Clinical trial NCT04992546
Conditions: Atopic Dermatitis
Sponsor: Principia Biopharma, a Sanofi Company
Start date: 2021-08-13; Completion date: 2022-12-28
Enrollment: 39 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a Ph2a study that consists of a double-blind, intra-patient placebo-controlled treatment period and an open-label uncontrolled treatment period with objective to evaluate the safety, tolerability, PK and preliminary efficacy of PRN473 in up to 40 patients with mild to moderate AD.

On Day 1 (Baseline) of the Blinded Period, 2 target lesions with a difference no greater than 1 point in Total Sign Score (TSS) were randomly assigned to treatment in an intra-patient 1:1 manner, one lesion to PRN473 and the other to matching placebo.

Participation took approximately 13 weeks, including up to a 5-week screening period, a 6-week treatment period, end of study assessments 1 day after last dose, and a safety follow-up phone call 2 weeks after last dose.

Detailed description:
Study duration per patient was approximately 56 days including a 42-days treatment period.

Arms: arm 1: During the double-blinded period, 2 target lesions per participant (with difference no greater than 1 point in total sign scores \[TSS\]) were randomized in 1:1 ratio to receive either SAR44727 Gel 5 percent (%) or matching placebo (i.e., each participant was treated with both SAR444727 5% BID and placebo in parallel). During open-label period, participants applied SAR444727 Gel, 5% twice daily (BID) to the all atopic dermatitis (AD)-affected areas, except the scalp, palms, soles and genitals through Days 15 to 42. arm 2: Multiple topical doses of placebo for 14 days, and PRN473 (SAR444727) for 28 days
Interventions: intervention 1: PRN473 (SAR444727) intervention 2: Placebo
Intervention descriptions: intervention 1: White to off-white gel suspension intervention 2: White to off-white gel suspension

Protocol documents:
Prot_000.pdf: 
Principia Biopharma, Inc. 
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01-Mar-2022 Final
AMENDED CLINICAL TRIAL PROTOCOL 02  
Protocol Title: 
A randomized, intra-patient, double-blind, 
placebo-controlled study to evaluate the safety, 
tolerability, and pharmacokinetics of topically 
administered PRN473 (SAR444727) in patients with 
mild to moderate atopic dermatitis 
Protocol Number: 
PRN473-0005 (ACT17131) 
Amendment Number: 
Amendment 02 
Compound number 
(INN/Trademark): 
PRN473 (SAR444727) 
Not applicable 
Brief Title: 
Phase 2a study of the safety, tolerability, 
and pharmacokinetics of topically administered 
PRN473 (SAR444727) in patients with mild to 
moderate atopic dermatitis 
Study Phase: 
2a 
Sponsor Name: 
Principia Biopharma, Inc. 
Legal Registered Address: 
220 E. Grand Avenue 
South San Francisco, CA 94080 
USA 
Sponsor’s Medical Contact: 
Monitoring team’s 
representative name and 
contact information 
Regulatory agency identifier number(s): 
IND Number: 
152941 
EudraCT: 
Not applicable  
NCT: 
NCT04992546 
WHO: 
Not applicable 
EUDAMED 
Not applicable  
Other: 
Not applicable  
Approval Date: 
01-Mar-2022 Final
Confidentiality Statement 
This document contains confidential information of Principia Biopharma, Inc. It is provided for 
the sole use of the Principal Investigator, sub-investigators, staff, institutional review boards, 
human research ethics committees, and regulatory authorities. By accepting this document, you 
agree to maintain the information as confidential and to use it only for the purpose of 
conducting or reviewing the study protocol. 
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Product Name: PRN473 (SAR444727) 
 
Clinical Study Protocol PRN473-0005 (ACT17131) 
Principia Biopharma, Inc. 
 
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01-Mar-2022 Final 
PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/countries 
impacted by amendment 
Date, version 
Amended Clinical Trial Protocol 02 
global 
01 March 2022, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 01 
global 
15 June 2021, version 1 (electronic 2.0) 
Original Protocol 
 
19 March 2021, version 1 (electronic 2.0) 
Amendment 02 (01 March 2022) 
OVERALL RATIONALE FOR THE AMENDMENT 
This protocol is being amended to provide more flexibility to allow the investigational product to 
be administered at home or external clinic during Blinded Period, update statistical interim 
analysis to facilitate the internal decision making and to make other clarifications deemed 
necessary by the Sponsor.  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
Updated the study Sponsor’s Medical 
Contact and study NCT numbers. 
Updated protocol version and date. 
Administrative. 
Protocol amendment summary of changes 
table 
Included the overall rationale and 
protocol amendment summary of 
changes table for current amendment. 
Administrative. 
Section 1.1 synopsis; Section 3 objectives 
and endpoints; Section 8.6 Biomarkers 
Included the RNA expression analysis in 
biomarker assessments.  
To determine the effect of IMP on 
lesional transcriptional profile and 
its associated mechanisms on skin 
inflammation and barrier function. 
Section 1.1 synopsis; Section 4.1 overall 
design; Section 6.2 
Preparation/handling/storage/accountability  
Added “The investigational products will 
be applied at the study site, at the 
patient’s home, or at an external clinic, 
where available.” 
To provide flexibility to allow IMP 
administration at home by trained 
medical professional or external 
clinic during Blinded Period.  
Section 1.1 synopsis; Section 4.1 overall 
design 
Specified the STS assessment to be 
performed predose on Days 1, 8 
(optional), 15, 29, and at Day 43 for the 
target lesions. 
For clarity.  
Section 1.1 synopsis; Section 9.5 interim 
analysis; Section 6.3 measures to minimize 
bias: randomization and blinding 
Updated the language on interim 
analysis. 
To facilitate internal decision 
making. 
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Clinical Study Protocol PRN473-0005 (ACT17131) 
Principia Biopharma, Inc. 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Throughout 
Adjusted the term of “at clinic” to “at study 
site”, where applicable. 
To distinguish from “external clinic” 
and to align the term throughout. 
Included a trained medical professional in 
addition to site staff, where applicable, 
considering that IMP might be applied at 
home or external clinic. 
To provide flexibility to allow IMP 
administration at home by trained 
medical professional or at external 
clinic during Blinded Period. 
Section 1.2 schema 
Updated the panel for blinded period by 
adding “at home or external clinic”.   
To provide flexibility to allow IMP 
administration at home by trained 
medical professional or at external 
clinic during Blinded Period. 
Section 1.2 schema, Section 1.3 schedule 
of activities 
Updated footnote “a” by adding “The 
investigational products could be applied 
by a trained medical professional at 
patient’s home or an external clinic, 
where available, as a backup option.” 
To provide flexibility to allow IMP 
administration at home by trained 
medical professional or at external 
clinic during Blinded Period. 
Section 1.3 schedule of activities 
Updated the header for blinded period 
from “in-clinic” to “at study 
site/home/external clinic”. 
To provide flexibility to allow IMP 
administration at home by trained 
medical professional or at external 
clinic during Blinded Period. 
Updated the footnote “t” and introduced a 
new footnote “u” to include study 
intervention dosing during blinded period 
visits to be applied at study site, at home 
or an external clinic, where available.  
Added annotation “b” to PP-NRS 
assessment and photographs at D15 and 
D29 visit. 
To clarify that the PP-NRS and 
photography will be performed 
predose.  
Added study intervention dosing at D29 
visit and included annotation “n”. 
To correct an omission. 
Footnote "n" was modified to clarify that 
the dosing at D29 visit to be done after 
predose assessments at study site. 
For clarity. 
Footnote "q" was modified to clarify that 
the STS assessment to be performed 
predose. Added annotation “b” to STS 
assessment at D15 and D29 visit. 
For clarity. 
Section 1.3 schedule of activities; Section 
8.9 lesion photography 
Corrected the D15 visit from Blinded 
Period to Open-Label Period in SoA table 
footnote “l” and in Section 8.9.  
To correct an error. 
Specified the photographs to be taken of 
the 2 target lesions predose at Baseline, 
D8, D15, D29 and at D43.  
For clarity.  
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Clinical Study Protocol PRN473-0005 (ACT17131) 
Principia Biopharma, Inc. 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.2 preparation/handling/storage/ 
accountability 
Defined the “study staff” who may supply 
or administer IMP during the Blinded 
Period. 
For clarity. 
 
Clarified that the Investigator or designee 
is responsible for the education of “site 
staff” rather than “study staff”. 
For clarity. 
 
Included text on specifying the condition 
when IMP application at home or external 
became applicable.   
To provide flexibility to allow IMP 
administration at home by trained 
medical professional or at external 
clinic during Blinded Period. 
Section 6.3 measures to minimize bias 
randomization and blinding 
Clarified that the local tolerability 
assessment to be performed by another 
trained medical professional different 
than the person administering the study 
intervention, if the investigational 
products are applied at the patient’s 
home or at an external clinic. 
Measures taken for minimize the 
bias. 
Section 6.4 study intervention compliance 
Clarified the trained medical professional, 
in addition to site staff, was responsible 
for study intervention administration and 
study conduct.  
For clarity. 
Section 7.1.1 permanent discontinuation 
Added ALT >5 × ULN in the listing of 
events leading to permanent IMP 
discontinuation.  
To correct an omission and align 
with decision chart in Section 10.3. 
Section 9.4.4.5 laboratory data 
Replaced the term 'vital signs' with 
'laboratory data'. 
To correct the error. 
Section 10.5 appendix 5: Protocol 
Amendment History 
Added the overall rationale and protocol 
amendment summary of changes table 
for amendment 01. 
To include the document history. 
Throughout document 
Other minor editorial changes 
(eg, grammatical, stylistic, and minor 
typographical error corrections). 
Minor, therefore, have not been 
summarized. 
  
 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 02 ..................................................................... 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES .................................................... 2 
TABLE OF CONTENTS .............................................................................................................. 5 
LIST OF TABLES ......................................................................................................................... 9 
LIST OF ABBREVIATIONS ..................................................................................................... 10 
1 
PROTOCOL SUMMARY .............................................................................................. 13 
1.1 
SYNOPSIS ............................................................................................................ 13 
1.2 
SCHEMA .............................................................................................................. 21 
1.3 
SCHEDULE OF ACTIVITIES (SOA) ................................................................. 22 
2 
INTRODUCTION ........................................................................................................... 26 
2.1 
STUDY RATIONALE .......................................................................................... 26 
2.2 
BACKGROUND ................................................................................................... 28 
2.2.1 
Nonclinical studies................................................................................ 28 
2.2.1.1 
Nonclinical pharmacology............................................................. 28 
2.2.1.2 
Pharmacokinetics and metabolism in animals ............................... 31 
2.2.1.3 
Nonclinical toxicology .................................................................. 32 
2.2.2 
Clinical studies...................................................................................... 33 
2.3 
BENEFIT/RISK ASSESSMENT .......................................................................... 34 
2.3.1 
Risk assessment .................................................................................... 34 
2.3.2 
Benefit assessment ................................................................................ 34 
2.3.3 
Overall benefit/Risk assessment ........................................................... 34 
3 
OBJECTIVES AND ENDPOINTS ................................................................................ 35 
4 
STUDY DESIGN ............................................................................................................. 37 
4.1 
OVERALL DESIGN ............................................................................................. 37 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ........................................... 38 
4.3 
JUSTIFICATION FOR DOSE .............................................................................. 39 
4.4 
END OF STUDY DEFINITION ........................................................................... 40 
5 
STUDY POPULATION .................................................................................................. 41 
5.1 
INCLUSION CRITERIA ...................................................................................... 41 
5.2 
EXCLUSION CRITERIA ..................................................................................... 42 
5.3 
LIFESTYLE CONSIDERATIONS....................................................................... 45 
5.3.1 
Meals and dietary restrictions ............................................................... 45 
5.3.2 
Caffeine, alcohol, and tobacco.............................................................. 45 
5.3.3 
Activity ................................................................................................. 45 
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5.4 
SCREEN FAILURES ............................................................................................ 45 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ADMINISTRATION OF 
STUDY INTERVENTION ................................................................................... 45 
6 
STUDY INTERVENTION AND CONCOMITANT THERAPY ............................... 46 
6.1 
STUDY INTERVENTION (S) ADMINISTERED .............................................. 46 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ..................... 46 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ... 48 
6.4 
STUDY INTERVENTION COMPLIANCE ........................................................ 50 
6.5 
DOSE MODIFICATION ...................................................................................... 50 
6.6 
CONTINUED ACCESS TO STUDY INTERVENTION AFTER THE END 
OF STUDY ............................................................................................................ 50 
6.7 
CONCOMITANT THERAPY .............................................................................. 50 
6.7.1 
COVID-19 vaccination ......................................................................... 51 
6.7.2 
Prohibited medications ......................................................................... 51 
6.7.3 
Permitted medications .......................................................................... 52 
6.7.4 
Rescue medicine ................................................................................... 52 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PATIENT 
WITHDRAWAL.............................................................................................................. 53 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ....................................... 53 
7.1.1 
Permanent discontinuation.................................................................... 53 
7.1.2 
Liver chemistry stopping criteria .......................................................... 54 
7.1.3 
QTc stopping criteria ............................................................................ 54 
7.1.4 
Hematology stopping criteria ............................................................... 54 
7.2 
PATIENT DISCONTINUATION/WITHDRAWAL FROM THE STUDY ........ 54 
7.3 
LOST TO FOLLOW-UP ....................................................................................... 55 
8 
STUDY ASSESSMENTS AND PROCEDURES .......................................................... 56 
8.1 
EFFICACY ASSESSMENTS ............................................................................... 56 
8.2 
SAFETY ASSESSMENTS ................................................................................... 57 
8.2.1 
Physical examinations .......................................................................... 57 
8.2.2 
Vital signs ............................................................................................. 57 
8.2.3 
Electrocardiograms ............................................................................... 58 
8.2.4 
Clinical safety laboratory assessments ................................................. 58 
8.2.4.1 
Clinical laboratory tests ................................................................. 59 
8.2.5 
Pregnancy testing .................................................................................. 60 
8.2.6 
Local Cutaneous Tolerability ............................................................... 60 
8.3 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS AND OTHER 
SAFETY REPORTING......................................................................................... 60 
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8.3.1 
AEs and SAEs: Definitions and procedures for recording, evaluating, 
follow-up, and reporting ....................................................................... 61 
8.3.1.1 
Definition of AE ............................................................................ 61 
8.3.1.2 
Definition of SAE .......................................................................... 62 
8.3.1.3 
Recording and follow-up of AE and/or SAE ................................ 63 
8.3.1.4 
Reporting of SAEs ......................................................................... 65 
8.3.2 
Time period and frequency for collecting AE and SAE information ... 66 
8.3.3 
Method of detecting AEs and SAEs ..................................................... 66 
8.3.4 
Follow-up of AEs and SAEs................................................................. 66 
8.3.5 
Regulatory reporting requirements for SAEs ....................................... 66 
8.3.6 
Pregnancy ............................................................................................. 67 
8.3.7 
Expedited reporting requirements......................................................... 67 
8.3.8 
Guidelines for reporting product complaints ........................................ 68 
8.4 
PHARMACOKINETICS ...................................................................................... 68 
8.5 
GENETICS AND/OR PHARMACOGENOMICS ............................................... 69 
8.6 
BIOMARKERS ..................................................................................................... 69 
8.7 
IMMUNOGENICITY ASSESSMENTS .............................................................. 70 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND 
HEALTH ECONOMICS....................................................................................... 70 
8.9 
LESION PHOTOGRAPHY .................................................................................. 70 
9 
STATISTICAL CONSIDERATIONS ........................................................................... 71 
9.1 
STATISTICAL HYPOTHESES ........................................................................... 71 
9.2 
SAMPLE SIZE DETERMINATION .................................................................... 71 
9.3 
ANALYSIS SETS ................................................................................................. 71 
9.4 
STATISTICAL ANALYSES ................................................................................ 72 
9.4.1 
General considerations.......................................................................... 72 
9.4.2 
Endpoints .............................................................................................. 72 
9.4.3 
Analysis of efficacy data ...................................................................... 72 
9.4.3.1 
Lesion Total Sign Score (TSS) ...................................................... 72 
9.4.3.2 
Further efficacy endpoints during the blinded period ................... 73 
9.4.3.3 
Eczema Area and Skin Severity Index (EASI) .............................. 73 
9.4.3.4 
Validated Investigator Global Assessment-Atopic Dermatitis 
(vIGA-AD) .................................................................................... 74 
9.4.3.5 
Further efficacy endpoints during the open-label period .............. 74 
9.4.4 
Analysis of safety data .......................................................................... 74 
9.4.4.1 
Assignment to treatment and study phase ..................................... 75 
9.4.4.2 
Analyses of adverse events ............................................................ 76 
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9.4.4.3 
Local cutaneous tolerability .......................................................... 76 
9.4.4.4 
Extent of study treatment exposure and compliance ..................... 76 
9.4.4.5 
Laboratory data .............................................................................. 77 
9.4.4.6 
Vital signs ...................................................................................... 77 
9.4.4.7 
Electrocardiogram ......................................................................... 77 
9.4.5 
Analysis of pharmacokinetic data ......................................................... 77 
9.4.5.1 
Pharmacokinetic parameters .......................................................... 77 
9.4.5.2 
Analysis of pharmacokinetic concentrations ................................. 77 
9.4.6 
Other analyses ....................................................................................... 78 
9.4.6.1 
Biomarkers .................................................................................... 78 
9.4.6.2 
Further exploratory endpoint(s) ..................................................... 78 
9.5 
INTERIM ANALYSIS .......................................................................................... 78 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ....................................................................................................... 79 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS ............................................................................................ 79 
10.1.1 
Regulatory and ethical considerations .................................................. 79 
10.1.2 
Financial disclosure .............................................................................. 79 
10.1.3 
Informed consent process ..................................................................... 80 
10.1.4 
Data protection...................................................................................... 80 
10.1.5 
Data quality assurance .......................................................................... 80 
10.1.6 
Source documents ................................................................................. 81 
10.1.7 
Study and site start and closure ............................................................ 82 
10.1.7.1 
Trial Stopping Rules ...................................................................... 82 
10.1.7.2 
Study/Site termination ................................................................... 82 
10.1.8 
Publication policy ................................................................................. 83 
10.2 
APPENDIX 2: CONTRACEPTIVE AND BARRIER GUIDANCE ................... 83 
10.2.1 
Definition .............................................................................................. 83 
10.2.2 
Contraception guidance ........................................................................ 84 
10.2.3 
Collection of pregnancy information .................................................... 86 
10.3 
APPENDIX 3: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS 
AND FOLLOW UP ASSESSMENTS AND STUDY INTERVENTION 
RECHALLENGE GUIDELINES ......................................................................... 87 
10.4 
APPENDIX 4: ADDITIONAL APPENDICES .................................................... 90 
10.4.1 
Grading of application site tolerability symptoms................................ 90 
10.4.2 
Validated investigator global assessment-atopic dermatitis 
(vIGA-AD) ........................................................................................... 91 
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10.4.3 
Lesion Total Sign Score (TSS) ............................................................. 92 
10.4.4 
Hanifin and rajka criteria ...................................................................... 92 
10.5 
APPENDIX 5: PROTOCOL AMENDMENT HISTORY .................................... 93 
11 
REFERENCES ................................................................................................................ 99 
 
