and Day 28  
• Proportion of subjects achieving at least a 2-point decrease in PPPGA at Day 7, Day 14, 
Day 21, and Day 28  
• Proportion of subjects achieving a 75% reduction in PPSI (PPSI-75) at Day 7, Day 14, 
Day 21, and Day 28 
• Relative change from baseline in pain VAS at Day 7, Day 14, Day 21, and Day 28  
Having said that, subjects meeting any of these criteria will be identified in the by-subject data 
listings. Similarly, the relative change from baseline in pain VAS will be included in the by-subject 
data listing. 
Count and percentage for each category of the PPPGA and PGA will be provided by visit and 
treatment group instead of descriptive statistics for the actual score, and absolute and relative 
changes from baseline by visit and treatment group.  Also, a chi-square test will be performed at 
each visit to detect any difference of distribution across the categories between the treatment group 
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4 POPULATIONS FOR ANALYSIS 
4.1 All Screened Subjects Analysis Set 
The all screened subjects analysis set will include all subjects who signed the informed consent. 
This analysis set will be used to summarize the subject disposition data. 
4.2 Modified Intent-to-Treat Analysis Set 
The modified intent-to-treat (mITT) analysis set will include all randomized subjects who received 
at least one dose of the study drug. All subjects will be analyzed according to the treatment group 
to which they were randomized. The mITT analysis set will be used as the primary analysis set for 
efficacy. 
4.3 Safety Analysis Set 
The safety analysis set will include all subjects who received at least one dose of the study drug. 
All subjects will be analyzed according to the treatment that they actually received.  This analysis 
set will be used to summarize the major protocol deviations, demographic and other baseline 
characteristics, surgical and medical history events, prior and concomitant medications, exposure 
and compliance, and safety data. 
5 GENERAL CONSIDERATIONS 
Formats and layouts of tables, listings, and figures (TLFs) will be provided in a separate document 
(outputs general layout is described in Appendix 1). 
5.1 Sample Size 
This trial is a proof-of-concept trial aimed at exploring preliminary indications of efficacy and 
safety of RIST4721 in PPP, with the aim of informing a decision about proceeding into full 
development. The exploratory nature of this study necessitates a minimum number of subjects to 
be exposed to the drug, yet without losing the possibility of inferring meaningful conclusions. 
Approximately 30 subjects with moderate to severe PPP will be randomized 1:1 to receive placebo 
or RIST4721. A sample size of 30 (approximately 15 per group) will ensure 85 % power to detect 
a statistically significant difference in the relative change from baseline in pustules counts at Day 
28 with a 2-sided level of significance of 10%. This assumes a log-Normal distribution of the 
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coefficient of variation (CV) in the original scale of 150%. This sample size is expected to result 
in approximately 90% power if the CV is 130%. 
5.2 Baseline 
Unless otherwise specified, baseline value will be defined as the last non-missing assessment prior 
to the first study treatment dose (including unscheduled assessments). If the last non-missing 
assessment is performed on the same date as the first study treatment and time is not available, the 
assessment will be considered as baseline, except for AEs and medications starting on the first 
study treatment dose date, which will be considered post-baseline. 
5.3 Reference Start Date and Analysis Day 
Analysis Day will be calculated from the first study treatment date and will be used to show 
start/end day of assessments or events.  
If the date of the assessment or event is before the date of the first dose of study treatment, the 
Analysis Day will be calculated as follows: 
(Date of first dose of study treatment – Date of assessment or event) 
If the date of the assessment or event is on or after the date of the first dose of study treatment, the 
Analysis Day will be calculated as follows: 
(Date of first dose of study treatment – Date of assessment or event) + 1 
In the situation where the assessment/event date is partial or missing, Analysis Day will be missing. 
5.4 Windowing Conventions 
No statistical windowing conventions apply for this study. 
5.5 Descriptive Statistics 
All continuous variables will be summarized by presenting the number of subjects with non-
missing data (n), mean, standard deviation (SD), median, interquartile range (IQR), minimum and 
maximum. Geometric mean and geometric coefficient of correlation (CV) will also be provided 
for the relative change from baseline in fresh and total pustule counts. Categorical variables will 
be presented as frequencies and percentages and will include a “Missing” category (when 
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Unless otherwise specified, summary tables will be presented by visit, when applicable, for each 
treatment. 
Change from baseline will be calculated as:  
Assessment value at post-baseline visit X – Baseline value. 
Percent change from baseline will be calculated as: 
(Assessment value at post-baseline visit X / Baseline value) * 100. 
Relative change from baseline will be calculated as: 
Assessment value at post-baseline visit X / Baseline value 
5.6 Statistical Tests 
Unless otherwise specified, all statistical tests will be two-sided and will be performed with a 
significance level of 0.10. Confidence intervals (CIs) will be two-sided with 90% coverage. 
5.7 Handling of Retests, Repeats, Unscheduled Visits, and Early Termination 
Data 
For the by-visit summary tables and figures, retest, repeat, and unscheduled measurements will 
not be considered, exception of the unscheduled measurements who might contribute to the 
baseline value.  Early Termination visit assessments will be summarized as a separate visit in by-
visit outputs. 
For the outputs not presented by visit (e.g., adverse events, etc.), all data will be analyzed, 
including retest, repeat, unscheduled, and early discontinuation measurements.  
All data from scheduled, retest, repeat, and unscheduled visits will be listed. 
5.8 Software Version 
All analyses will be performed using SAS® software Version 9.4 or higher. 
6 STATISTICAL CONSIDERATIONS 
6.1 Adjustments for Covariates 
For the efficacy parameters analyzed using a mixed model for repeated measures (MMRM), the 
corresponding baseline value will be included as covariate in the statistical model. 


 
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6.2 Handling of Dropouts or Missing data 
See Appendix 2 for handling of completely or partially missing dates for prior and concomitant 
medications and adverse events.  Imputed AE onset and end dates/medication start and stop dates 
will only be used for the determination of the treatment-emergent/concomitant status.  That is, they 
will not be used to compute any study day or duration and will not be presented in the by-patient 
data listings. 
For the continuous efficacy endpoints (i.e. absolute and relative changes from baseline), the 
primary method of addressing missing data will be the MMRM method without explicit 
imputations for missing data because MMRM has an inherent mechanism of imputing missing 
data under the assumption of missing at random (MAR). 
For the categorical efficacy endpoints (i.e., proportion of subjects achieving at least a 50% 
reduction, etc.), subjects with a missing post-baseline assessment at a specific visit will be 
considered as not having achieved at least a 50% reduction for that visit. 
Missing safety and other data will not be imputed. 
6.3 Interim Analysis and Data Monitoring 
No interim analysis is planned for this study. 
6.4 Multicenter Studies 
Subjects from all study centers will be combined for the analyses. Center effect will not be included 
in the statistical analysis models due to the small sample size for each site.  
6.5 Multiple Comparisons/Multiplicity 
The two primary efficacy endpoints and the secondary efficacy endpoints will be tested using a 
Gatekeeper strategy and the Hochberg’s method. The primary endpoints (i.e. relative change in 
fresh pustules at Day 28 and relative change in total pustules at Day 28) will first be tested at alpha 
of 10% (2-sided). If the larger p-value is less than 10% (2-sided), both primary endpoints will be 
declared statistically significant. If the larger p-value is greater than 10%, but the smaller p-value 
is less than 5% (2‑sided), then the primary endpoint with the smaller p-value will be declared 
statistically significant. With Hochberg’s method, the study will be considered positive in terms 
of efficacy, if at least one of the primary endpoints is declared statistically significant. 
Secondary and exploratory endpoints will be tested at nominal alpha of 10% with no adjustment 
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6.6 Examination of Subgroups 
No subgroup analysis is planned for this study. 
7 STUDY SUBJECTS 
7.1 Disposition of Subjects 
All subjects who provide informed consent will be accounted for in this study. The total number 
of subjects screened and rescreened will be presented. The total number and percentage of subjects 
with screen failure will be presented as well as their reason for screen failure, except for those who 
were rescreened and did not fail the second screening.  
Moreover, the number and percentage of subjects randomized and included in each analysis set 
will be presented for each treatment and overall. Study completion status and the reason for study 
discontinuation will be presented similarly.  
The percentage of subjects with screen failure will be calculated using the number of subjects 
screened as denominator. The percentage of screen failures by reason will be calculated using the 
number of screen failures as denominator. The percentage of study discontinuations by reason will 
be calculated using the number of subjects who did not complete study as denominator. Otherwise, 
the percentages will be calculated using the number of subjects randomized as denominator.  
Descriptive summaries for the subjects’ number of days in the study will be provided for each 
treatment and overall, where number of days in the study will be calculated as follows: 
Number of days in study = Date of completion/discontinuation – 1st dose date +1 
A listing of subject’s disposition and a listing of subject’s randomization information will be 
provided. A listing of subjects included in and excluded from each of the analysis sets will also 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. 
7.2 Protocol Deviations 
The number of events, and the number and percentage of subjects with at least one major protocol 
deviation will be summarized by deviation category for each treatment and overall. A listing of all 
protocol deviations will also be provided.  