LIST OF TABLES  
Table 1 - Summary of biochemical and cellular characterization of PRN473 .............................. 30 
Table 2 - Summary of PRN473 clinical studies ............................................................................ 33 
Table 3 - Objectives and endpoints ............................................................................................... 35 
Table 4 - Study intervention .......................................................................................................... 46 
Table 5 - Excluded medications and treatments ............................................................................ 51 
Table 6 - Laboratory tests .............................................................................................................. 59 
Table 7 - Analysis sets ................................................................................................................... 71 
Table 8 - Safety analysis................................................................................................................ 75 
 
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Product Name: PRN473 (SAR444727) 
 
Clinical Study Protocol PRN473-0005 (ACT17131) 
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LIST OF ABBREVIATIONS  
Abbreviation or 
Specialist Term 
Explanation 
AD 
atopic dermatitis 
AE 
adverse event 
ALT 
alanine aminotransferase 
API 
active pharmaceutical ingredient 
ATP 
adenosine triphosphate  
AUC 
area under the concentration-time curve 
AUC0-∞ 
area under the plasma concentration-time curve from zero to infinity  
AUC0-last 
area under the plasma concentration-time curve from zero to the last 
measurable concentration  
BCR 
B cell receptor 
BID 
twice daily 
BLQ 
below the limit of quantification  
BSA 
body surface area 
BTK 
Bruton’s tyrosine kinase 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CLint 
intrinsic clearance 
Cmax 
maximum plasma concentration 
COVID-19 
coronavirus disease 2019 
CV% 
percent coefficient of variation  
DLQI 
Dermatology Life Quality Index 
DTP 
direct to patient 
EASI 
Eczema Area and Skin Severity Index 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor  
FcR 
Fc-gamma receptor 
FcR 
Fc-epsilon receptor 
FDA 
Food and Drug Administration 
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Abbreviation or 
Specialist Term 
Explanation 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
geometric CV% 
geometric coefficient of variation 
IC50 
half maximum inhibitory concentration  
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IGA 
Investigator Global Assessment 
IgE 
immunoglobulin E  
IgG 
immunoglobulin G  
IL 
interleukin 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous  
IWRS 
interactive web response system 
NIMP 
non investigational medicinal product 
NOAEL 
no-observed-adverse-effect level  
OD 
optical density  
OTC 
over-the-counter  
PCSA 
potentially clinically significant abnormality 
PK 
pharmacokinetic 
PO 
per oral 
POEM 
Patient-Oriented Eczema Measure 
PP-NRS 
Peak Pruritus Numeric Rating Scale 
QD 
once daily 
SAE 
serious adverse event  
SAP 
Statistical Analysis Plan 
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Clinical Study Protocol PRN473-0005 (ACT17131) 
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Abbreviation or 
Specialist Term 
Explanation 
SCORAD 
SCORing atopic dermatitis 
SD 
standard deviation  
STS 
skin tape stripping 
SUSAR 
suspected unexpected serious adverse reaction 
TCI 
topical calcineurin inhibitor 
TSS 
total sign score 
ULN 
upper limit of normal 
UV 
ultraviolet 
vIGA-AD 
validated Investigator Global Assessment-Atopic Dermatitis 
WHO 
World Health Organization 
 
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Product Name: PRN473 (SAR444727) 
 
Clinical Study Protocol PRN473-0005 (ACT17131) 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol Title: A randomized, intra-patient, double-blind, placebo-controlled study to evaluate 
the safety, tolerability, and pharmacokinetics of topically administered PRN473 
(SAR444727) in patients with mild to moderate atopic dermatitis 
Brief Title: 
Phase 2a study of the safety, tolerability, and pharmacokinetics of topically 
administered PRN473 (SAR444727) in patients with mild to moderate atopic 
dermatitis 
Rationale: 
PRN473 (also known as SAR444727), a selective Bruton’s tyrosine kinase (BTK) 
inhibitor, is an investigational drug being developed as a topical agent for the 
treatment of immune-mediated dermatological diseases. This study will explore 
the safety, tolerability, and plasma pharmacokinetics (PK) of topically 
administered PRN473 in patients with mild to moderate atopic dermatitis (AD). 
Objectives and Endpoints: 
 
Objectives 
Endpoints 
Primary 
 
Safety: 
To assess the safety and tolerability of PRN473 Gel, 
5% versus placebo administered twice daily (BID) up to 
6 weeks in patients with mild to moderate atopic 
dermatitis (AD) 
Safety: 
• 
Incidence and severity of adverse events (AEs) 
• 
Changes in vital signs, electrocardiograms (ECGs), 
and laboratory tests 
• 
Assessment of local cutaneous tolerability 
assessment: incidence and severity 
of application-site events such as burning/stinging, 
itching, and erythema  
Secondary 
 
PK: To evaluate the plasma PK of PRN473 following 
administration of multiple topical doses of PRN473 
Gel, 5% for 42 days in patients with mild to moderate 
AD 
• 
PK: Plasma PRN473 concentrations at specified 
timepoints 
Exploratory 
• 
Biomarker: To evaluate blood and skin changes in 
protein and RNA expression, lymphocyte 
infiltration, and epidermal thickness following 
treatment with PRN473 Gel, 5% at Days 8 and 15 
• 
Biomarker: Change from Baseline in biomarkers 
using blood samples, skin tape stripping, and skin 
biopsy 
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Product Name: PRN473 (SAR444727) 
 
Clinical Study Protocol PRN473-0005 (ACT17131) 
Principia Biopharma, Inc. 
 
14 of 100 
Confidential and Proprietary 
 
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Objectives 
Endpoints 
• 
Efficacy: To evaluate the preliminary efficacy 
following double-blind treatment with PRN473 
Gel, 5% compared to placebo at Days 8 and 15 
Efficacy During Blinded Period: 
• 
Change from Baseline in lesion total sign score 
(TSS) at Days 8 and 15 
• 
Change from Baseline in daily lesional Peak 
Pruritus Numeric Rating Scale (PP-NRS) score up 
to Day 15 
• 
Change from Baseline in lesional validated 
Investigator Global Assessment (IGA) score at 
Days 8 and 15 
 
• 
Lesion validated IGA response (proportion of 
patients with an IGA score of 0 or 1 and ≥2-grade 
improvement from Baseline) at Days 8 and 15 
• 
Efficacy: To evaluate the preliminary efficacy 
following open-label treatment with PRN473 Gel, 
5% at Days 29 and 43 
Efficacy During Open-Label Period 
• 
Change from Baseline in TSS for the 2 target 
lesions at Days 29 and 43. 
• 
Change from Baseline in Eczema Area and Skin 
Severity Index (EASI) at Days 29 and 43 
• 
Change from Day 15 in EASI to Days 29 and 43 
• 
Proportion of patients with EASI 50, EASI 75, 
and EASI 90 from Day 15 to Days 29 and 43 
• 
Change in PP-NRS from Day 15 to Days 29 and 43 
• 
Proportion of patients achieving at least 3-point 
reduction from Day 15 in PP-NRS at Days 29 
and 43 
• 
Proportion of patients achieving at least a 4-point 
reduction from Day 15 in PP-NRS at Days 29 
and 43 
• 
Change from Day 15 in weekly mean of PP-NRS at 
Days 29 and 43 
• 
Proportion of patients achieving at least 2 grade 
reduction in vIGA-AD to clear (vIGA-AD 0) 
or almost clear (vIGA-AD 1) from Day 15 to 
Days 29 and 43 
• 
Change from Day 15 in SCORing atopic dermatitis 
(SCORAD) at Days 29 and 43 
• 
Change from Day 15 in percentage of treatable 
body surface area (BSA) at Days 29 and 43  
• 
Change from Baseline in Patient-Oriented Eczema 
measure (POEM) at Days 15, 29, and 43 
• 
Change from Baseline in Dermatology Life Quality 
Index (DLQI) at Days 15, 29, and 43 
VV-CLIN-0613618 3.0


Product Name: PRN473 (SAR444727) 
 
Clinical Study Protocol PRN473-0005 (ACT17131) 
Principia Biopharma, Inc. 
 
15 of 100 
Confidential and Proprietary 
 
01-Mar-2022 Final 
Overall Design: 
This is a Ph2a study that consists of a double-blind, intra-patient placebo-controlled treatment 
period and an open-label uncontrolled treatment period with objective to evaluate the safety, 
tolerability, PK and preliminary efficacy of PRN473 in up to 40 patients with mild to moderate 
AD. All patients are required to apply an emollient (except urea-containing or medicated 
emollients that are regulated as medical device) daily from Day -7 to Day 1 (see Section 6.2). On 
Day 1 (Baseline) of the Blinded Period, 2 target lesions with a difference no greater than 1 point 
in TSS will be randomly assigned to treatment in an intra-patient 1:1 manner, one lesion to 
PRN473 Gel, 5%, and the other to matching placebo. PRN473 Gel, 5% and matching placebo are 
weighed and applied twice daily (BID; morning and evening) at a quantity of approximately 
2.5 mg/cm2 to a 100 cm2 area of each target lesion on Days 1-14 (Blinded Period). The 
investigational products will be applied at the study site, at the patient’s home, or at an external 
clinic, where available.   
During the Blinded Period, if the target lesion is less than 100 cm2, the application area should 
include surrounding nonlesional skin (note: two target lesion skin biopsy specimens on Days 1 
and 15 are only on lesional skin); if the target lesion is larger than 100 cm2, only 100 cm2 of the 
lesion should be marked and treated. On Days 15-42 (Open Label Period), patients are instructed 
to apply PRN473 Gel, 5% BID to all AD-affected areas in a thin layer (excluding the scalp, 
palms, soles, and genitals) and should continue to treat the assigned areas throughout the Open 
Label Period. 
Safety assessments include application site tolerability assessments (Appendix 4, Section 10.4.1), 
vital signs, ECGs, physical examination, safety labs, and AEs. 
To evaluate the PK (plasma concentrations) and biomarkers of PRN473, blood samples will be 
collected at study visits accordingly to the SoA (Section 1.3).  
Efficacy assessments of: 
• The lesional PP-NRS will be administered daily predose during the Blinded Period 
(Days 1-14) and at predose Day 15. 
• The lesional validated IGA will be performed predose at Baseline (Day 1), Days 8, and 15.  
• The lesion TSS (Appendix 4, Section 10.4.3) will be performed predose at Baseline 
(Day 1), Days 8, 15, and 29, and at End of Study/Early Termination visit (Day 43). 
• The EASI, the POEM, and the DLQI will be performed predose at Baseline (Day 1), 
Days 15 and 29, and at End of Study/Early Termination visit (Day 43). 
• The vIGA-AD (Appendix 4, Section 10.4.2) will be performed at Screening, predose at 
Days 15 and 29, and at End of Study/Early Termination visit (Day 43).  
• The SCORAD will be performed predose at Days 15 and 29, and at End of Study/Early 
Termination visit (Day 43). 
VV-CLIN-0613618 3.0


Product Name: PRN473 (SAR444727) 
 
Clinical Study Protocol PRN473-0005 (ACT17131) 
Principia Biopharma, Inc. 
 
16 of 100 
Confidential and Proprietary 
 
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• The PP-NRS will be administered daily predose before patient morning application during 
the Open-Label Period (Days 15-42) and at End of Study/Early Termination visit 
(Day 43).  
• The percentage of treatable BSA will be calculated at Screening, Days 15 and 29, and 
at End of Study/Early Termination visit (Day 43). 
To be included in the population analyzed for efficacy, the patient must have received at least 
80% of prescribed study intervention in the Blinded Period and/or at least 80% of prescribed 
study intervention in the Open-Label Period. 
Skin tape stripping (STS) will be performed predose on Days 1, 8 (optional), 15, 29, and at 
Day 43 for the two target lesions, and on Day 1 for the normal skin. For a minimum of 20 patients 
(may be reduced to 15 patients if there is an impact on enrollment from coronavirus disease 2019 
[COVID-19]), a 4 or 5 mm punch skin biopsy will be collected from each target lesion on Days 1, 
15, and 29 (optional) and from normal skin on Day 1. The lesional biopsy specimens at Days 15 
and 29 will be collected in the vicinity of the Day 1 (Baseline lesional sample) biopsy but must be 
at least 1 cm away from the prior biopsy site. If the target lesion cleared after Day 1 and before 
Day 15, the biopsy specimen will be taken from the lesional skin location of the target area 
identified at Baseline. 
Additional information regarding study assessments and their timing is located in the Schedule of 
Activities (Section 1.3). 
Study Duration: 
Participation will take approximately 13 weeks, including up to a 5-week screening period, 
a 6-week treatment period, end of study assessments 1 day after last dose, and a safety follow-up 
phone call 2 weeks after last dose. 
Number of Patients:  
Up to 40 patients with mild to moderate AD are planned to be enrolled.  
Investigational Product 
PRN473 Gel, 5% (w/w) and placebo to match. 
Study Population: 
Inclusion Criteria 
Patients are eligible to be included in the study only if all the following criteria are met: 
1. Male and female adults 18 to 70 years of age (inclusive) at the time of informed consent. 
VV-CLIN-0613618 3.0


Product Name: PRN473 (SAR444727) 
 
Clinical Study Protocol PRN473-0005 (ACT17131) 
Principia Biopharma, Inc. 
 
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2. Diagnosed with mild to moderate AD, meeting at least 3 major and 3 minor criteria 
according to Hanifin and Rajka (Hanifin 1980; Appendix 4, Section 10.4.4) prior to or at 
the Screening visit. 
3. History of AD for at least 6 months as determined by the Investigator through patient 
interview.  
4. Stable disease for the 4 weeks prior to the screening visit with no significant flares in AD 
as determined by the Investigator. 
5. Validated Investigator Global Assessment-atopic dermatitis (vIGA-AD) score of Moderate 
(3) or Mild (2) at Screening. The vIGA-AD is evaluated for the entire body except scalp, 
palms, soles, and genitals. 
6. Has AD involvement (excluding scalp, palms, soles and genitals) of at least 1.0% BSA and 
no more than 14.0% BSA. 
7. Has at least two target lesions 100cm2 or greater with a difference no greater than 1 point 
in lesion TSS and at least 5 cm apart located on the trunk (excluding genitals) or upper 
extremities (excluding palms). 
8. Male patients are eligible to participate if they agree to the following during the 
intervention period and for at least 2 days (eg, 5 terminal half-lives) after the last dose of 
study intervention, 
• Refrain from donating sperm 
PLUS, either: 
- 
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent.  
OR 
- 
Must agree to use contraception/barrier as detailed below: 
Agree to use a male condom and an additional highly effective contraceptive method 
as described in Appendix 2 Contraceptive and barrier guidance Section 10.2) when 
having sexual intercourse with a woman of childbearing potential (WOCBP) who is 
not currently pregnant. 
9. A female patient is eligible to participate if she is not pregnant or breastfeeding, and one of 
the following conditions applies: 
• Is a woman of nonchildbearing potential (WONCBP) as defined in Appendix 2 
Contraceptive and barrier guidance (Section 10.2). 
OR 
• Is a WOCBP and agrees to use a contraceptive method that is highly effective (with a 
failure rate of <1% per year), preferably with low user dependency, as described in 
VV-CLIN-0613618 3.0


Product Name: PRN473 (SAR444727) 
 
Clinical Study Protocol PRN473-0005 (ACT17131) 
Principia Biopharma, Inc. 
 