 
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8 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographics and baseline characteristics will be summarized with descriptive statistics for each 
treatment and overall. The list of demographics and baseline characteristics to be summarized will 
include:  
• Age (years) – calculated relative to date of consent 
• Gender 
• Race* 
• Ethnicity 
• Baseline height (cm) 
• Baseline weight (kg) 
• Baseline fresh pustule count (total and right/left palm/sole) 
• Baseline total pustule count (total and right/left palm/sole)  
• Baseline PPPASI 
• Baseline PPPGA 
• Baseline PPSI 
• Baseline BSA, PGA and PASI (only for subjects who have psoriasis elsewhere on the body 
at Day -1) 
• Palmoplantar pustulosis history 
• Baseline smoking status. 
* Subjects who reported more than one race will be summarized under the ‘Multiple’ race category, 
but all races selected will be displayed in the listing. 
A listing of all demographics and baseline characteristics will be provided. 


 
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9 SURGICAL AND MEDICAL HISTORY 
Medical history will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA), Version 21.1. 
Surgical and medical history will be summarized by system organ class (SOC) and preferred term 
(PT) for each treatment and overall. A subject who experienced the same surgical and medical 
history event multiple times within the same PT will be counted only once for the that PT. 
Similarly, if a subject experienced multiple surgical and medical history events within the same 
SOC, the subject will be counted only once for that SOC. Surgical and medical history events will 
be sorted alphabetically by SOC and PTs will be presented by decreasing order of total frequency 
within each SOC. 
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), September 2018 B3. 
Prior medications are defined as any medication started and discontinued prior to the first study 
treatment dose. Concomitant medications are defined as any medication taken on or after the first 
study treatment dose and the last study treatment dose, including those that started prior to the first 
study treatment date and continued past that date. See Appendix 2 for handling of completely or 
partially missing dates for prior and concomitant medications.  
Incidence of prior and concomitant medications will be tabulated by anatomical therapeutic 
chemical (ATC) level 3 and preferred drug name for each treatment and overall. A subject with 
the same medication taken multiple times 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, then the subject will be counted only once for that ATC. Prior and concomitant 
medications will be sorted alphabetically by ATC level and preferred drug name will be presented 
by decreasing order of total frequency within each ATC level. 
A listing of all prior and concomitant medications will be provided by subjects. 


 
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11 STUDY TREATMENT EXPOSURE AND TREATMENT 
COMPLIANCE 
A summary of exposure will be presented for each treatment and overall, where exposure to study 
drug will be calculated as (Date of last dose of study drug – Date of first dose of study drug) +1.  
Descriptive statistics for the number of missed doses will be presented similarly. 
For each treatment, compliance will be calculated as follows: 
 
Number of doses taken 
Number of expected doses ×  100 
 
where the number of expected doses is determined until the end of study participation. 
Descriptive statistics for the compliance will be presented for each treatment and overall. 
Compliance will also be categorized as follows: <85%, 85% to 100%, and >100%.  Frequencies 
and percentages will be presented for each category by treatment. 
Exposure and compliance will be displayed in a listing of study treatment administration by 
subject.  A listing of drug accountability, including kit number, dispensed and returned used and 
unused bottles will also be provided. 
12 EFFICACY ANALYSIS 
12.1 Primary Efficacy Endpoints 
The relative change from baseline in fresh pustule count at Day 28 and the relative change from 
baseline in total pustule count at Day 28 are the primary efficacy endpoints in this study. 
The number of fresh and total pustules will be counted on each palm and sole. Fresh pustules are 
defined as macroscopically visible pustules that are white/yellow in color with no brown color, 
with or without crust, and present on the glabrous skin of the palms and/or soles. The fresh/total 
pustule count will refer to the sum of fresh/total pustules counted on all palms and soles. 
Descriptive statistics on fresh and total pustule counts will be presented for each treatment. 
Absolute and relative change from baseline will also be summarized for each treatment.  


 
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A MMRM model will be used for analyzing the relative change from baseline in fresh and total 
pustule counts. Each endpoint will be transformed as follows (McCune et al., 2002) for each 
treatment group and each visit separately: 
1. First, the ratio (x) of the post-baseline values to baseline will be computed; 
2. Then, the smallest nonzero ratio (min(x)) will be identified; 
3. The following constants will be calculated: 
a. The order of magnitude of the data (c), which will be equal to the truncated value 
of the natural log of min(x) to the integer by dropping the digits after the decimal 
point i.e., the smallest integer of ln(min(x)); 
b. The decimal constant (d), which will be equal to the exponential of c i.e., exp c; 
4. Finally, each ratio (xij) will be transformed as follows: 
𝑏𝑏𝑖𝑖= ln(𝑥𝑥𝑖𝑖+ 𝑑𝑑) 
where i represents the subjects (i = 1 to maximum number of subjects included in the analysis 
population for that treatment group at that visit). 
The transformed ratios bi will be used as dependent variables in the analysis. The model will 
include fixed effects for treatment, visit (Days 7, 14, 21, and 28) and treatment-by-visit interaction, 
and natural log of baseline value as covariate. Unstructured covariance will be used to model the 
correlation. In the case where convergence issues arise, the autoregressive (AR(1)) structure will 
be used. The least squares (LS) mean estimates and associated standard errors (SEs) will be 
provided for each treatment and for each visit.  The LS mean estimates will be transformed backed 
to the original scale to calculate the LS mean relative change from baseline for each treatment.  
The SEs of the LS means will be calculated by the Delta Method.  The LS mean difference between 
the two treatment groups along with the associated SEs, two-sided 90% CIs, and p-values will be 
reported for each visit. In this model, the estimates will be back-transformed to the ratio scale and 
presented as a relative change-from-baseline for ease of interpretation.  The Delta Method will be 
applied to obtain the difference in the ratios between the two treatments, their SEs, and the 90% 
CIs.  The treatment effect of interest will be the contrast between treatment groups at Day 28.  Line 
plots of LS mean estimates with the two-sided 90% CI for the absolute and relative changes from 
baseline will be presented graphically by visit. 


 
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Assumptions of heteroscedasticity and normality of the residuals will be visually inspected and 
different transformations of the dependant variable may be used as sensitivity analysis if the 
assumptions do not appear valid.  
All summaries and analyses will be based on the mITT analysis set. 
12.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints are listed below: 
• absolute change from baseline in fresh pustule count at Day 28 
• absolute change from baseline in total pustule count at Day 28 
• proportion of subjects achieving at least a 50% reduction in fresh pustule count at Day 28 
• proportion of subjects achieving at least a 50% reduction in total pustule count at Day 28 
The absolute change from baseline in fresh and total pustule counts at Day 28 will be summarized 
and analyzed similarly to the primary efficacy endpoints (refer to section 12.1), where the absolute 
change from baseline will be used as dependent variable in the analysis.  The absolute change from 
baseline will not be transformed for the analysis.   
Proportion of subjects achieving at least a 50% reduction in fresh pustule count at Day 28 and the 
proportion of subjects achieving at least a 50% reduction in total pustule count at Day 28 will be 
summarized (frequencies and percentages) by treatment group. Difference in response between 
the treatment groups at Day 28 will be analyzed using a Fisher’s exact test. A 90% CI for the 
treatment difference in response will also be provided (exact unconditional confidence limits). 
Subjects with a missing a percent change from baseline in fresh or total pustule count at Day 28 
will be classified as subjects who did not achieve at least a 50% reduction. 
A sensitivity analysis will also be performed based only on subjects with a non-missing percent 
change from baseline at Day 28 for the proportion of subjects achieving at least a 50% reduction 
(i.e. missing observations will not be treated as non-responders). 
All summaries and analyses will be based on the mITT analysis set. 
12.3 Exploratory Efficacy Endpoints 
The following exploratory efficacy endpoints will be summarized and analyzed. 