18 of 100 
Confidential and Proprietary 
 
01-Mar-2022 Final 
Appendix 2 Contraceptive and barrier guidance (Section 10.2) during the study 
intervention period and for at least 2 days (eg, 5 terminal half-lives) after the last dose 
of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of 
reproduction during this period. 
A WOCBP must have a negative highly sensitive pregnancy test (urine and/or serum as 
required by local regulations) within 28 days before the first administration of study 
intervention, see Section 8.2.5 Pregnancy testing. 
- 
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the patient must be excluded from 
participation if the serum pregnancy result is positive. 
10. In good health as judged by the Investigator, based on medical history, physical 
examination, serum chemistry labs, hematology values, and urinalysis. 
11. Patients are considered reliable and capable of adhering to the protocol and visit schedule, 
according to the judgment of the Investigator. 
12. Able to provide written informed consent and agreeable to the schedule of activities. 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria are met: 
1. Patients who have failed 2 or more prior systemic treatments for AD (not including those 
who discontinued systemic treatments due to safety or tolerability issues). 
2. Patients with any serious or uncontrolled medical condition or clinically significant 
laboratory, ECG, vital signs, or physical examination abnormality that would prevent 
study participation or place the patient at significant risk, as judged by the Investigator. 
3. Patients who have received a live or attenuated vaccine in the last 12 weeks or intend to 
receive a live or attenuated vaccine during the study. 
4. Patients who cannot discontinue medications and treatments prior to the Baseline visit and 
during the study as described in the Excluded Medications and Treatments table. 
5. Has unstable AD, based on the judgement of the Investigator, or any consistent 
requirement for high potency topical steroids to manage AD signs or symptoms. 
6. Patients who have significant active systemic or localized bacterial, viral, fungal, and 
helminth infection in the last 30 days (including known actively infected skin at or around 
a lesion of AD). Non-complicated recurrent muco-cutaneous infections such as cold sores 
are not considered exclusionary. 
7. Patients unwilling to refrain from prolonged sun exposure or use of a tanning bed or other 
artificial light emitting devices for 4 weeks prior to Baseline and during the study. 
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Product Name: PRN473 (SAR444727) 
 
Clinical Study Protocol PRN473-0005 (ACT17131) 
Principia Biopharma, Inc. 
 
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8. Patients with other skin conditions that would interfere with evaluations of the effect of the 
study medication on AD, as determined by the Investigator. Patients with any condition on 
the treatment area which, in the opinion of the Investigator, could confound efficacy 
measurements. 
9. Patients with known genetic dermatological conditions that overlap with AD, such as 
Netherton syndrome. 
10. Patient has any state of immunodeficiency including but not limited to primary or 
secondary immunodeficiency syndromes, organ transplant (except corneal transplant), and 
previous opportunistic infections, as judged by the Investigator.  
11. Known allergies to excipients in PRN473 Gel.  
12. Previous use of a BTK inhibitor. 
13. Women who are pregnant, wishing to become pregnant during the study, or are 
breastfeeding. 
14. Patients currently undergoing allergy (eg, food allergy testing or skin prick testing), patch 
testing, or food challenges, or plan to do so during the study. 
15. Patients who have undergone major surgery within 4 weeks prior to Day 1 or patients who 
have a major surgery planned during the study. 
16. Regular use of drugs of abuse or regular alcohol consumption within 6 months prior to the 
study defined as: an average weekly intake of >35 units for males or >35 units for females. 
One unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of 
wine, or 1 (25 mL) measure of spirits. 
17. History of any malignancy except skin basal cell or squamous cell carcinomas in situ that 
have been removed and completely resolved at least 5 years ago. 
18. Any of the following laboratory abnormalities at the screening visit (identified by the 
central laboratory): 
- 
Absolute neutrophil count <1.5 x 109/L  
- 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 x upper limit 
of normal (ULN)  
- 
Total bilirubin >1.5 x ULN, (isolated bilirubin >1.5 x ULN is acceptable if total 
bilirubin is fractionated and direct bilirubin <35%) 
- 
Abnormal international normalized ratio (INR) test and activated partial 
thromboplastin time (aPTT) judged by the Investigator to be clinically significant 
- 
A platelet count <150 000/μL 
VV-CLIN-0613618 3.0


Product Name: PRN473 (SAR444727) 
 
Clinical Study Protocol PRN473-0005 (ACT17131) 
Principia Biopharma, Inc. 
 
20 of 100 
Confidential and Proprietary 
 
01-Mar-2022 Final 
19. Electrocardiogram (ECG) findings of QT corrected for heart rate (QTc) >450 msec 
(males) or >470 msec (females), poorly controlled atrial fibrillation (ie, symptomatic 
patients or a ventricular rate above 100 beats/min on ECG), or other clinically significant 
cardiovascular abnormalities. 
20. Positive human immunodeficiency virus (HIV) antibody test. 
21. Presence of Hepatitis B surface antigen (HBsAg) and/or core antibody positive at 
screening or within 3 months prior to first dose of study intervention.  
22. Positive Hepatitis C antibody test result at screening or within 3 months prior to starting 
study intervention. NOTE: Patients with positive Hepatitis C antibody due to prior 
resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is 
obtained.  
23. Evidence of active or latent tuberculosis (TB) as documented by medical history and 
examination, chest X-rays (posterior anterior and lateral), and TB testing: either a positive 
tuberculin skin test (TST; defined as a skin induration ≥5 mm at 48 to 72 hours, regardless 
of Bacillus Calmette-Guerin (BCG) or other vaccination history) or a positive (not 
indeterminate) TB test such as QuantiFERON®-TB Gold Plus test. NOTE: The choice to 
perform a TST or a QuantiFERON-TB Gold Plus test will be made by the investigator 
according to local licensing and standard of care. The QuantiFERON-TB Gold Plus test 
can only be used in countries where it is licensed, and the use of this test is dependent on 
previous treatment(s). This test may not be suitable if previous treatment(s) produced 
significant immunosuppression. 
24. History of serious infections requiring intravenous therapy with the potential for 
recurrence or currently active moderate to severe infection at Screening (Grade 2 or 
higher) including active coronavirus disease 2019 (COVID-19). 
25. Patients who have received the last dose of a COVID-19 vaccine within 14 days prior to 
Day 1. 
26. Patients who are family members of the clinical study site, clinical study staff, or Sponsor, 
or family members of enrolled patients living in the same house. 
Interim Analysis 
An interim analysis for internal decision making may be performed. The Sponsor team that will 
analyze the data will include: a Medical Monitor, a biostatistician, a programmer, and safety 
designee. The outcome of the Interim Analysis may lead to early termination of the study in case 
of unfavorable signals or continuation without any changes. 
See Section 9.5 for more details.  
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Product Name: PRN473 (SAR444727) 
 
Clinical Study Protocol PRN473-0005 (ACT17131) 
Principia Biopharma, Inc. 
 
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1.2 
SCHEMA  
 
a Two target lesions with a difference no greater than 1 point in total sign scores (TSS) will be randomly assigned in an intra-patient manner 
1:1 to PRN473 Gel, 5% or matching placebo. The two target lesions will be dosed twice daily at study site during the Blinded Period with 
the second dose application approximately 12 hours after previous dose. The investigational products could be applied by a trained 
medical professional at patient’s home or an external clinic, where available, as a backup option. 
b During the Open Label Period, patients will apply PRN473 Gel, 5% BID to the all AD-affected areas, except the scalp, palms, soles, and 
genitals and should continue to treat the assigned areas throughout the Open Label Period.   
VV-CLIN-0613618 3.0








Product Name: PRN473 (SAR444727) 
Clinical Study Protocol PRN473-0005 (ACT17131) 
Principia Biopharma, Inc. 
 
25 of 100 
Confidential and Proprietary 
 
01-Mar-2022 Final 
r 
PK samples will be collected at the following timepoints relative to the morning dose: predose and at 1, 4, and 6 hours postdose on Days 1 and 15; predose on Days 8 and 29; and at the Day 43 visit, approximately 
12 hours after the last dose of study intervention. The time of last application of study intervention prior to the Day 8, Day 15, Day 29, and Day 43 visits should be recorded. The allowed time deviation window 
before a deviation is recorded for blood sample collection post dose is 15 minutes for time points up to and including 6 hours post dose; pre-dose samples should be collected within 30 minutes prior to the next 
application of study intervention. 
s Samples for blood biomarker levels should be drawn predose on Days 1, 8 and 15, and at the Day 43 visit approximately 12 hours after the last dose of study intervention. 
t 
Local tolerability assessment will be performed within approximately 30 minutes of dosing by site staff using the symptom grading in Appendix 4 (Section 10.4.1) at each dosing when patients are at study site 
during dosing. During the blinded period in case the investigational products are applied at the patient’s home or external clinic, the local tolerability assessment will be performed by a trained medical professional, 
different than the person administering the study intervention. 
u If it becomes difficult for the patient to visit the study site, investigational products could be applied by a trained medical professional at patient’s home or an external clinic, where available, as a backup option. The 
morning Visit of D1 and D8 must be conducted at the study site. 
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Product Name: PRN473 (SAR444727) 
Clinical Study Protocol PRN473-0005 (ACT17131) 
Principia Biopharma, Inc. 
 
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2 
INTRODUCTION  
2.1 
STUDY RATIONALE  
Bruton’s tyrosine kinase (BTK) is an essential signaling element downstream of the B cell 
receptor (BCR), Fc-gamma receptor (FcR), and Fc-epsilon receptor (FcR). BTK is 
a non-receptor tyrosine kinase and is a member of the TEC tyrosine protein kinase family 
of kinases (Mohamed 2009). BTK activation is critical for B cell differentiation, activation, 
and maturation. BTK also regulates the activation of other hematopoietic cells, such as mast cells, 
macrophages, and neutrophils primarily through Fc receptor signaling (Rip 2018). Platelets 
express high levels of BTK, which is involved in collagen/glycoprotein VI (GPVI) signaling; 
however, alternative signaling pathways exist with bypass BTK signaling to retain normal platelet 
functions and thrombus formation (Futatani 2001, Byrd 2013).  
BTK inhibition results in the down regulation of various immune cell activities including cell 
proliferation, differentiation, maturation, survival, cytokine production and the induction 
of apoptosis. Inhibition of BTK activity in B cells produces phenotypic changes consistent with 
blockade of the BCR, preventing activation, maturation, and antibody production. Inhibition 
of BTK in FcγR and FcεR expressing cells (such as macrophages or mast cells) blocks the 
inflammatory cytokine cascade driven by antibody cross-linking to the surface receptors 
(Chang 2011, Xu 2012). Deficiency or inhibition of BTK has been shown to reduce disease 
in several immune-mediated rodent models. Pertinent to the treatment of patients with 
immune-mediated diseases, inhibitors of BTK have been shown to be anti-inflammatory in 
several rodent models of arthritis (Chang 2011, Di Paolo 2011, Honigberg 2010, Kim 2011, 
Xu 2012), and lupus (Crofford 2016, Honigberg 2010, Hutcheson 2012) with inhibition of 
proteinurea, kidney histopathology, nephritis, and cutaneous endpoints. BTK inhibitors also 
inhibit acute skin inflammation and vasculitis in antibody induced arthus reaction model 
and murine passive cutaneous anaphylaxis models (Chang 2011). Several orally administered 
BTK inhibitors, including PRN1008, SAR442168/PRN2246, evobrutinib, and fenebrutinib, 
are currently in clinical development for a range of immune-mediated diseases such as 
pemphigus, chronic spontaneous urticaria, multiple sclerosis, systemic lupus erythematosus, 
and rheumatoid arthritis.  
A topically applied BTK inhibitor could block the initiation and propagation of various 
immune-mediated dermatological diseases locally in the skin, with a potential clinical advantage 
of very limited systemic exposure. Such local skin mechanisms include inhibition of local 
immune cell activation, blockade of antibody-mediated Fc receptor induced inflammation, 
and recruitment and retention of neutrophils in the affected skin areas. Excessive and persistent 
infiltration of neutrophils into tissues has a role in multiple inflammatory diseases (Oliveira 2016), 
making neutrophil behavior a potential target for drug therapies, ideally to achieve resolution of 
inflammation at a specific site without causing systemic immunosuppression. 
PRN473 is an investigational drug that is being developed as a topical agent for the treatment 
of immune-mediated dermatological diseases. PRN473 demonstrates selectivity for BTK and a small 
number of kinases containing a homologous cysteine with durable but reversible BTK occupancy in 
biochemical assays which translates into a long duration of action in cellular systems.  
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Product Name: PRN473 (SAR444727) 
Clinical Study Protocol PRN473-0005 (ACT17131) 
Principia Biopharma, Inc. 
 
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Atopic Dermatitis 
Atopic dermatitis (AD) is a common, chronic, relapsing, pruritic, inflammatory skin disease. It is 
characterized by xerosis and acute (erythematous papules, vesicles, edema, exudation, crusting), 
subacute and chronic (scaly, erythematous papules and plaques, lichenification, excoriations, 
fissuring) eczematous skin lesions (Bieber 2010, Eichenfield 2014, Bieber 2017, 
Boguniewicz 2017, Silverberg 2017). Typically, AD presents with an age-related morphology and 
distribution (Eichenfield 2014, Bieber 2017). 
The global prevalence of AD is estimated to be approximately 15-30% in children 
and approximately 2-10% in adults. In children with AD, onset occurs in 45% during the first 
6 months of life, 60% during the first year, and 90% are affected before the age of 5 (Bieber 2010, 
Bieber 2017, Boguniewicz 2017, Silverberg 2017). Patients can experience spontaneous disease 
remission later in adolescence but up to 50% will live with AD throughout adulthood 
(Bieber 2010, Eichenfield 2014, Bieber 2017, Silverberg 2017). 
The pathogenesis of AD is multifactorial and includes abnormalities of the skin barrier, defects in 
the innate and adaptive immune response and alterations in the resident skin microflora 
(Boguniewicz 2011). While there is a genetic basis for AD with loss-of-function mutations in the 
filaggrin gene (FLG) which leads to skin barrier abnormalities, there are a number of systemic and 
cutaneous immune abnormalities also present in AD. It is unclear if the abnormalities in skin 
barrier precedes the immune dysregulation or vice versa.  
Dysregulation of the innate immune system in AD include changes in antimicrobial peptide 
(AMP) levels, reduced toll-like receptor (TLR) function, increased mast cells in the skin, 
increased levels of serum immunoglobulin E (IgE), IgE-mediated degranulation and cytokine 
production, increased thymic stromal lymphopoietin (TSLP) by keratinocytes, increase in 
eosinophil infiltrates, dermal dendritic cell involvement, and basophil recruitment and activation 
(Boguniewicz 2011, Werfel 2016, Weidinger 2018). In addition to the innate immune system, 
there are also abnormalities of the adaptive immune system in AD. Some of these abnormalities 
include an increase in TH2 lymphocytes, increased TH2 cytokine activity A (IL-4 and IL-13) 
which initiates B-cell IgE class switching, increase in TH1, TH17, and TH22 cells and their related 
cytokine and chemokine production (Weidinger 2018). Topical treatments are the standard 
therapies for patients with mild to moderate AD. Topical steroids are typically the first line 
of treatment but they are used intermittently to reduce the localized adverse effects such as skin 
atrophy, purpura, telangiectasis, and dyspigmentation (Weidinger 2018). Topical calcineurin 
inhibitors (TCIs) have been used in AD as a steroid sparing treatment, however, these agents 
include a Food and Drug Administration (FDA) black box warning of a potential increase in the 
risk of lymphoma. In addition, the use of TCIs has been limited by their inferior efficacy 
compared to the topical steroids. The most recently FDA approved topical therapy for AD is 
crisaborole ointment, a cAMP-specific phosphodiesterase-4 inhibitor. Crisaborole ointment has 
been shown to have a modest improvement of disease (32% improvement from baseline) 
compared with the vehicle alone (18-25% improvement) (Ahmed 2018). In addition, crisaborole 
has a significant localized burning and stinging at the site of application. Moderate efficacy 
combined with localized adverse effects has led to the reduced use of crisaborole over TCIs 
and topical steroids. 
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Product Name: PRN473 (SAR444727) 
Clinical Study Protocol PRN473-0005 (ACT17131) 
Principia Biopharma, Inc. 
 
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Despite progress in the treatment of mild to moderate AD, there is still a need for a safe 
and efficacious agent that has: 
• Superior or comparable efficacy to Class 1 topical corticosteroids  
• Excellent safety and tolerability profile 
• Safe and effective as a maintenance therapy 
• No rebound effect after discontinuation 
As stated above, based on the multiple roles BTK plays in adaptive and innate immunity, a topical 
BTK inhibitor has the potential to block the initiation and propagation of various 
immune-mediated dermatological diseases such as AD locally in the skin, with a potential clinical 
advantage of very limited systemic exposure. 
2.2 
BACKGROUND  
2.2.1 Nonclinical studies  
PRN473 has undergone an extensive nonclinical safety evaluation. All nonclinical studies 
conducted for PRN473 are described in detail in the PRN473 Investigator’s Brochure. 
PRN473 has demonstrated slow off-rate binding kinetics to the BTK enzyme; this has 
an advantage over fast off-rate molecules in that the longer a molecule can interact with its target, 
the longer the inhibition and resulting increase in efficacy. Slow off-rates also lead to longer 
duration of action with the potential to reduce the frequency of re-application while maximizing 
effective target inhibition at the topically applied target site. The potential clinical advantage of 
a topical PRN473 is that a longer target residence time may prolong efficacy locally with very low 
systemic exposures observed in the plasma.  
PRN473 has been evaluated in pharmacology, PK, and toxicology studies in mice, rats, dogs, and 
mini pigs as an oral and topical agent. Oral PRN473 has been demonstrated to be 
pharmacologically active in mice and rats using collagen-induced arthritis, and in dogs with 
naturally occurring spontaneous pemphigus foliaceus. This is expected since the amino acid 
sequences of mouse, rat, dog, mini pig, and human BTK are essentially identical 
(99% homology), with no differences across species in the adenosine triphosphate (ATP) binding 
site where PRN473 binds. Topical PRN473 Gel has also been demonstrated to be 
pharmacologically active in mice and rats, using passive cutaneous anaphylaxis and reverse 
passive arthus as in vivo models of efficacy. 
2.2.1.1 Nonclinical pharmacology  
PRN473 is a potent, ATP-competitive, reversible inhibitor of BTK. PRN473 demonstrates rapid 
on and slow off-rate kinetics on BTK, as well as a few closely related TEC kinase family 
members: BMX, TEC, and TXK. PRN473 does not demonstrate durable target occupancy of 
B lymphocyte kinase or interleukin (IL)-2-inducible T-cell kinase. 
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Product Name: PRN473 (SAR444727) 
Clinical Study Protocol PRN473-0005 (ACT17131) 
Principia Biopharma, Inc. 
 
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PRN473 is an ATP-competitive inhibitor of BTK. Half maximal inhibitory concentration (IC50) 
values for PRN473 were 2.1 ±0.1, 5.1 ±0.3, and 13.0 ±0.7 nM at ATP concentrations of 16, 160, 
800 µM, respectively. 
The binding characteristics of PRN473 to other kinases that had demonstrated cross-reactivity 
with PRN473 was assessed utilizing fluorescence competition (Kim 2011). These studies 
demonstrated that PRN473 exhibited durable occupancy on BMX, TEC, and TXK but not on 
BLK and ITK. 
PRN473 was screened at a concentration of 10 µM in a radioligand binding assay against a panel 
of receptors, ion channels, and transporters. In this screen, results showing an inhibition higher 
than 50% were then re-evaluated with a full IC50 determination (A3 adenosine receptor [74.7%], 
dopamine D2s receptor [60.4%], the gamma-aminobutyric acid [GABA]-gated Cl- channel 
[69.3%], and dopamine transporter [94.8%]). Follow-up IC50 assays for these receptors 
demonstrated only weak activity (IC50 >1 μM) with no measurable IC50 for dopamine D2s receptor 
up to 100 μM. Activity against all other receptors, transporters, and channels in this panel was less 
than 50%. This data reaffirms the selectivity of PRN473 for BTK and reduced potential for off 
target binding and signaling. 
The activity of PRN473 was evaluated in several cell-based assays in which the occupancy 
of BTK and the resulting functional effects of the compound in primary cells was assessed. 
The data from the cell-based assays support the in vitro biochemical data showing that PRN473 is 
a potent inhibitor of BTK and inhibits the BCR mediated activation of B cells, IgE-mediated 
activation of mast cells and basophils, immunoglobulin G (IgG)-mediated activation of 
monocytes, and neutrophil migration. PRN473 demonstrated weak cytotoxicity in cell lines not 
expressing BTK and exhibited only weak activity on T-cell activation and epidermal growth 
factor receptor (EGFR) activation. 
A summary of the in vitro pharmacology of PRN473 is provided Table 1. Values greater than 
5000 nM or 20 000 nM indicate no activity in the assay at the limits of the concentrations tested. 
These data are consistent with PRN473 being a potent BTK inhibitor. 
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Table 1 - Summary of biochemical and cellular characterization of PRN473  
Assay 
Value ±SD 
BTK enzymatic IC50  
1.8 ±0.2 nM 
BTK biochemical occupancy at 24 hr  
83 ±5% 
Ramos B cell occupancy IC50  
30 ±15 nM 
Occupancy of BTK in Ramos cells at 4 hr and 18 hr  
91 ±3% (4 hr), 54 ±6% (18 hr) 
Occupancy of BTK in WB IC50  
364 ±112 nM 
B cell activation in HWB IC50  
274 ±95 nM 
IgG induced TNFα production in human monocytes  
76 ±40 nM 
IgE induced WB human basophil CD63 activation 
1130 ±510 nM  
IgE mast cell degranulation β-hexaminidase release 
89 nM 
IgE mast cell degranulation histamine release 
175 nM 
EGFR signaling reporter assay IC50  
>5000 nM 
Cytotoxicity in HCT-116 cells IC50  
>20 000 nM 
Abbreviations: BTK = Bruton’s tyrosine kinase; EGFR = epidermal growth factor receptor; IC50 = half maximal inhibitory 
concentration; IgE = immunoglobulin E; IgG = immunoglobulin G; SD = standard deviation; TNFα = tumor necrosis factor 
alpha. 
In vivo pharmacology studies were conducted with oral PRN473 in naturally occurring 
pemphigus foliaceus in dogs, and experimental rodent collagen-induced arthritis models.  
In all preclinical studies, PRN473 demonstrated anti-inflammatory effects with dose-dependent 
inhibition of clinical scores achieved as monotherapy. Both topical PRN473 Gel or oral PRN473 
demonstrated similar efficacy to corticosteroids (topical betamethasone dipropionate or high dose 
oral prednisolone). 
Topical PRN473 Gel inhibition of IgG antibody-mediated skin inflammation was studied in the rat 
arthus model. Topical PRN473 Gel demonstrated significant dose-dependent inhibition of passive 
arthus reaction, as measured by reduction in diameter of intra-dermal dye extravasation and OD610nm 
from skin biopsy following IgG antibody challenge. A single administration of topical PRN473 Gel 
(over approximately 3 cm2 area) 3 hours prior to IgG antibody challenge achieved significant 
inhibition at strengths greater than 0.5% (1 mg/cm2). Similarly, multiday (3 days) application once 
daily (QD) also achieved significant inhibition at strengths greater than 0.5%. Complete responses 
equivalent to topical betamethasone dipropionate were achieved with 1% (2 mg/cm2) and 2% 
(4 mg/cm2) PRN473 Gel treatment after single day or multiday (3 days) application. Multiday 
(3-day) treatment with QD application of PRN473 Gel revealed that the maximal efficacy equivalent 
to corticosteroids could be achieved with the lower strength of topical gel compared to single day gel 
application. PRN473 Gel demonstrated prolonged inhibitory effect, maintaining significant dose-
dependent inhibition when applied 16 hours prior to challenge. 
To confirm that systemic pharmacology did not contribute to the efficacy of the topical 
PRN473 Gel, the systemic BTK occupancy was assessed in spleens collected terminally from the 
arthus rats on study (4 hours post challenge). Topically applied 2% (4 mg/cm2) PRN473 Gel did 
not result in measurable systemic BTK occupancy following either single dose or multiday 
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(3-day) dosing, confirming that the efficacy of PRN473 Gel was driven by local skin effects 
and not by systemic pharmacology. Topical PRN473 Gel efficacy was equivalent to oral PRN473 
(10- 40mg/kg, per oral [PO], QD) and oral prednisone (10 mg/kg) treatments in a comparable rat 
arthus study. Taken together, these results demonstrate that topically applied PRN473 Gel can 
effectively inhibit IgG-mediated FcγR signaling, equivalent to topical or oral corticosteroids, 
and prevent downstream IgG antibody-mediated immune effects locally in the skin. 
There was little impact on efficacy when a single dose of 1% PRN473 Gel was administered three 
hours, one hour or 10 minutes prior to challenge for the inhibition of passive arthus reaction in 
rats. Similarly, there was no impact on efficacy if this single dose of 1% gel was washed off prior 
to challenge, demonstrating that PRN473 Gel achieved a prolonged inhibitory effect without the 
need for continual exposure in the Rat Passive Arthus model. 
Topical PRN473 Gel demonstrated significant dose-dependent inhibition of mouse passive 
cutaneous anaphylaxis, as measured by reduction in diameter of intra-dermal dye extravasation 
and optical density (OD610) from skin biopsy following IgE-mediated challenge. A single 
administration of topical PRN473 Gel 3 hours prior to challenge achieved significant inhibition 
at strengths greater than 1% (0.6 mg/cm2). Multiday (3 days) treatment with QD application 
achieved similar levels of inhibition. Significant responses approaching topical betamethasone 
dipropionate or antihistamine were achieved with 4% (2.4 mg/cm2) PRN473 Gel treatment. 
These results demonstrate that topically applied PRN473 Gel (over an approximately 3 cm2 area) 
can effectively inhibit IgE-mediated FcεR signaling, equivalent to corticosteroid or antihistamine 
treatment, and prevent downstream IgE antibody-mediated immune effects locally in the skin. 
2.2.1.2 Pharmacokinetics and metabolism in animals  
Metabolism was assessed in vitro with S9 liver fractions, liver microsomes, and cryopreserved 
hepatocytes from several species. The species-specific microsomal system the highest clearance 
was observed in dog (intrinsic clearance [CLint] = 188 µL/min/mg protein) and the lowest 
clearance was observed in human (CLint = 140 µL/min/mg protein). 
In the S9 fractions from mouse, rat, dog, monkey, and human, a total of 8 potential metabolites 
from PRN473 were identified. Most of the metabolites were minor (1-10% relative peak area 
by mass spectrometry). Two metabolites, M6 and M7, were identified as potential major 
metabolites (10% relative peak area) in a subset of species.  
In vivo metabolic profile studies of oral PRN473 in mice, rat, dog, monkey, and mini pig 
identified three major metabolites: the reduced metabolite (PRN684), the hydrolyzed metabolites 
(PRN834, PRN835), and the oxidation metabolite (PRN664). Overall, the metabolites observed in 
all animal species were similar. No unique human metabolites have been detected from studies 
conducted to date. 
Plasma protein binding was >99% in all species and the blood to plasma ratio for distribution in 
evaluated species was ranged from 0.43 (in dog) to 0.66 (in monkey).  
CYP450 inhibition and induction studies have also been completed. The results of the in vitro 
inhibition studies with 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 showed that PRN473 does not 
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significantly inhibit CYP450 enzymes (IC50 >6 μM across isoforms). In a CYP induction study no 
induction was seen with PRN473 at 10 μM for the tested isoforms of CYP 1A2, 2B6, and 3A4. 
The in vivo PK of PRN473 was assessed in rats, dogs, and mini pigs via intravenous (IV) and PO 
administration. All species demonstrated good bioavailability following oral administration. 
Oral bioavailability was lowest in dog (7%) and comparable in mini pig (approximately 17%) and 
rat (21%). Following topical administration of a single dose in dogs and mini pigs, the systemic 
exposure was limited (<10 ng/mL for most of the samples) and lower than the exposure observed 
following oral administration in both rat and mini pig species, suggesting that the topical 
administration likely demonstrate limited systemic absorption and lower concentration levels 
compare to oral administration in human. Nonclinical PK studies following IV and PO 
administration of PRN473 are described in detail in the PRN473 Investigator’s Brochure. 
2.2.1.3 Nonclinical toxicology  
Dermal administration of PRN473 Gel to mini pigs at 0.5% (0.05 mg/cm2), 2% (0.2 mg/cm2), 
and 10% (1 mg/cm2), strengths for at least 28 days was well tolerated. There were no 
PRN473-related changes. The maximum tolerated dose was not reached even at the highest 
dose of 10% when administered QD over a 10 % body surface area (approximately 400 cm2 
at a gel application rate of 10 mg/cm2/day) of mini pig. At the low dose (0.5% gel) due to the low 
exposure levels, the kinetic properties of PRN473 were not able to be determined, except one 
animal on Day 28. The maximum concentrations observed on Day 7 and Day 28, following 
10% gel application were 2.32 ng/mL and 3.17ng/mL, respectively. The corresponding area under 
the concentration-time curve (AUC) values were 11.3 ng×hr/mL and 25.1 ng×hr/mL, respectively. 
Additionally, the 10% PRN473 Gel did not cause ocular irritation and the PRN473 Gel may have 
the potential to be a contact sensitizer as discussed in the Investigators Brochure. 
In a 28-Day oral rat study, all treated animals had measurable systemic exposure following 
both single and repeated QD oral PRN473 administration at doses of 150 and 500 ng/mL. 
PRN473 mean maximum plasma concentration (Cmax) values increased less than proportionally 
and area under the plasma concentration-time curve from time zero to the last measurable 
concentration (AUC0-last exposures increased proportionally with increases in dose. No significant 
accumulation was observed (as assessed by mean Cmax and AUC0-last on Day 28 vs Day 1). 
A higher exposure was observed in females then males as assessed by mean Cmax and AUC0-last. 
Treatment with PRN473 was well tolerated. Liver weight changes with associated hepatocellular 
hypertrophy were observed following oral treatment with 500 mg/kg. Based on these findings, the 
no-observed-adverse-effect level (NOAEL) in rats is considered 150 mg/kg (Cmax: female 
713 ng/mL, male 308 ng/mL; AUC: female 6600 ng×hr/mL, male 3170 ng×hr/mL). 
In a 28-day oral dog study, all treated animals had measurable systemic exposure. PRN473 
plasma exposure (as assessed by average Cmax and AUC0-last) increased in a greater than dose 
proportional manner over the full dose range on both collection days, with the exception of 
Day 28 male Cmax values. PRN-473 plasma exposure (as assessed by mean Cmax and AUC0-last) 
increased comparing Day 28 values to Day1 values. Sex differences were noted when comparing 
PRN473 plasma exposure on Day 1 and Day 28 values. Treatment with PRN473 was well 
tolerated. Based on these findings, the NOAEL is at least 400 mg/kg (Cmax: female 2220 ng/mL, 
male 3390 ng/mL; AUC: female 10 600 ng×hr/mL, male 23 900 ng×hr/mL). 
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In a 13-week oral rat study, treatment with PRN473 was well tolerated at the dosages tested. 
Administration of 60 or 150 mg/kg PRN473 was associated with dose-dependent increases 
in liver weights for males and females with no histomorphologic correlates. Based on these 
findings, the NOAEL in rats following was considered to be above 150 mg/kg (Cmax: female 
726 ng/mL, male 339ng/mL; AUC: female 4590 ng×hr/mL, male 2940 ng×hr/mL).  
In a 13-week oral dog study, treatment of PRN473 at the dosages tested was well tolerated. 
Administration of any dosage of PRN473 tested was associated with decreased activity 
and reduced body weight in females. Administration of 400 mg/kg in females was associated with 
decreased food consumption. Based on these findings, the NOAEL in dogs following oral dosing 
is considered to be 400 mg/kg (Cmax 2220 ng/mL and AUC 8860ng×hr/mL) in males and 
120 mg/kg (Cmax 918 ng/mL and AUC 3110 ng×hr/mL) in females. 
2.2.2 Clinical studies  
First-in-human administration of PRN473 in 38 healthy volunteers occurred in completed Phase 1 
Study PRN473-001 using the PRN473 liquid and tablet formulations. The results following oral 
dose administration up to a single dose of 600 mg (the maximum dose) demonstrated very limited 
systemic exposure (<10 ng/mL) of PRN473.  
Due to the very low systemic exposure, PRN473 was reformulated into a topical gel and then 
tested in two Phase 1 studies. PRN473 topical has been administered to 42 healthy volunteers in 
Study PRN473-0002 and 21 patients with IgE-mediated allergies in Study PRN473-0003. Plasma 
concentrations of PRN473 were measured in PRN473-0002 but not in PRN473-0003. The results 
from PRN473-0002 showed that the majority of PK samples were not measurable (ie, below the 
quantitation limit). The samples that were measurable were too low to support computation of PK 
parameters following topical application in healthy participants. 
The individual studies are summarized Table 2 in below. 
Table 2 - Summary of PRN473 clinical studies  
Study Number/ 
Formulation 
Population  
(sample size) 
Study Purpose 
Dose Levels 
Status 
Phase 1 
PRN473-0001/ 
liquid and tablet 
Healthy 
volunteer  
Part A  
(N = 38 active)  
Part B (N = 0) 
Single and Repeat 
dose to assess safety, 
tolerability, and PK  
(First-in-Human 
Study) 
50, 100, 200, 600 mg  
(6, 8, or 10 active; 2 PBO 
per group in Part A) 
Completed 
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Study Number/ 
Formulation 
Population  
(sample size) 
Study Purpose 
Dose Levels 
Status 
PRN473-0002/ 
topical gel 
Healthy 
volunteer 
(N = 60) 
Single and Repeat 
dose to assess safety, 
tolerability, and PK 
0.5, 2.0, 5.0%  
(8 active; 2 PBO in each 
of 5 single-dose cohorts)  
5.0%  
(8 active; 2 PBO in 
a repeat-dose cohort) 
Completed 
PRN473-0003/ 
topical gel 
Patients with 
IgE-mediated 
allergies 
(N = 21) 
Single doses to assess 
pharmacologic 
activity, safety, 
and tolerability 
0.5, 2, 5%; or PBO 
Completed 
Abbreviations: MD = multiple-dose; PBO = placebo; PK = pharmacokinetic. 
Available data from the Phase 1 studies are summarized in the PRN473 Investigator’s Brochure. 
2.3 
BENEFIT/RISK ASSESSMENT  
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PRN473 may be found in the Investigator’s Brochure. 
2.3.1 Risk assessment  
No risks other than those previously mentioned in the Investigator’s Brochure are known at this 
time. 
2.3.2 Benefit assessment  
Patients may benefit from having regular clinical and laboratory evaluations throughout the study. 
There may be no direct health benefit for patients from receipt of study intervention.  
2.3.3 Overall benefit/Risk assessment  
PRN473 is being developed for topical skin application for the treatment of immune-mediated 
dermatological diseases. 
The toxicity potential of PRN473 is well characterized in in vitro assays, safety pharmacology 
studies, and repeat dose oral and topical toxicity studies in multiple animal species. PRN473 has 
also been well tolerated when orally administered in single ascending doses to healthy volunteers. 
The overall preclinical and clinical profile of PRN473 to date continues to favor continued 
investigation of PRN473.  
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3 
OBJECTIVES AND ENDPOINTS  
Table 3 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
 