 
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• Absolute and relative change from baseline in fresh pustule count at Day 7, Day 14, and Day 
21  
• Absolute and relative change from baseline in total pustule count at Day 7, Day 14, and Day 
21  
• Proportion of subjects achieving a 50% reduction in fresh pustule count at Day 7, Day 14, and 
Day 21 
• Proportion of subjects achieving a 75% reduction in fresh pustule count at Day 7, Day 14, Day 
21 and Day 28 
• Proportion of subjects achieving a 50% reduction in total pustule count at Day 7, Day 14, and 
Day 21 
• Proportion of subjects achieving a 75% reduction in total pustule count at Day 7, Day 14, Day 
21 and Day 28 
• Absolute and relative change from baseline in PPPASI at Day 7, Day 14, Day 21, and Day 28  
• Proportion of subjects achieving a PPPASI-50/PPASI-75 at Day 7, Day 14, Day 21, and Day 
28  
• Absolute and relative change from baseline in PPPGA at Day 7, Day 14, Day 21, and Day 28 
• Proportion of subjects achieving a PPPGA of clear (0) or almost clear (1) with a 2-point 
decrease at Day 7, Day 14, Day 21, and Day 28  
• Proportion of subjects achieving at least a 2-point decrease in PPPGA at Day 7, Day 14, Day 
21, and Day 28  
• Absolute and relative change from baseline in PPSI at Day 7, Day 14, Day 21, and Day 28  
• Proportion of subjects achieving a PPSI-50/PPSI-75 at Day 7, Day 14, Day 21, and Day 28  
• Absolute and relative change from baseline in pain VAS at Day 7, Day 14, Day 21, and Day 
28  
• Absolute and relative change from baseline in DLQI at Day 7, Day 14, Day 21, and Day 28 
• Absolute and relative change from baseline in BSA at Day 7, Day 14, Day 21, and Day 28 
• Absolute and relative change from baseline in PASI at Day 7, Day 14, Day 21, and Day 28 


 
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• Absolute and relative change from baseline in PGA at Day 7, Day 14, Day 21, and Day 28 
• Proportion of subjects achieving a PGA of clear (0) or almost clear (1) at Day 7, Day 14, Day 
21, and Day 28 
• Proportion of subjects achieving at least a 2-point decrease in PGA at Day 7, Day 14, Day 21, 
and Day 28 
12.3.1 Exploratory Efficacy Endpoint Variables 
Fresh and Total pustules 
As described in section 12.1, the absolute and relative change from baseline in fresh pustule 
count and total pustule count will be evaluated at Day 7, Day 14, and Day 21. 
 
Palmoplantar Pustulosis Psoriasis Area Severity Index (PPPASI) 
The PPPASI is a scale from 0 to 72 that is used to evaluate the severity of PPP on palms and soles. 
Left palm, right palm, left sole, and right sole are assessed based on three target symptoms: 
erythema, desquamation (scaling) and pustules, as seen on the day of the examination.  
The severity of each sign is assessed using a 5-point scale: 
0 = not present 
1 = slight  
2 = moderate  
3 = severe 
4 = very severe 
The affected area within a given anatomic site (left palm, right palm, left sole, and right sole) is 
estimated as a percentage of the total area of that anatomic site and assigned a numerical value 
according to the degree of PPP involvement as follows: 
0 = no involvement 
1 = < 10% involvement 
2 = 10 to < 30% involvement 
3 = 30 to < 50% involvement 




 
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The absolute and relative change from baseline in PPPGA will be evaluated by visit and treatment 
group. The proportion of subjects achieving a rating of “Clear” (0) or “Almost clear” (1) and at 
least a 2-point decrease on the 5-point scale using the PPPGA will be evaluated by visit and 
treatment group. The proportion of subjects achieving at least a 2-point decrease from baseline 
will also be evaluated by visit and treatment group. 
Palmoplantar Pustulosis Severity Index (PPSI) 
The PPSI is a scale from 0 to 12 that is used to evaluate the severity of PPP lesions on palms and 
soles. The severity of PPP lesions on palms and soles is assessed based on three target symptoms; 
erythema, desquamation (scaling), and pustules or vesicles, as seen on the day of the examination.  
The severity of each sign is assessed using a 5-point scale: 
0 = not present 
1 = minimal  
2 = mild 
3 = moderate 
4 = severe 
The PPSI score can vary from 0 (absence of disease) to 12 (most severe PPP possible), and is 
obtained by using the formula below: 
PPSI = E + D + P 
where E, D, and P denote erythema, desquamation (scaling), and pustules or vesicles, respectively. 
The score will be set to missing in case of at least one missing value. 
The absolute and relative change from baseline in PPSI will be evaluated by visit and treatment 
group. Proportion of subjects who have achieved PPSI-50, as well as those who have achieved 
PPSI-75, will be determined by visit and treatment group 
Pain Visual Analog Scale (VAS) 
Pain intensity will be evaluated by asking subjects to place a line perpendicular to the VAS line at 
the point that represents their worst pain intensity over the last 24 hours. The pain VAS is a scale 
from 0 to 10, where 0 indicates no pain and 10 indicate the worst imaginable pain. 
 