Safety: 
To assess the safety and tolerability of PRN473 Gel, 5% 
versus placebo administered BID up to 6 weeks in 
patients with mild to moderate AD 
Safety: 
• 
Incidence and severity of AEs 
• 
Changes in vital signs, ECGs, and laboratory tests 
• 
Assessment of local cutaneous tolerability: 
incidence and severity of application-site events 
such as burning/stinging, itching, and erythema   
Secondary 
 
PK: To evaluate the plasma PK of PRN473 following 
administration of multiple topical doses of PRN473 
Gel, 5% for 42 days in patients with mild to moderate 
AD 
• 
PK: Plasma PRN473 concentrations at specified 
timepoints 
Exploratory 
• 
Biomarker: To evaluate blood and skin changes in 
protein and RNA expression, lymphocyte 
infiltration, and epidermal thickness following 
treatment with PRN473 Gel, 5% at Days 8 and 15 
• 
Biomarker: Change from Baseline in biomarkers 
using blood samples, skin tape stripping, and skin 
biopsy 
• 
Efficacy: To evaluate the preliminary efficacy 
following double-blind treatment with PRN473 
Gel, 5% compared to placebo at Days 8 and 15 
Efficacy During Blinded Period: 
• 
Change from Baseline in lesion TSS at Days 8 and 
15 
• 
Change from Baseline in daily lesional PP-NRS 
score up to Day 15 
• 
Change from Baseline in lesional validated IGA 
score at Days 8 and 15 
• 
Lesional validated IGA response (proportion of 
patients with a validated IGA score of 0 or 1 and 
≥2-grade improvement from Baseline) at Days 8 
and 15 
• 
Efficacy: To evaluate the preliminary efficacy 
following open-label treatment with PRN473 Gel, 
5% at Days 29 and 43 
Efficacy During Open-Label Period 
• 
Change from Baseline in TSS for the 2 target 
lesions at Days 29 and 43. 
• 
Change from Baseline in EASI at Days 29 and 43 
• 
Change from Day 15 in EASI to Days 29 and 43 
• 
Proportion of patients with EASI 50, EASI 75, 
and EASI 90 from Day 15 to Days 29 and 43 
• 
Change in PP-NRS from Day 15 to Days 29 and 43 
• 
Proportion of patients achieving at least 3-point 
reduction from Day 15 in PP-NRS at Days 29 
and 43 
• 
Proportion of patients achieving at least a 4-point 
reduction from Day 15 in PP-NRS at Days 29 
and 43 
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Objectives 
Endpoints 
 
• 
Change from Day 15 in weekly mean of PP-NRS at 
Days 29 and 43 
• 
Proportion of patients achieving at least 2 grade 
reduction in vIGA-AD to clear (vIGA-AD 0) or 
almost clear (vIGA-AD 1) from Day 15 to Days 29 
and 43 
• 
Change from Day 15 in SCORAD at Days 29 and 
43 
• 
Change from Day 15 in percentage of treatable 
BSA at Days 29 and 43  
• 
Change from Baseline in POEM at Days 15, 29, 
and 43 
• 
Change from Baseline in DLQI at Days 15, 29, and 
43 
 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a Ph2a study that consists of a double-blind, intra-patient placebo-controlled treatment 
period and an open-label uncontrolled treatment period with objective to evaluate the safety, 
tolerability, PK and preliminary efficacy of PRN473 in up to 40 patients with mild to moderate 
AD. All patients are required to apply an emollient (except urea-containing or medicated 
emollients that are regulated as medical device) daily from Day -7 to Day 1 (see Section 6.2). 
On Day 1 (Baseline) of the Blinded Period, 2 target lesions with a difference no greater than 
1 point in TSS will be randomly assigned to treatment in an intra-patient 1:1 manner, one lesion to 
PRN473 Gel, 5%, and the other to matching placebo. PRN473 Gel, 5% and matching placebo are 
weighed and applied BID (morning and evening) at a quantity of approximately 2.5 mg/cm2 to 
a 100 cm2 area of each target lesion on Days 1- 14 (Blinded Period). The investigational products 
will be applied at the study site, at the patient’s home, or at an external clinic, where available.  
During the Blinded Period, if the target lesion is less than 100 cm2, the application area should 
include surrounding nonlesional skin (note: two target lesion skin biopsy specimens on Days 1 
and 15 are only on lesional skin); if the target lesion is larger than 100 cm2, only 100 cm2 of the 
lesion should be marked and treated. On Days 15-42 (Open-Label Period), patients are instructed 
to apply PRN473 Gel, 5% BID to all AD-affected areas in a thin layer (excluding the scalp, 
palms, soles and genitals) and should continue to treat the assigned areas throughout the Open 
Label Period. 
Safety assessments include application site tolerability assessments (Appendix 4, Section 10.4.1), 
vital signs, ECGs, physical examination, safety labs, and AEs. 
To evaluate the PK (plasma concentrations) and biomarker of PRN473, blood samples will be 
collected at study visits accordingly to the SoA (Section 1.3). 
Efficacy assessments of: 
• The lesional PP-NRS will be administered daily predose during the Blinded Period 
(Days 1-14) and at predose Day 15. 
• The lesional validated IGA will be performed predose at Baseline (Day 1), and Days 8 and 
15.  
• The lesion TSS (Appendix 4, Section 10.4.3) will be performed predose at Baseline 
(Day 1), Days 8, 15, and 29, and at End of Study/Early Termination visit (Day 43). 
• The EASI, the POEM, and the DLQI will be performed predose at Baseline (Day 1), 
Days 15 and 29, and at End of Study/Early Termination visit (Day 43). 
• The vIGA-AD (Appendix 4, Section 10.4.2) will be performed, predose at Days 15 and 
29, and at End of Study/Early Termination visit (Day 43). 
• The SCORAD will be performed predose at Days 15 and 29, and at End of Study/Early 
Termination visit (Day 43). 
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• The PP-NRS will be administered daily predose before patient morning application during 
the Open-Label Period (Days 15-42) and at End of Study/Early Termination visit 
(Day 43).  
• The percentage of treatable BSA will be calculated at Screening, Days 15 and 29, and 
at End of Study/Early Termination visit (Day 43). 
To be included in the population analyzed for efficacy, the patient must have received at least 
80% of prescribed study intervention in the Blinded Period and/or at least 80% of prescribed 
study intervention in the Open-Label Period. 
Skin tape stripping (STS) will be performed predose on Days 1, 8 (optional), 15, 29, and at 
Day 43 for the two target lesions and on Day 1 for the normal skin. For a minimum of 20 patients 
(may be reduced to 15 patients if there is an impact on enrollment from COVID-19, a 4 or 5 mm 
punch skin biopsy will be collected from each target lesion on Days 1, 15, and 29 (optional) and 
from normal skin on Day 1. The lesional biopsy specimens at Days 15 and 29 will be collected in 
the vicinity of the Day 1 (Baseline lesional sample) biopsy but must be at least 1 cm away from 
the prior biopsy site. If the target lesion cleared after Day 1 and before Day 15, the biopsy 
specimen will be taken from the lesional skin location of the target area identified at Baseline. 
Additional information regarding study assessments and their timing is located in the Schedule of 
Activities (Section 1.3). 
Inclusive of an up to 5-week screening period, a 6-week treatment period, end of study 
assessments 1 day after last dose, and a safety follow-up phone call 2 weeks after last dose, the 
participation will take approximately 13 weeks. 
Due to the COVID-19 pandemic, safety measures may be implemented to ensure continued 
supply of study medication and safety monitoring for patients. When the COVID-19 pandemic 
resolves, the measures will be repealed back to the previous state as government rules 
and benefit/risk assessment allow. 
As required, these approaches (in accordance with local regulations) will be documented in site 
guidance materials. 
Additionally, during the COVID-19 pandemic, drug supply may be sent to patients when the 
patient is not able to travel to the site or the site cannot host a patient visit. At-site study visits as 
outlined in the Schedule of Activities may be changed to a remote visit (eg, phone call, video call, 
or visiting nurse) as needed to address the COVID-19 restrictions. 
If the change to remote visits is implemented due to COVID-19 to protect the safety 
and well-being of patients, the inability to perform/obtain protocol-specified assessments at 
a required study visit will be documented. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
See Section 2.1. 
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4.3 
JUSTIFICATION FOR DOSE  
The dose of PRN473 selected for topical administration during the Blinded Period on Days 1-14 
in PRN473-0005 (ACT17131) is PRN473 Gel, 5% or matching placebo at approximately 
2.5 mg/cm2 over a 100 cm2 area encompassing each target lesion BID (approximately 12 hours 
apart). During the Open-Label Period on Days 15-42, PRN473 Gel, 5% at 2.5 mg/cm2 will be 
applied BID to all AD-affected areas excluding the scalp, palms, soles, and genitals over a body 
surface area of up to 14%. This dose is in the range of those associated with biological activity 
based on preclinical disease models and is therefore considered appropriate to evaluate in this 
initial assessment of PRN473 Gel efficacy in patients with AD.  
The proposed dosing regimens are supported by clinical safety data from the PRN473-0002 study. 
The total daily dose during the Blinded Period of the study (25 mg PRN473 active pharmaceutical 
ingredient [API] per day) is approximately 7-fold lower than the daily dose applied in the multiple 
dose arm of PRN473-0002 (175 mg PRN473 API per day). This dose was safe and well-tolerated 
and there were no serious adverse events (SAEs) or AEs that led to discontinuation. 
In the Open-Label Period, the dosing regimen of PRN473 5% (w/w) gel at 2.5 mg/cm2 gel over 
14% BSA BID will provide a daily PRN473 (API) dose of 665 mg to a patient with a total body 
surface area of 1.9 m2. This is less than the dose of 700 mg PRN473 (API), which was the highest 
dose administered in the PRN473-0002 single ascending dose/multiple dose study in healthy 
participants. This dose was safe and well-tolerated and there were no SAEs or AEs that led to 
discontinuation.  
Patients will measure the dose by the fingertip unit method and the expected dose variability when 
the compound is topically self-applied by this method may be up to two-fold excess of compound 
which is reasonably below the safety margin. 
In both the Blinded and Open-Label Periods, the locally applied dose of 0.125 mg API/cm2 is the 
same as that evaluated in the multiple dose arm of the PRN473-0002 study and is 4-fold lower 
than the highest dose that was evaluated in the single ascending dose part of PRN473-0002. 
In addition, this dose is approximately 8-fold lower than the maximum dose (1 mg API/cm2) used 
in the 28-day mini pig dermal repeated dose study (DVR489), in which there were no PRN473-
related changes, providing further support for the safety of the locally applied PRN473 dose of 
0.125 mg API/cm2. 
Systemic PRN473 exposures following administration of PRN473 Gel at all dose levels in study 
PRN473-0002 were negligible to nonexistent, with insufficient data to estimate PK parameters 
as plasma PRN473 concentrations were only sporadically detectable in a few participants. 
However, the safety of systemic PRN473 has been characterized in dog and rat toxicity studies in 
which the NOAEL doses in both species were substantially higher than the exposures following 
oral administration to humans. On Day 28, the male and female rat (most sensitive species) mean 
PRN473 Cmax values were 308 ng/mL and 713 ng/mL, respectively. At Week 13, the male 
and female rat mean PRN473 Cmax values were 339 ng/mL and 726 ng/mL, respectively. These 
systemic exposures represent a very large safety margin compared to measured exposures of 
PRN473 following topical administration of a 10% gel to the mini pig and following oral 
administration of PRN473 in healthy volunteers (Study PRN473-001). 
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In summary, the totality of the clinical and preclinical data supports the evaluation of the dosing 
regimen of 5% (w/w) PRN473 Gel at 2.5 mg gel/cm2 over up to 14% BSA in patients with AD. 
4.4 
END OF STUDY DEFINITION  
The end of the study is defined as the date of the last visit of the last patient in the study. 
A patient is considered to have completed the study if he/she has completed all phases of the 
study including the Day 43 and Day 56 safety follow up phone call.  
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA  
Patients are eligible to be included in the study only if all the following criteria are met: 
1. Male and female adults 18 to 70 years of age (inclusive) at the time of informed consent. 
2. Diagnosed with mild to moderate AD, meeting at least 3 major and 3 minor criteria 
according to Hanifin and Rajka (Hanifin 1980; Appendix 4, Section 10.4.4) prior to or at 
the Screening visit. 
3. History of AD for at least 6 months as determined by the Investigator through patient 
interview.  
4. Stable disease for the 4 weeks prior to the screening visit with no significant flares in AD 
as determined by the Investigator. 
5. Validated Investigator Global Assessment-atopic dermatitis (vIGA-AD) score of Moderate 
(3) or Mild (2) at Screening. The vIGA-AD is evaluated for the entire body except scalp, 
palms, soles and genitals. 
6. Has AD involvement (excluding scalp, palms, soles and genitals) of at least 1.0% BSA and 
no more than 14.0% BSA. 
7. Has at least two target lesions 100 cm2 or greater with a difference no greater than 1 point 
in lesion TSS and at least 5 cm apart located on the trunk (excluding genitals) or upper 
extremities (excluding palms) 
8. Male patients are eligible to participate if they agree to the following during the 
intervention period and for at least 2 days (eg, 5 terminal half-lives) after the last dose of 
study intervention, 
• Refrain from donating sperm 
PLUS, either: 
- 
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent.  
OR 
- 
Must agree to use contraception/barrier as detailed below: 
Agree to use a male condom and an additional highly effective contraceptive method 
as described in Appendix 2 Contraceptive and barrier guidance (Section 10.2) when 
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having sexual intercourse with a woman of childbearing potential (WOCBP) who is 
not currently pregnant. 
9. A female patient is eligible to participate if she is not pregnant or breastfeeding, and one of 
the following conditions applies: 
• Is a WONCBP as defined in Appendix 2 Contraceptive and barrier guidance 
(Section 10.2). 
OR 
• Is a WOCBP and agrees to use a contraceptive method that is highly effective (with a 
failure rate of <1% per year), preferably with low user dependency, as described in 
Appendix 2 Contraceptive and barrier guidance (Section 10.2) during the study 
intervention period and for at least 2 days (eg, 5 terminal half-lives) after the last dose of 
study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of 
reproduction during this period. 
A WOCBP must have a negative highly sensitive pregnancy test (urine and/or serum as 
required by local regulations) within 28 days before the first administration of study 
intervention, see Section 8.2.5 Pregnancy testing. 
- 
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the patient must be excluded from 
participation if the serum pregnancy result is positive. 
10. In good health as judged by the Investigator, based on medical history, physical 
examination, serum chemistry labs, hematology values, and urinalysis. 
11. Patients are considered reliable and capable of adhering to the protocol and visit schedule, 
according to the judgment of the Investigator. 
12. Able to provide written informed consent and agreeable to the schedule of activities. 
5.2 
EXCLUSION CRITERIA  
Patients are excluded from the study if any of the following criteria are met: 
1. Patients who have failed 2 or more prior systemic treatments for AD (not including those 
who discontinued systemic treatments due to safety or tolerability issues). 
2. Patients with any serious or uncontrolled medical condition or clinically significant 
laboratory, ECG, vital signs, or physical examination abnormality that would prevent 
study participation or place the patient at significant risk, as judged by the Investigator. 
3. Patients who have received a live or attenuated vaccine in the last 12 weeks or intend to 
receive a live or attenuated vaccine during the study. 
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4. Patients who cannot discontinue medications and treatments prior to the Baseline visit and 
during the study listed in the Excluded Medications and Treatments table. 
5. Has unstable AD, based on the judgement of the Investigator, or any consistent 
requirement for high potency topical steroids to manage AD signs or symptoms. 
6. Patients who have significant active systemic or localized bacterial, viral, fungal, and 
helminth infection in the last 30 days (including known actively infected skin at or around 
a lesion of AD). Non-complicated recurrent muco-cutaneous infections such as cold sores 
are not considered exclusionary. 
7. Patients unwilling to refrain from prolonged sun exposure or use of a tanning bed or other 
artificial light emitting devices for 4 weeks prior to Baseline and during the study. 
8. Patients with other skin conditions that would interfere with evaluations of the effect of the 
study medication on AD, as determined by the Investigator. Patients with any condition on 
the treatment area which, in the opinion of the Investigator, could confound efficacy 
measurements. 
9. Patients with known genetic dermatological conditions that overlap with AD, such as 
Netherton syndrome. 
10. Patient has any state of immunodeficiency including but not limited to primary or 
secondary immunodeficiency syndromes, organ transplant (except corneal transplant), and 
previous opportunistic infections, as judged by the Investigator.  
11. Known allergies to excipients in PRN473 Gel.  
12. Previous use of a BTK inhibitor. 
13. Women who are pregnant, wishing to become pregnant during the study, or are 
breastfeeding. 
14. Patients currently undergoing allergy (eg, food allergy testing or skin prick testing), patch 
testing, or food challenges, or plan to do so during the study. 
15. Patients who have undergone major surgery within 4 weeks prior to Day 1 or patients who 
have a major surgery planned during the study. 
16. Regular use of drugs of abuse or regular alcohol consumption within 6 months prior to the 
study defined as: an average weekly intake of >35 units for males or >35 units for females. 
One unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of 
wine, or 1 (25 mL) measure of spirits. 
17. History of any malignancy except skin basal cell or squamous cell carcinomas in situ that 
have been removed and completely resolved at least 5 years ago. 
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18. Any of the following laboratory abnormalities at the screening visit (identified by the 
central laboratory): 
- 
Absolute neutrophil count <1.5 x 109/L  
- 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 x upper limit 
of normal (ULN)  
- 
Total bilirubin >1.5 x ULN, (isolated bilirubin >1.5 x ULN is acceptable if total 
bilirubin is fractionated and direct bilirubin <35%) 
- 
Abnormal international normalized ratio (INR) test and activated partial 
thromboplastin time (aPTT) judged by the Investigator to be clinically significant 
- 
A platelet count <150 000/μL 
19. Electrocardiogram (ECG) findings of QT corrected for heart rate (QTc) >450 msec 
(males) or >470 msec (females), poorly controlled atrial fibrillation (ie, symptomatic 
patients or a ventricular rate above 100 beats/min on ECG), or other clinically significant 
cardiovascular abnormalities. 
20. Positive human immunodeficiency virus (HIV) antibody test. 
21. Presence of Hepatitis B surface antigen (HBsAg) and/or core antibody positive at 
screening or within 3 months prior to first dose of study intervention.  
22. Positive Hepatitis C antibody test result at screening or within 3 months prior to starting 
study intervention. NOTE: Patients with positive Hepatitis C antibody due to prior 
resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is 
obtained.  
23. Evidence of active or latent tuberculosis (TB) as documented by medical history and 
examination, chest X-rays (posterior anterior and lateral), and TB testing: either a positive 
tuberculin skin test (TST; defined as a skin induration ≥5 mm at 48 to 72 hours, regardless 
of Bacillus Calmette-Guerin (BCG) or other vaccination history) or a positive (not 
indeterminate) TB test such as QuantiFERON®-TB Gold Plus test. NOTE: The choice to 
perform a TST or a QuantiFERON-TB Gold Plus test will be made by the investigator 
according to local licensing and standard of care. The QuantiFERON-TB Gold Plus test 
can only be used in countries where it is licensed, and the use of this test is dependent on 
previous treatment(s). This test may not be suitable if previous treatment(s) produced 
significant immunosuppression. 
24. History of serious infections requiring intravenous therapy with the potential for 
recurrence or currently active moderate to severe infection at Screening (Grade 2 or 
higher) including active coronavirus disease 2019 (COVID-19). 
25. Patients who have received the last dose of a COVID-19 vaccine within 14 days prior to 
Day 1. 
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26. Patients who are family members of the clinical study site, clinical study staff, or Sponsor, 
or family members of enrolled patients living in the same house. 
5.3 
LIFESTYLE CONSIDERATIONS  
5.3.1 Meals and dietary restrictions  
There are no dietary restrictions in this study. 
5.3.2 Caffeine, alcohol, and tobacco  
Patients will be excluded from the study if there is a history of chronic alcohol abuse within 
6 months prior to the first study intervention administration. 
5.3.3 Activity  
Given that natural outdoor ultraviolet (UV) exposure can help treat AD lesions, patients must 
limit excessive UV exposure when possible (including refraining from suntanning) and should use 
sunblock SPF 30 or above when outdoor activities are planned. 
Patients must keep the topical gel on the skin for at least 4 hours after application of study 
intervention by refraining from swimming, bathing, using a sauna, or washing the treated areas. 
After applying the topical gel, patients should avoid wiping the study intervention off the area 
or covering the treated areas with wraps or bandages. To avoid ingestion of study intervention, 
wash hands immediately after application of topical gel, and avoid putting hands in mouth. 
5.4 
SCREEN FAILURES  
Screen failures are defined as patients who consent to participate in the study but are subsequently 
not enrolled. A minimal set of screen failure information is required to ensure transparent 
reporting of screen failure patients. Minimal information includes informed consent, demography, 
eligibility criteria, and any concomitant medications and AEs. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ADMINISTRATION OF STUDY 
INTERVENTION   
Not applicable. 
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6 
STUDY INTERVENTION AND CONCOMITANT THERAPY  
Study intervention is defined as any investigational intervention(s), marketed product(s), or 
placebo intended to be administered to a study patient according to the study protocol. 
6.1 
STUDY INTERVENTION (S) ADMINISTERED  
Table 4 - Study intervention  
 