 


 
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Dermatology Life Quality Index Questionnaire (DLQI) 
The DLQI is a simple 10-question validated questionnaire that has been used in more than 40 
different skin condition. The DLQI is the most frequently used instrument in studies of randomized 
controlled trials in dermatology. The questionnaire is provided in Appendix 3 of the protocol. The 
DLQI total score is defined as the sum of the 10 item scales, ranging from 0 to 30. If missing 
answers or mistakes, the following rules will be followed: 
1. If one question is left unanswered this is scored 0 and the scores are summed and expressed 
as usual out of a maximum of 30. 
2. If two or more questions are left unanswered the questionnaire is not scored. 
3. If question 7 is answered ‘yes’ this is scored 3 even if in the same question one of the other 
boxes is ticked. 
4. If question 7 is answered ‘no’ or ‘not relevant’ but then either ‘a lot’ or ‘a little’ is ticked 
this is then scored 2 or 1. If it is answered ‘no’, but the second half is left incomplete, the 
score will remain 0. 
Body Surface Area (BSA) 
The overall BSA affected by psoriasis, excluding lesions on palms and soles, will be evaluated 
(from 0% to 100%). One subject’s palm with the palmar aspect of all fingers represents 1% of his 
or her total BSA. 
Psoriasis Area Severity Index (PASI) 
The PASI is the Investigator’s assessment of the area and severity of psoriasis on the subject’s 
entire body, including areas that are not treated with the study drug. The PASI describes the area 
and severity of a subject’s psoriasis at a point in time.  
 
The body is divided into 4 sections: head/neck (H) (10% of total BSA); upper extremities (U) (20% 
of total BSA); trunk (T) (30% of total BSA); and lower extremities (40% of total BSA). Within 
each area, the severities of psoriatic plaques are determined for 3 signs of psoriasis: erythema (E), 
induration/infiltration (I), and desquamation (D) on each body region on a 5-point scale of 0 to 4, 
from no sign to very marked. The area covered by psoriasis (A) on each body region is evaluated 
on a score from 0 to 6, i.e., 0=0%; 1=>0–9%; 2=10–29%; 3=30–49%; 4=50–69%; 5=70–89% and 
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• Proportion of subjects achieving a 75% reduction in total pustule count at Day 7, Day 14, 
Day 21, and Day 28 
• Proportion of subjects achieving a 75% reduction in PPPASI (PPPASI-75) at Day 7, Day 
14, Day 21, and Day 28 
• Proportion of subjects achieving a PPPGA of clear (0) or almost clear (1) with a 2-point 
decrease at Day 7, Day 14, Day 21, and Day 28  
• Proportion of subjects achieving at least a 2-point decrease in PPPGA at Day 7, Day 14, 
Day 21, and Day 28  
• Proportion of subjects achieving a 75% reduction in PPSI (PPSI-75) at Day 7, Day 14, 
Day 21, and Day 28 
• Relative change from baseline in pain VAS at Day 7, Day 14, Day 21, and Day 28  
Having said that, subjects meeting any of these criteria will be identified in the by-subject data 
listings. Similarly, the relative change from baseline in pain VAS will be included in the by-subject 
data listing. 
For all other exploratory endpoints, descriptive statistics on continuous parameters will be 
presented by visit and treatment group. Change and relative change from baseline will also be 
summarized descriptively by visit and treatment group. Categorical variables will be presented as 
frequencies and percentages by visit and treatment group. 
A MMRM model will be used for analyzing the absolute and relative changes from baseline in 
fresh and total pustule count, PPPASI, PPSI, pain VAS, DLQI, BSA, and PASI. The same models 
as described in sections 12.1 and 12.2 will be used. The treatment effect will be the contrast 
between treatment groups at specified visit(s) (e.g., Day 7, Day 14, Day 21 and Day 28). 
For the PPPGA and PGA, a Chi-square test will be used to compare the distribution each treatment 
group across the PPPGA/PGA categories at each visit.  Missing data will not be imputed for these 
endpoints. 
For each post-dose study visit, a Fisher’s exact test will be used to compare the proportion of 
subjects with a 50% reduction in fresh and total pustule count, the proportion of subjects with a 
75% reduction in fresh pustule count, and the proportion of subjects achieving PPPASI-50, PPSI-
50, at Day 7, Day 14, Day 21 and Day 28 (if applicable) between the treatment groups. Ninety (90) 
percent CI for the treatment difference in response will also be provided (exact unconditional 
confidence limits). Subjects without an absolute change from baseline at a specific visit will be 
classified as subjects who did not achieve at least a 50%/75% reduction for that visit. 