PRN473 
Placebo 
Drug Name 
PRN473 Gel, 5% 
PRN473 Gel, Placebo 
Type  
Drug 
Placebo 
Dose Formulation 
White to off-white gel suspension 
containing PRN473, inactive 
ingredients (propylene glycol, 
glycerin, polysorbate 80, medium 
chain triglycerides, Carbopol 980, 
preservatives [methylparaben 
and propylparaben], and water). The 
gel suspension is adjusted to pH 5. 
White to off-white gel suspension 
containing the same inactive 
ingredients, except that titanium 
dioxide used to match the color of 
PRN473 active ingredient. 
Unit Dose Strength(s) 
5% (w/w) 
0% 
Dosage Level(s) 
5% (w/w) gel at 2.5 mg gel/cm2 over 
100 cm2 BID (Blinded Period) or up to 
14% BSA BID (Open-Label Period)  
Matching placebo at 2.5 mg gel/cm2 
over 100 cm2 BID (Blinded Period) 
Route of Administration 
Topical 
Topical 
Use 
Experimental 
Experimental 
IMP or NIMP 
IMP 
IMP 
Sourcing 
Provided centrally by the Sponsor 
Provided centrally by the Sponsor 
Packaging and Labeling 
PRN473 Gel products are filled into 
aluminum tubes (approximately 30 g 
in each aluminum tube). 
Placebo Gel products are filled into 
aluminum tubes (approximately 30 g 
in each aluminum tube). 
Former Name(s) or Alias(es) 
SAR444727 
not applicable 
Abbreviations: API = active pharmaceutical ingredient; IMP = investigational medicinal product; NIMP = non-investigational 
medicinal product. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
The Sponsor will supply the study intervention to the study site. The study intervention provided 
for this study was manufactured under Current Good Manufacturing Practices (CGMP) 
and will be suitable for human use. The Sponsor is responsible for the preparation and labelling 
and providing details of batch numbers, safety, and stability data. The study intervention will be 
labelled in accordance with local regulatory requirements and will be shipped at a temperature of 
2-8oC. 
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The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention. The recommended storage condition is 2-8°C 
(Investigator’s Brochure). 
Only patients enrolled in the study may receive study intervention, and only authorized study staff 
(eg, site staff, trained medical professional, home health vendor, external clinic staff, etc) may 
supply or administer study intervention during the Blinded Period. At the study site, all study 
intervention must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to the 
Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). When the study is completed, the 
Investigator will return or destroy any used and unused trial medication (eg, empty, partially used, 
and unused containers) to the Sponsor as requested. 
The Investigator or designee is responsible for the education of site staff as to the correct 
administration of the study intervention.  
When operationally feasible and if treating physician determines that it is appropriate and safe, 
administration of IMP may occur at study patient’s home or at an external clinic by a trained 
medical professional. These approaches will only be implemented if allowed by local regulations, 
and agreed by the treating physician, while ensuring blinding measures are maintained.  
Patients are required to apply an emollient (except urea-containing or medicated emollients that 
are regulated as medical device) daily from Day -7 to Day 1. Beginning on Day 1, emollient is to 
be applied only on untreated areas (eg, may not be used on the 2 target lesions during Days 1-14, 
and may not be used on any parts of the body being treated with PRN473 Gel, 5% during 
Days 15-42). 
PRN473 Gel, 5% or matching placebo will be removed from storage at 2-8°C and held at room 
temperature for at least 30 minutes prior to administration. Site staff or trained medical 
professional will apply PRN473 Gel, 5% or matching placebo with nitrile gloves to the 2 target 
lesions per the randomization assignment, as follows: 
• Approximately 2.5 mg gel/cm2 to each 100 cm2 target lesion on Days 1-14. If the target 
lesion is less than 100 cm2, the application area should include surrounding nonlesional 
skin; if the target lesion is larger than 100 cm2, only 100 cm2 of the lesion should be 
marked and treated.  
• On Days 15-42 (open-label period), patients are instructed to apply PRN473 Gel, 5% BID 
to all AD-affected areas in a thin layer, excluding the scalp, palms, soles, and genitals. 
Under no circumstances will the Investigator supply study intervention to a third party (except for 
direct to patient [DTP] shipment or direct to designated clinic for home health care option if 
patient is not able to be dosed at home, for which a courier company has been approved by the 
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Sponsor), allow the study intervention to be used other than as directed by this clinical trial 
protocol, or dispose of study intervention in any other manner.  
Intervention units are returned by the patient at each visit. In case of DTP process, the intervention 
units can be returned by the carrier (if defined in the contract).  
Further details will be outlined in the Pharmacy Manual. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
PRN473 Gel, 5% or placebo will be randomized in a blinded fashion to be administered in each 
patient to 2 separate target lesions (one lesion with PRN473 Gel, 5%, the other with matching 
placebo) during the Blinded Period (Days 1-14). During the Open-Label Period (Days 15-42), 
PRN473 will be administered to all AD-affected areas in a thin layer, excluding the scalp, palms, 
soles, and genitals. 
To minimize bias, all safety and efficacy measurements will be performed by a study staff 
member who is not involved in the study intervention application during the Blinded Period. If the 
investigational products are applied at the patient’s home or at an external clinic, the local 
tolerability assessment will be performed by another trained medical professional, different than 
the person administering the study intervention. 
Allocation of lesions on patients to treatment group will proceed through the use of an interactive 
web response system (IWRS) that is accessible 24 hours a day, 365 days a year. A randomized 
treatment kit number list will be generated centrally by Sanofi for the study interventions. The 
study interventions (PRN473 Gel, 5% or matching placebo) will be packaged in accordance with 
the list. All patients will be centrally assigned to randomized study intervention using an 
interactive response technology (IRT). Before the study is initiated, the telephone number and 
call-in directions for the IVRS and/or the log in information and directions for the IWRS will be 
provided to each site. During the Blinded Period of the study, the treatment each patient receives 
will not be disclosed to the Investigator, trial center personnel, patients, or the Sponsor’s 
representatives on the clinical study team. Further details for blinding and dispensing of blinded 
treatment are provided in the Pharmacy Manual.  
Access to the randomization code will be limited; all Sponsor personnel (and representatives), and 
site personnel who are directly involved in the conduct of the trial will be blinded to 
randomization codes. 
The pharmacist or designee will be required to enter or select information that will include, but 
not be limited to; the user ID, and password, patient number, patient year of birth, as well as other 
information (as allowed locally). The pharmacist or designee will then be provided with a patient 
randomization number and treatment assignment. Once patient numbers and randomization 
numbers have been assigned, they cannot be reassigned. Specific instructions will be provided in 
the IWRS trial reference guide.  
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Study intervention will be dispensed at the study visits summarized in the Schedule of Activities. 
Returned study intervention should not be re-dispensed to the patients. 
Sponsor safety staff may unblind the intervention assignment for any patient with an SAE. 
If the SAE requires that an expedited regulatory report be sent to one or more regulatory agencies, 
a copy of the report, identifying the patient’s intervention assignment, may be sent to Investigators 
in accordance with local regulations and/or Sponsor policy.  
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
Investigator has the sole responsibility for determining if unblinding of a patient’s intervention 
assignment is warranted (eg, in case of available antidote). Patient safety must always be the first 
consideration in making such a determination. If the Investigator decides that unblinding is 
warranted, the Investigator should make every effort to contact the Sponsor prior to unblinding 
a patient’s intervention assignment unless this could delay emergency treatment of the patient. If a 
patient’s intervention assignment is unblinded, the Sponsor must be notified within 24 hours after 
breaking the blind. The date and reason that the blind was broken must be recorded in the source 
documentation and case report form, as applicable. 
• In case of an interim analysis, the Sponsor team that will analyze the data would be 
composed of a Medical Monitor, a biostatistician, a programmer, and a safety designee. 
Only the biostatistician and the programmer will have the access to unblinded individual 
data at the time of the analysis, which will not be provided to other Sponsor team members 
reviewing the data. They will keep the randomization schedule in a locked area, which is 
not accessible to the Sponsor’s clinical team and will not disclose the randomization or the 
individual unblinded data before the official opening of the randomization (see 
Section 9.5).  
• The bioanalyst and the pharmacokineticist responsible for the sample analysis and PK 
evaluation will analyze data under blinded conditions and they will not have access to the 
randomization schedule. 
The Sponsor’s clinical study team, Investigator, Medical Monitor, study personnel, and patients 
are not to make any effort during the Blinded Period to determine which lesions are being treated 
with PRN473 Gel, 5%, and which are treated with matching placebo. 
Only in the case of an emergency, when knowledge of the lesion treatment assignment is essential 
for the clinical management or welfare of a specific patient, the Investigator may unblind a 
patient’s lesion treatment assignment. However, prior to any unblinding, the Investigator is 
strongly advised to discuss options with the Medical Monitor, Sponsor, or appropriate study 
personnel. The Investigator will record in source documentation, the date and reason for revealing 
the blinded lesion treatment assignment for that patient and the names and roles of personnel 
unblinded. 
As soon as possible, and without revealing the patient’s lesion treatment assignment (unless 
important to the safety of patients remaining in the study), the Investigator must notify the 
Sponsor if the blind is broken for any reason and the Investigator was unable to contact the 
Sponsor prior to unblinding.  
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If the Investigator considers an AE to be of such severity as to require immediate specific 
knowledge of the identity and dose of the relevant product, the Investigator may break the study 
code for that patient.  
6.4 
STUDY INTERVENTION COMPLIANCE  
Study intervention will be administered under site staff or trained medical professional 
supervision during the Blinded Period. The date and time of each dose administered at the study 
site, at patient’s home, or at external clinic will be recorded. The dose of study intervention and 
patient identification will be confirmed at the time of dosing by site staff or trained medical 
professional other than the person administering the study intervention. Documentation will 
include the lesion identification for the patient’s 2 target lesions.  
During the Open-Label Period, patients will complete a daily diary to record PRN473 
administered. 
6.5 
DOSE MODIFICATION  
No dose modifications will be permitted. 
6.6 
CONTINUED ACCESS TO STUDY INTERVENTION AFTER THE END OF 
STUDY  
PRN473 will not be provided to patients after completion of the study. 
6.7 
CONCOMITANT THERAPY  
All medications, including over-the-counter (OTC) medications, vitamins, and herbal 
supplements, taken during the 30 days prior to the first study intervention administration will be 
recorded and reviewed by the Investigator to determine whether the patient is suitable for 
inclusion in the study.  
All medications, and vaccines including OTC medications, vitamins, and herbal supplements, 
taken by patients during the course of the study will be recorded in the electronic case report form 
(eCRF) and coded using the most current World Health Organization (WHO) drug dictionary. 
Prior and concomitant medications will be listed by patient and summarized by anatomical 
therapeutic chemical (ATC) and preferred name. Any concomitant medication that the patient 
receives to treat an AE during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
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6.7.1 COVID-19 vaccination  
To allow for an optimal immune response as well as protection against COVID-19, it is strongly 
recommended that study patients receive their COVID vaccine (per local requirements) a 
minimum of 14 days prior to receiving the first dose of study medication. The safety profile and 
effectiveness of COVID-19 vaccines on people with compromised immune systems or therapies 
that modify or that suppress their immune response, is not yet established. While vaccination with 
an approved COVID-19 vaccine is widely recommended, this decision should only be made by 
the patient, after discussing with his/her physician as well as the investigator to assess the benefits 
and risks of receiving a COVID-19 vaccination during this study. If the vaccine is authorized, 
available, and recommended by the local regulatory health authority, it may be administered 
during the study and should be administered according to the label or local health authority 
recommendations. 
6.7.2 Prohibited medications  
Excluded medications and treatments with the applicable washout period prior to Baseline are 
listed in Table 5. 
Table 5 - Excluded medications and treatments  
Excluded Medications and Treatments 
Washout Period Prior to Baseline 
Rituximab or anti-CD-20-targeted therapies 
12 months 
Other biologics including dupilumab and investigational 
biologics  
12 weeks or 5 half-lives, whichever is longer 
JAK-inhibitors and investigational JAK-inhibitors 
8 weeks or 5 half-lives, whichever is longer 
Systemic treatments that could affect AD (eg, corticosteroids, 
retinoids, calcineurin inhibitors, hydroxycarbamide 
[hydroxyurea], methotrexate, cyclosporine, azathioprine, 
hydroxychloroquine, mycophenolate mofetil, or other 
immunosuppressive therapies, or systemic treatment with 
non-sedating antihistamines in a nonstable regimen). Systemic 
treatments with non-sedating antihistamines in a stable regimen 
are allowed. 
4 weeks or 5 half-lives, whichever is longer 
PUVA or NBUVB phototherapy 
4 weeks 
Topical products containing urea 
1 week 
Sedating antihistamines and doxepin 
1 week 
Topical corticosteroids, calcineurin inhibitors, or crisaborole. 
Topical antibacterial medications or products, including soaps, 
dilute bleach baths, or sodium hypochlorite-based products 
anywhere on the body. 
4 weeks  
Systemic antibiotics 
2 weeks 
Tanning beds, other light emitting devices  
4 weeks  
All other investigational drugs 
4 weeks or 5 half-lives, whichever is longer 
Any live vaccines 
12 weeks 
 
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Note:  
Topical antibiotics, topical antihistamines, or any other topical agents are not permitted to be applied to treated areas. Only 
study intervention should be applied to treated areas. 
6.7.3 Permitted medications  
Use of hormonal contraception is allowed prior to and during the study.  
The Medical Monitor should be contacted if there are any questions regarding concomitant 
or prior therapy.  
Non-medicated emollients, moisturizers, and sunscreens will be permitted once daily in a stable 
regimen as normally used by the patients and applied at least 2 hours after application of 
randomized study intervention to untreated areas only (topical agents are not permitted to be 
applied to treated areas; only study intervention should be applied to treated areas). 
6.7.4 Rescue medicine  
Rescue topical medications use will be at the discretion of the Investigator after discussion with 
the Medical Monitor if the patient is flaring above 14% treatable BSA (excluding scalp, palms, 
soles and genitalia) during the last two weeks of the Open Label Period. Investigators should 
make every attempt to conduct efficacy and safety assessments (eg, disease severity scores, safety 
labs) immediately before administering any rescue treatment. An unscheduled visit may be used 
for this, if necessary. Patients who receive rescue treatment will be asked to continue with study 
treatment and procedures.  
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7 
DISCONTINUATION OF STUDY INTERVENTION AND PATIENT 
WITHDRAWAL  
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
7.1.1 Permanent discontinuation  
In rare instances, it may be necessary for a patient to permanently discontinue study intervention. 
If study intervention is permanently discontinued, the Investigator must discuss with the Medical 
Monitor to determine if the patient will be asked to continue with PK sample collection 
(if applicable and depending upon the study day on which the discontinuation occurs), 
and have early termination safety assessments (Day 43). See the Schedule of Activities in 
Section 1.3. 
Patients who are enrolled but who do not receive any dose of study intervention will be replaced. 
Patients may be replaced at the discretion of the Sponsor.  
The Investigator/Sponsor must permanently discontinue dosing with study intervention in a 
patient if any of the following patient-level stopping rules are met:  
• Pregnancy will lead to definitive study intervention discontinuation in all cases.  
• Change in compliance with inclusion/exclusion criteria that is clinically relevant and 
affects patient’s safety. 
• Intake of non-permitted concomitant medications that might affect patient’s safety or 
study assessments/objectives. 
• An allergic reaction, including an anaphylactic reaction, in association with IMP 
administration. 
• Occurrence of AEs, that, in the opinion of Investigator/Sponsor, may jeopardize patient’s 
safety or data integrity. These include, but are not limited to 
- 
Any opportunistic infection, such as TB or other infections whose nature or course 
may suggest an immunocompromised status. 
- 
Serum ALT >5 × ULN or ALT >3 × ULN and total bilirubin >2 ULN (see 
Section 10.3). 
Any clinically significant abnormal laboratory value, as assessed by the investigator, will be 
rechecked for confirmation as soon as possible before making a decision of definitive 
discontinuation of the IMP for the concerned patient. 
Handling of patients after permanent intervention discontinuation  
Patients will be followed-up according to the study procedures specified in this protocol up to the 
scheduled date of study completion, or up to recovery or stabilization of any AE to be followed-
up as specified in this protocol, whichever comes last. 
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If possible, and after the permanent discontinuation of intervention, the patients will be assessed 
using the procedure normally planned for the last dosing day with the IMP including a 
pharmacokinetics sample, if appropriate. 
All cases of permanent intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed. 
7.1.2 Liver chemistry stopping criteria  
Discontinuation of study intervention for abnormal liver tests is required by the Investigator when 
a patient meets one of the conditions outlined in Appendix 3 (Section 10.3) or in the presence of 
abnormal liver chemistries not meeting protocol-specified stopping rules if the Investigator 
believes that it is in best interest of the patient. 
7.1.3 QTc stopping criteria  
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QT interval corrected using Fridericia’s formula [QTcF] after enrollment, the Investigator or 
qualified designee will determine if the patient can continue in the study and if any change in 
patient management is needed. This review of the ECG printed at the time of collection must be 
documented. Any new clinically relevant finding should be reported as an AE. 
7.1.4 Hematology stopping criteria  
Discontinuation of study intervention for abnormal neutrophil or platelet tests is required by the 
Investigator when a patient meets one of the conditions outlined in Appendix 3 (Section 10.3) or 
in the presence of abnormal results not meeting protocol-specified stopping rules if the 
Investigator believes that it is in best interest of the patient. 
7.2 
PATIENT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
A patient may withdraw from the study at any time at his/her own request or may be withdrawn at 
any time at the discretion of the Investigator or Sponsor for safety, behavioral, or compliance 
reasons. 
The patient may be discontinued from the study intervention but continue in the study for PK 
sample collection (if applicable) and follow-up visits. 
At the time of discontinuation, the patient should have early termination safety assessments 
(Day 43). See the Schedule of Activities in Section 1.3. 
If the patient withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
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If a patient withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
7.3 
LOST TO FOLLOW-UP  
A patient will be considered lost to follow-up if he or she is unable to be contacted by the study 
site, and the following actions must be taken: 
• The site must attempt to contact the patient and reschedule the End of Study/Early 
Termination visit as soon as possible, counsel the patient on the importance of 
participating, and ascertain whether or not the patient wishes to participate. 
• Before a patient is deemed lost to follow-up, the Investigator or designee must make every 
effort to regain contact with the patient (where possible, 3 telephone calls 
and, if necessary, a certified letter to the patient's last known mailing address or local 
equivalent methods). These contact attempts should be documented in the patient’s 
medical record. 
• Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of the study as a whole is described in Section 10.1.7. 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
Study procedures and their timing are summarized in the Schedule of Activities in Section 1.3. 
Protocol waivers or exemptions are not permitted. 
Immediate safety concerns should be discussed with the Medical Monitor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study 
intervention. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients meet 
all eligibility criteria. Patients are permitted to be re-screened once. The Investigator will maintain 
a screening log to record details of all patients screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
Procedures conducted as part of the patient's routine clinical management (eg, blood count) 
and obtained before signing of the informed consent form (ICF) may be utilized for screening 
or baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the Schedule of Activities. 
The maximum amount of blood collected from each patient over the duration of the study, 
including any extra assessments that may be required, will not exceed 550 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
8.1 
EFFICACY ASSESSMENTS  
Efficacy assessments will be performed per the Schedule of Assessments in Section 1.3: 
• Lesional PP-NRS is a patient-completed assessment to determine the intensity of lesion 
pruritus. 
• Lesional validated IGA is an Investigator assessment of the 2 target lesions during the 
Blinded Period and predose at D15 during the Open-Label Period. 
• Eczema Area and Skin Severity Index (EASI) is a validated Investigator-administered 
scoring system used to measure the severity of clinical signs in AD. 
• Validated Investigator Global Assessment-Atopic Dermatitis (vIGA-AD; Appendix 4, 
Section 10.4.2) is an Investigator assessment of the global severity of clinical signs in AD. 
• Lesion TSS (Appendix 4, Section 10.4.3) is a scale that rates the severity of each of 4 AD 
symptoms (erythema, induration/papulation, excoriation, and lichenification) on a 4-point 
scale from 0 (none) to 3 (severe), for a total score ranging from 0 to 12. 
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• SCORing atopic dermatitis (SCORAD) is a clinical tool used to assess AD by intensity, 
extent, and subjective signs. 
• Peak Pruritus Numeric Rating Scale (PP-NRS) is a patient-completed assessment to 
determine the intensity of peak pruritus over the previous 24 hours. 
• Patient-Oriented Eczema Measure (POEM) is a validated, patient-derived assessment 
measure for monitoring atopic eczema severity. 
• Dermatology Life Quality Index (DLQI) is a validated, self-administered questionnaire 
designed to measure the health-related quality of life of adult patients suffering from a skin 
disease. 
• Estimation of treatable BSA. 
8.2 
SAFETY ASSESSMENTS  
Safety will be assessed by means of application site tolerability assessments (Appendix 4, 
Section 10.4.1), occurrence of AEs, clinical laboratory tests (serum chemistry, hematology, 
coagulation, urinalysis), vital signs measurements, 12-lead ECGs, and physical examinations. 
Planned timepoints for all safety assessments are provided in the Schedule of Activities in 
Section 1.3. 
8.2.1 Physical examinations  
A complete physical examination includes, at a minimum: assessments of the abdomen, chest, ear, 
head and neck, heart, lower limb, upper extremity, lung, musculoskeletal, neurological, rib, skin, 
thoracic vertebra, lumbar spine, and cervical vertebra. Height (only at screening) and weight will 
also be measured and recorded. 
A symptom-directed physical exam is to be performed as clinically indicated at visits when 
a complete examination is not specified. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.2.2 Vital signs  
Vital signs will be measured at the timepoints specified in the study schedule with patients resting 
for at least 5 minutes in a supine position. When the time of vital signs measurement coincides 
with a blood draw, the vital signs will be taken before the scheduled blood draw where possible, 
ensuring the blood draw is within the window specified. 
Additional vital sign measurements may be performed at other times if deemed necessary. 
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8.2.3 Electrocardiograms  
A 12-lead ECG will be performed at the timepoints indicated in the study schedule. Additional 
ECG monitoring may be conducted at other times as deemed necessary. Refer to Section 7.1.3 for 
QTc withdrawal criteria and any additional QTc readings that may be necessary. 
The ECGs will be performed prior to vital signs with patients in a supine position. Patients must 
remain in this position for at least 5 minutes before the reading is taken. All ECG tracings will be 
reviewed by the Investigator or designee.  
When the time of ECG monitoring coincides with a blood draw, the ECG will be performed 
before the scheduled blood draw while ensuring the blood draw is within the window specified in 
the protocol. 
A repeat ECG can be performed if results are abnormal. 
8.2.4 Clinical safety laboratory assessments  
See Section 8.2.4.1 for the list of clinical laboratory tests to be performed and the Schedule 
of Activities in Section 1.3 for the timing and frequency. 
The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports must be 
filed with the source documents. 
Abnormal laboratory findings associated with the underlying disease are not considered clinically 
significant unless judged by the Investigator to be more severe than expected for the patient's 
condition.  
Any treatment-emergent abnormal laboratory or ECG result that is clinically significant 
(ie, meeting one or more of the following conditions) should be recorded as a single diagnosis on 
the AE page in the eCRF: 
• Accompanied by clinical symptoms 
• Leading to a change in study intervention (eg, dose modification, interruption, or 
permanent discontinuation) 
• Requiring a change in concomitant therapy (eg, addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy, 
or treatment) 
Note: Any laboratory or ECG result abnormality fulfilling the criteria for a SAE must be 
reported as such, in addition to being recorded as an AE in the eCRF. 
The laboratory reports must be filed with the source documents. 
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Abnormal laboratory findings associated with the underlying disease are not considered clinically 
significant unless judged by the Investigator to be a more severe variation in patient's disease 
activity than expected. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 4 weeks after the last dose of study intervention should be repeated until the 
values return to normal or baseline or are no longer considered clinically significant by the 
Investigator or Medical Monitor. 
If clinically significant values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the Sponsor notified. 
All protocol-required laboratory tests, as defined in Section 8.2.4.1, must be conducted in 
accordance with the laboratory manual and the Schedule of Activities. 
If laboratory values from non-protocol-specified laboratory tests performed at the institution's 
local laboratory require a change in patient management or are considered clinically significant by 
the Investigator (eg, SAE or AE or dose modification), the results must be recorded. 
8.2.4.1 Clinical laboratory tests  
The tests detailed in Table 6 will be performed. Investigators must document their review of each 
laboratory safety report. Additional tests may be performed at any time during the study as 
determined necessary by the Investigator or required by local regulations. 
Table 6 - Laboratory tests  
Laboratory Test 
Parameters 
Hematology 
Hemoglobin  
Hematocrit 
Red blood cell (RBC) count including: 
• 
reticulocyte % 
Platelet Count 
White blood cell (WBC) count with 
differential: 
• 
Neutrophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Eosinophils 
• 
Basophils  
Coagulation 
International Normalized Ratio (INR) 
Activated partial thromboplastin time 
(aPTT) 
Clinical Chemistry a 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Gamma-GT (GGT) 
Total and direct bilirubin 
Alkaline phosphatase (ALP) b 
Creatinine 
Blood urea nitrogen (BUN)/Albumin 
Bicarbonate 
 