 
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Sensitivity analysis will also be performed for each post-dose study visit based only on subjects 
with a non-missing relative change from baseline for the proportion of subjects achieving at least 
a 50%/75% reduction (i.e. missing observations will not be treated as non-responders). 
Similar analyses will be performed on the proportion of subjects achieving a PGA of clear (0) or 
almost clear (1) and the proportion of subjects achieving at least a 2-point decrease in PGA. 
All the analyses will be based on the mITT analysis set. 
12.4 Additional Exploratory Endpoint 
Additional analyses will be performed for the absolute change from baseline to Day 42 and relative 
change from baseline to Day 42 in fresh and total pustule counts as well as each concerned 
secondary and exploratory efficacy endpoint. An analysis of covariance (ANCOVA) will be 
performed on the absolute change from baseline to Day 42 for each efficacy endpoint. The 
ANCOVA model will include treatment as fixed effect and baseline as covariate. The treatment 
effect will be the contrast between treatment groups estimated through LS means. The LS mean 
estimates, associated two-sided 90% CIs, and p-values will be reported. The analyses will be based 
on the mITT analysis set. Similar analyses will be performed for the relative change from baseline 
to Day 42 for each efficacy endpoint, with the exception that  the transformed ratios bi will be used 
as dependent variable in the analysis (refer to Section 12.1  for additional details on the transformed 
ratios bi). 
The proportion of subjects with a 50% reduction in fresh and total pustule count, 75% reduction 
in fresh pustule count, achieving PPPASI-50, achieving PPSI-50, achieving a PGA of clear (0) or 
almost clear (1) and achieving at least a 2-point decrease in PGA will also be analyzed at Day 42 
using the same analysis described in Section 12.3.2. 
Moreover, the fresh and total pustule counts on treatment will be analyzed through area under the 
curve (AUC) type approach. A MMRM model will be performed with the fresh (or total) pustule 
counts as dependent variable. The model will include fixed effects for treatment, visit (including 
baseline, Day 7, Day 14, Day 21 and Day 28) and treatment-by-visit interaction. Unstructured 
covariance will be used to model the correlation. In the case where convergence issues arise, the 
autoregressive (AR(1)) structure will be used. A linear contrast in PROC MIXED of SAS such as: 
ESTIMATE “Pustule MEAN in treatment 1” intercept 1 treatment 1 0 treatment*visit 0.2 0.2 
0.2 0.2 0.2 0 0 0 0 0;  
will be used to estimate the average pustule counts over 4 weeks per treatment. The LS mean 
estimates, associated two-sided 90% CIs, and p-values will be reported. 


 
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13 SAFETY ANALYSIS 
All safety analyses will be conducted using the safety analysis set. 
13.1 Adverse Events 
Adverse events (AEs) will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA), Version 21.1. 
Treatment-emergent adverse event (TEAEs) are defined as any condition that was not present prior 
to treatment with the study product but appeared following treatment, was present at treatment 
initiation but worsened during treatment, or was present at treatment initiation but resolved and 
then reappeared while the individual was on treatment (regardless of the intensity of the AE when 
the treatment was initiated). See Appendix 2 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. 
An overall summary table of adverse events will be provided. The number of events and the 
number and percentage of subjects who experienced AE, TEAE, TEAE by greatest reported 
relationship, TEAE by highest reported severity, related TEAE by highest reported severity, 
serious TEAE, related serious TEAE, TEAE leading to study drug discontinuation, TEAE leading 
to discontinuation from study, and TEAE leading to death will be presented. 
Unless otherwise specified, a subject experiencing the same TEAE multiple times will be counted 
only once for the corresponding PT. Similarly, if a subject experienced multiple TEAEs within the 
same SOC, the subject will be counted only once for that SOC. TEAEs will be sorted alphabetically 
by SOC and PT will be presented by decreasing order of total frequency within each SOC. 
Frequency and percentage of subjects who experienced TEAE will be summarized by SOC and 
PT within SOC. 
Frequency and percentage of subjects who experienced TEAE will be summarized by SOC, PT 
and relationship. A treatment-related AE is defined as any TEAE that is assessed by the 
Investigator as related to study treatment. TEAE that is assessed as not related will be defined as 
not treatment related. If a subject experienced more than one TEAE within different relationship 
categories within the same SOC/PT, only the worst case (greatest reported relationship) will be 
reported. TEAE with an unknown relationship will be considered as treatment related. 
Frequency and percentage of subjects who experienced TEAE will be summarized by SOC, PT 
and severity (mild/moderate/severe). If a subject experienced more than one TEAE within different 


 
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severity categories within the same SOC/PT, only the worst case (worst reported severity) will be 
reported. TEAE with an unknown severity will be considered as severe. 
Frequency and percentage of subjects who experienced TEAE will be summarized by SOC, PT, 
relationship and severity (mild/moderate/severe). Each subject will be counted only once within a 
SOC or PT by using 1) the greatest reported relationship followed by 2) the highest reported 
severity. 
Frequency and percentage of subjects who experience serious TEAE will be summarized by SOC 
and PT within SOC.  
Frequency and percentage of subjects who experience serious TEAE will be summarized by SOC, 
PT and relationship (related/not-related). If a subject experienced more than one serious TEAE 
within different relationship categories within the same SOC/PT, only the worst case (greatest 
reported relationship) will be reported. Serious TEAE with an unknown relationship will be 
considered as treatment-related.  
Listings of all AEs, all AEs leading to death, all serious AEs, all TEAEs leading to study drug 
discontinuation, and all TEAES leading to discontinuation from study will be provided. 
Information pertaining to AEs noted during the study will be listed by subject, detailing verbatim, 
SOC, PT, start date, stop date, intensity, outcome, and relationship to study drug. The AE onset 
will also be shown relative (in number of days) to the first day of study drug administration. 
13.2 Clinical Laboratory 
Descriptive statistics will be presented for data related to biochemistry, hematology and 
quantitative urinalysis by visit and treatment group. Change from baseline values will be presented 
for each post-baseline assessment and tabulated by visit and treatment group. Frequencies and 
percentages for each result will be provided for qualitative urinalysis data by visit and treatment 
group. 
Shift tables from baseline to the worst post-baseline assessment describing shifts to abnormality 
will be provided for data related to biochemistry and hematology as well. Only subjects with a 
baseline result and a result at least one post-dose result for the parameter will be considered.  For 
parameters for which a worst post-baseline result could be identified for each directionality (lower 
and upper), shift tables from baseline to the worst post-baseline assessment for each directionality 
will be provided. 
Separate listings of all data for biochemistry, hematology, urinalysis and pregnancy tests will be 
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In addition, separate listings of data for biochemistry, hematology, and urinalysis will be provided 
for each parameter where a subject had at least one abnormal result. 
13.3 Vital Signs 
Descriptive statistics will be presented for data related to vital signs (systolic blood pressure 
diastolic blood pressure, pulse rate, respiratory rate and body temperature) by visit and treatment 
group. Change from baseline values will be presented for each post-baseline assessment by visit 
and treatment group.  
Shift tables from baseline to the worst result/abnormality will be provided as well. Only subjects 
with a baseline result and at least one post-dose result for the parameter will be considered. 
A listing of all vital sign assessments by subject will be provided. 
13.4 Electrocardiogram (ECG) 
Descriptive statistics will be presented for data related to ECGs (heart rate, PR interval, QRS 
interval, QT interval, QTc interval, and QTc interval by Fredericia [QTcF]) by visit and treatment 
group. The QTcF interval will be derived as follows: 
QTcF = QT inverval
√RR interval
3
 
where RR interval = (60 / heart rate). 
Change from baseline values will be presented for each post-baseline assessment by visit and 
treatment group. 
Shift tables from baseline to the worst result/abnormality will be provided as well for overall 
interpretation. Only subjects with a baseline result and at least one post-dose result will be 
considered. 
A listing of all ECG assessments by subject will be provided. 
 
 


 
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14 REFERENCE 
McCune B, Grace JB, and Urban DL. Analysis of Ecological Communities. MjM Software 
Design, 2002, 300 pages.  ISBN 0972129006, 9780972129008 
 
 
 




 
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Appendix 2 
Algorithm for Imputation of Start/End Date of Adverse Events and 
Prior/Concomitant Medications 
Event Start Date Imputation 
• Imputation of event end date should be done before imputation of event start date; 
• Completely missing: Impute to the first study treatment date; 
• Missing day and month: Impute to January 1st, unless year is the same as year of first study 
treatment dose; if so, impute to the first study treatment date; 
• 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; if so, impute to the first study treatment date; 
• 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 
• Completely Missing: Impute to the last contact date; 
• Missing day and month: Impute to December 31st, unless year is the same as last contact 
date; if so, impute to the last contact date; 
• 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; if so, impute to the last contact date.