Sodium 
Potassium 
Calcium 
Chloride 
Phosphate 
Glucose (fasting labs only) 
C-reactive protein 
Creatine kinase (CK) w/h reflex 
Troponin I >ULN 
Lactate dehydrogenase (LDH) 
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Laboratory Test 
Parameters 
Routine Urinalysis 
Specific gravity, pH, glucose, protein, occult blood, ketones, urobilinogen, nitrite, 
leukocytes 
Pregnancy testing 
Highly sensitive serum (at the Screening visit) or urine (Day 1, Day 29, End of Study 
visits) human chorionic gonadotropin (hCG) pregnancy test (as needed for women of 
childbearing potential) c 
Other Screening 
Tests 
• 
Follicle-stimulating hormone (as needed in post-menopausal women of 
non-childbearing potential only) 
• 
Serology (HIV, hepatitis B [surface antigen and core antibodies], hepatitis C 
[anti-HCV antibody confirmed with Hepatitis C RNA]) 
• 
Tuberculosis test (interferon-gamma release assay [IGRA]) 
a Details of liver chemistry stopping criteria and required actions and follow-up are given in Section 7.1.2 Liver Chemistry Stopping 
Criteria and Appendix 5 Liver and other safety: suggested actions and follow-up assessments. All events which may indicate severe 
liver injury (possible Hy’s Law) must be reported to Sponsor in an expedited manner (excluding studies of hepatic impairment or 
cirrhosis). 
b If alkaline phosphatase is elevated, consider fractionating. 
c Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
8.2.5 Pregnancy testing  
• Refer to Section 5.1 Inclusion criteria for pregnancy testing criteria; the Investigator is 
responsible for review of medical history, menstrual history, and recent sexual activity to 
decrease the risk for inclusion of a female patient with an early undetected pregnancy. 
• Pregnancy testing (urine or serum as required by local regulations) should be conducted at 
study visits accordingly to the SoA (Section 1.3). 
• Pregnancy testing (urine or serum as required by local regulations) must be conducted 
corresponding with the time frame for female patient contraception in Section 5.1 
Inclusion criteria. 
• Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the investigator or required by local regulation, to establish the absence of pregnancy at 
any time during the patient’s participation in the study. 
8.2.6 Local Cutaneous Tolerability  
Grading of application site local tolerability symptoms will be recorded using the grading scale 
(Appendix 4, Section 10.4.1) following each dosing during the blinded period. Each target lesion 
will be graded within approximately 30 minutes after dosing by site staff or trained medical 
professional and a record of the worst symptom grade during time period will be recorded. During 
the Open Label period symptom grading will record worst symptom observed on the lesional 
areas treated within approximately 30 min after dosing. 
8.3 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS AND OTHER SAFETY 
REPORTING  
The definitions of AEs and SAEs can be found in Section 8.3.1. 
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AE will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the patient’s 
legally authorized representative).  
The Investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or study 
procedures, or that caused the patient to discontinue the study intervention (see Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Section 8.3.1. 
8.3.1 AEs and SAEs: Definitions and procedures for recording, evaluating, follow-up, and 
reporting  
8.3.1.1 Definition of AE  
AE Definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events Meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease): 
- 
Symptomatic and/or 
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to study intervention discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
• Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
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• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
Events NOT Meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the patient’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the patient’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social 
and/or convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
8.3.1.2 Definition of SAE  
An SAE is defined as any AE that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the patient has been admitted (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as 
to whether “hospitalization” occurred or was necessary, the AE should be considered 
serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d) Results in persistent or significant disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
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- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) Other situations: 
- 
Medical or scientific judgment should be exercised by the Investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant medical 
events that may jeopardize the patient or may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
Note: The following list of medically important events is intended to serve as 
a guideline for determining which condition has to be considered as a medically 
important event. The list is not intended to be exhaustive:  
- 
Intensive treatment in an emergency room or at home for:  
- 
Allergic bronchospasm   
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc) 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc) 
- 
Development of drug dependence or drug abuse  
- 
Suicide attempt or any event suggestive of suicidality  
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling)  
- 
Bullous cutaneous eruptions   
8.3.1.3 Recording and follow-up of AE and/or SAE  
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the Investigator to send photocopies of the patient’s medical 
records to the Sponsor’s representative in lieu of completion of the required form. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor’s representative. In this case, all patient identifiers, with the exception of the 
patient number, will be redacted on the copies of the medical records before submission to 
the Sponsor’s representative. 
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• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
• Mild: An event that is easily tolerated by the patient, causing minimal discomfort and not 
interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort to interfere with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. “Severe” is a category used for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of Causality 
• The Investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than that a relationship cannot 
be ruled out. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the Investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to the Sponsor. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
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Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor’s 
representative to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a patient dies during participation in the study or during a recognized follow-up period, 
the Investigator will provide the Sponsor with a copy of any post-mortem findings 
including histopathology. 
• New or updated information will be recorded in the originally submitted documents. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
8.3.1.4 Reporting of SAEs  
SAE reporting to the Sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor’s representative will be the 
electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study patient or receives updated data on 
a previously reported SAE after the electronic data collection tool has been taken off-line, 
then the site can report this information on a paper SAE form (see next section) or to the 
Sponsor’s representative by telephone. 
• Contacts for SAE reporting can be found in the study reference manual. 
SAE reporting to the Sponsor via paper data collection tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the Sponsor’s representative. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE data collection tool within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the study reference manual. 
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8.3.2 Time period and frequency for collecting AE and SAE information  
All AEs (serious or nonserious) will be collected from the signing of the ICF until the follow-up 
visit at the timepoints specified in the Schedule of Activities (Section 1.3). 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 8.3.1. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion 
of the study participation. However, if the Investigator learns of any SAE, including a death, 
at any time after a patient has been discharged from the study, and he/she considers the event 
to be reasonably related to the study intervention or study participation, the Investigator must 
promptly notify the Sponsor. 
8.3.3 Method of detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the patient is the preferred method to inquire about AE 
occurrences. 
8.3.4 Follow-up of AEs and SAEs  
After the initial AE /SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. At the pre-specified study end-date, all SAEs, and will be followed 
until resolution, stabilization, the event is otherwise explained, or the patient is lost to follow-up 
(as defined in Section 7.3). Further information on follow-up procedures is provided in 
Section 8.3.1. 
8.3.5 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of 
a study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Serious adverse events that are considered expected will be specified in the reference 
safety information in the Investigator’s Brochure.  
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
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• An Investigator who receives an Investigator safety report describing an SAE, SUSAR, or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. It is the responsibility of the 
Sponsor to assess whether an event meets the criteria for a SUSAR, and therefore, is 
expedited to regulatory authorities. 
8.3.6 Pregnancy  
• Details of all pregnancies in female patients and female partners of male patients will be 
collected after the start of study intervention and through 30 days after the final dose of the 
study intervention. 
• If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of learning of the female 
patient or female partner of male patient (after obtaining the necessary signed informed 
consent from the female partner) pregnancy. 
- 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such 
• The patient/pregnant female partner will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the patient/pregnant 
female partner and the neonate, and the information will be forwarded to the Sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.5. While the Investigator is not obligated to actively seek this information in 
former study patient/pregnant female partner, he or she may learn of an SAE through 
spontaneous reporting. 
• Any female patient who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
8.3.7 Expedited reporting requirements   
The AEs below will be recorded and reported to the Sponsor or designee immediately and under 
no circumstance should this exceed 24 hours. Such events may require further investigation in 
order to characterize and understand them.  
• Symptomatic overdose (serious or nonserious) with study intervention  
- 
An overdose (accidental or intentional) with the study intervention is an event 
suspected by the Investigator or spontaneously notified by the patient (not based on 
study intervention tube weight) and defined as greater than twice the intended dose 
within the intended therapeutic interval, adjusted according to the tested drug. 
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• Elevation of liver enzymes as below (see Appendix 3, Section 10.3 for flow chart of 
required activities)  
- 
ALT >3 × upper limit of normal (ULN)  
• If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of learning of the pregnancy 
(see Section 8.3.6). 
8.3.8 Guidelines for reporting product complaints  
Any defect in the study intervention must be reported as soon as possible by the Investigator to 
the monitoring team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels, or documents like pictures or photocopies) 
related to product identification and to the potential deficiencies may need to be gathered. 
The Investigator will assess whether or not the quality issue has to be reported together with 
an AE or SAE. 
8.4 
PHARMACOKINETICS  
Blood samples of approximately 4 mL per sample will be collected for measurement of plasma 
concentrations of PRN473 as specified in the Schedule of Activities in Section 1.3. Venipuncture 
should not occur within a treated area. 
Instructions for the collection and handling of biological samples will be provided by the Sponsor. 
The actual date and time (24-hour clock time) of each sample will be recorded. 
The actual collection time of each sample must be recorded in the source data documentation, and 
in the eCRF. The allowed time deviation window before a deviation is recorded for blood sample 
collection post dose is 15 minutes for timepoints up to and including 6 hours postdose; predose 
samples should be collected within 30 minutes prior to the next application of study intervention . 
Samples will be used to evaluate the PK of PRN473. Samples collected for analyses of PRN473 
plasma concentration may also be used to evaluate safety or efficacy aspects related to concerns 
arising during or after the study. Pharmacokinetic endpoints are listed in Section 3. 
After the blood samples are analyzed for plasma PRN473 concentrations, any residual samples 
may be used for analysis such as metabolite profiling and identification, interacting drug 
concentration measurements, ex vivo protein binding, or development of PK assays. Residual PK 
samples will be destroyed within 1 month of withdrawal of consent. Residual PK samples will be 
stored for 5 years after the final Clinical Study Report, at which point they will be destroyed. 
Genetic analyses will not be performed on these samples. Patient confidentiality will be 
maintained.  
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8.5 
GENETICS AND/OR PHARMACOGENOMICS  
Genetics and/or pharmacogenomics will not be evaluated in this study. 
8.6 
BIOMARKERS  
Changes in protein and RNA expression, lymphocyte infiltration, and epidermal thickness 
following treatment with PRN473 will be evaluated using blood samples, skin tape stripping and 
skin biopsy. 
Changes in blood biomarkers will be assessed following treatment with PRN473. 
Future research may help further the understanding of disease subtypes, disease biology, related 
conditions, drug response and toxicity, and can help identify new drug targets or biomarkers that 
predict participant response to treatment. Therefore, data and biological samples will be stored 
and used for future research when consented to by participants (see Section 10.1.3) unless 
prohibited by local laws or IRBs/IECs (in such case, consent for future use of sample will not be 
included in the local ICF).  
For patients who consent to the storage and use of their data and remaining and/or extra clinical 
samples, data and samples may be used after the study ends for future research related either to 
the drug, the mechanism of action, and the disease or its associated conditions. Such research may 
include, but is not limited to, performing assessments on DNA, RNA, proteins, or metabolites. If 
future research on genetic material is performed, this will also be limited to the purpose of 
addressing research questions related to the drug, the mechanism of action, the disease, or its 
associated conditions. 
In the event future research is conducted for other purposes, the study patients will be informed of 
those purposes and will be given means to object to those research projects. 
Data and samples will be used in compliance with the information provided to patients in the ICF. 
All study patient data and samples will be coded such that no patient direct identifiers will be 
linked to them. Coded data and samples may be transferred to a Sponsor site (or a subcontractor 
site), which may be located outside of the country where the study is conducted. The Sponsor 
adopts safeguards for protecting patient confidentiality and personal data (see Section 10.1.4). 
The samples will be stored for a maximum of 15 years after the end of the study. Any samples 
remaining at the end of retention period will be destroyed. If a patient requests destruction of 
his/her samples before the end of the retention period, the Investigator must notify the Sponsor (or 
its contract organization) in writing. In such case, samples will be destroyed, and related coded 
data will be anonymized unless otherwise required by applicable laws. 
Study patient coded data will be stored for future research for up to 25 years after the end of the 
study. If data are still considered of important scientific value after this period, coded data already 
available will be anonymized unless otherwise required by applicable laws (the same will apply to 
the data of a study patient who has requested the destruction of his/her samples). 
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The patient’s coded data sets provided to researchers for a specific research project will be 
available to the researchers for a maximum of 2 years after the end of their specific project (end of 
project is defined by publication of the results or finalization of the future research project report). 
8.7 
IMMUNOGENICITY ASSESSMENTS  
Immunogenicity assessments will not be performed as part of this study. 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND 
HEALTH ECONOMICS  
Health Economics or Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
8.9 
LESION PHOTOGRAPHY  
Photographs will be used to document change/improvement in lesions, and to document biopsy 
location as detailed in the lab manual and will not be used to evaluate AEs.  
For the Blinded Period, photographs will be taken of the 2 target lesions at predose Baseline and 
Day 8. For the Open-Label Period, photographs of the 2 target lesions will be taken predose at 
Day 15, Day 29 and at Day 43. 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
No statistical hypotheses will be tested. 
9.2 
SAMPLE SIZE DETERMINATION  
No sample size calculations were performed due to the exploratory nature of this study. 
The sample size of up to 40 for this study with patients receiving both PRN473 Gel, 5% 
and placebo is based upon empirical clinical consideration. The sample size is considered 
adequate to evaluate the safety, tolerability, and PK of topically administered PRN473.  
This study is signal seeking and neither aimed nor powered to provide formal inferential statistical 
analyses. 
9.3 
ANALYSIS SETS  
For the purposes of analysis, the following analysis sets are defined: 
Table 7 - Analysis sets  
Patient Analysis Set 
Description 
Screened 
All patients who signed the ICF. 
Enrolled/Randomized 
All patients from the screened population who have been allocated to 
a randomized intervention by IRT regardless of whether the intervention was 
received. 
Safety 
All randomized patients who receive any amount of study intervention 
(PRN473 or placebo) will be included in the Safety population. The Safety 
population will be based on the intervention actually received and will be used 
for the summaries of all safety assessments.  
Pharmacokinetic 
All patients who received any amount of active study intervention (PRN473) 
and have at least one PK sample taken will be included in the PK population. 
The PK population will be used for the summaries of all PK data. 
ITT 
All randomized patients who did actually receive at least 1 complete dose of 
study intervention with at least 1 post-study intervention administration 
measurement, with available efficacy. 
Efficacy 
All randomized patients who did actually receive at least 80% of prescribed 
study intervention in the Blinded Period and/or at least 80% of prescribed 
study intervention in the Open-Label Period and with at least 1 post-study 
intervention administration efficacy measurement in the corresponding period, 
Patients will be analyzed according to the intervention they actually received.  
Biomarker 
All patients with no important deviations impacting Biomarker measurements, 
for whom the Biomarker data are considered sufficient and interpretable.  
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9.4 
STATISTICAL ANALYSES  
The Statistical Analysis Plan (SAP) will be issued prior to database lock and will include a more 
technical and detailed description of the statistical analyses and the tables and graphs described in 
this section.  
This section is a summary of the planned statistical analyses of the key endpoints. 
9.4.1 General considerations  
In general, descriptive statistics (ie, arithmetic mean, standard deviation [SD], median, minimum, 
and maximum) will be calculated for continuous valued measurements, for each treatment where 
appropriate. Changes and percent changes from baseline to each applicable scheduled post-
baseline timepoint will similarly be summarized by treatment where appropriate. Frequency 
summaries (ie, count and percentage of observations at each category level) will be applied for 
categorical data for each scheduled timepoint by treatment where appropriate. 
9.4.2 Endpoints  
Endpoints are listed in Table 3. 
9.4.3 Analysis of efficacy data  
Efficacy analyses will be based on the Efficacy population. A patient will be considered evaluable 
per endpoint and study period, if they receive at least 80% of prescribed study intervention in that 
period and have a post-baseline assessment of the corresponding endpoint for that period (ie, after 
Day 1 or after Day 15). 
Where appropriate, supplemental analyses will be presented excluding observations after 
administration of rescue medication. Imputation would then be performed for missing 
observations including those due to withdrawal due to lack of efficacy, as will be specified in the 
SAP. 
Efficacy analyses will be an early explorative assessment and performed without the aim of 
formal inferential statistics. No adjustment will be made for multiple analyses.  
Treatment differences or ratios will be assessed for PRN473 Gel, 5% versus placebo, mainly at 
Day 15. Data will be presented by treatment for the Blinded Period where assessed per lesion, and 
overall otherwise, as well as for the Open-Label Period. 
9.4.3.1 Lesion Total Sign Score (TSS)  
Main comparison for TSS will be the comparison between PRN473 Gel, 5% and placebo for 
change from Baseline to Day 15. 
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Change in TSS will be analyzed with a linear mixed effects model with fixed terms for treatment 
and with baseline TSS as a covariate 
Change in TSS = baseline TSS + treatment + error 
and with an unstructured matrix of treatment variances and covariance for patient, using SAS Proc 
Mixed®. In case of convergence problems, other variance-covariance structures will be explored. 
Baseline TSS will be defined as the mean TSS from the two treated lesions at baseline.  
The 95% Confidence Interval (CI) for the treatments effect will be obtained for the difference 
between treatment means within the linear mixed effects model framework. Additionally, 
80% CIs will be derived and presented.  
Descriptive statistics and graphical displays will be provided for all timepoints. 
Additional explorative analyses may be performed. 
9.4.3.2 Further efficacy endpoints during the blinded period  
Further efficacy endpoints during the blinded period will be summarized per treatment 
and timepoint: 
• Change from Baseline in daily lesional PP-NRS score up to Day 15 
• Change from Baseline in lesional validated IGA score at Days 8 and 15 
• Lesional validated IGA response (proportion of patients with a validated IGA score of 0 or 
1 and ≥2-grade improvement from Baseline) at Days 8 and 15 
Further explorative analyses may be performed. 
9.4.3.3 Eczema Area and Skin Severity Index (EASI)  
The following endpoints will be derived and analysed: 
• Change from Baseline in EASI at Days 29 and 43 
• Change from Day 15 in EASI to Days 29 and 43 
• Proportion of patients with EASI 50, EASI 75, and EASI 90 from Day 15 to Days 29 
and 43 
Changes in EASI from Day 15 to Day 29 and to Day 43 will be analyzed descriptively. 
Estimations with 95% and 80% CIs may be derived. Descriptive statistics and graphical displays 
will be provided per timepoint. 
Frequency tables will be provided for EASI 50, EASI 75, and EASI 90. 
Further explorative analyses may be performed.  
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9.4.3.4 Validated Investigator Global Assessment-Atopic Dermatitis (vIGA-AD)  
The proportion of patients achieving at least 2 grade reduction in vIGA-AD to clear (vIGA-AD 0) 
or almost clear (vIGA-AD 1) from Day 15 to Days 29 and 43 will be summarized. 
Further explorative analyses may be performed.  
9.4.3.5 Further efficacy endpoints during the open-label period   
Further efficacy endpoints during the open label period will be summarized per timepoint: 
• Change from Baseline in TSS for the 2 target lesions at Days 29 and 43. 
• Change in PP-NRS from Day 15 to Days 29 and 43 
• Proportion of patients achieving at least 3-point reduction from Day 15 in PP-NRS at 
Days 29 and 43 
• Proportion of patients achieving at least a 4-point reduction from Day 15 in PP-NRS 
at Days 29 and 43 
• Change from Day 15 in weekly mean of PP-NRS at Days 29 and 43 
• Change from Day 15 in SCORAD at Days 29 and 43 
• Change from Day 15 in percentage of treatable BSA at Days 29 and 43  
• Change from Baseline in POEM at Days 15, 29, and 43 
• Change from Baseline in DLQI at Days 15, 29, and 43 
9.4.4 Analysis of safety data  
The safety evaluation will be based upon the review of the individual values (clinically significant 
abnormalities), descriptive statistics (summary tables, figures) and, if needed, on statistical 
analysis (appropriate estimations, confidence intervals). No statistical significance tests will be 
performed on safety data. 
Potentially clinically significant abnormality (PCSA) values are defined as abnormal values 
considered medically important by the Sponsor, according to predefined criteria/thresholds based 
on literature reviews and defined by the Sponsor for clinical laboratory tests, vital signs, and ECG 
parameters. 
All the safety analyses will be performed based on the safety population. Where appropriate, 
supplemental analyses will be presented excluding observations after administration of rescue 
medication. 
For all safety data variables, the following observation periods are defined and used for 
classification of AEs, determination of on-treatment PCSA values, and the last on-treatment value 
for laboratory and vital sign parameters: 
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• The pre-treatment period is defined as the time between informed consent signature 
and the first study intervention administration. 
• The treatment-emergent period is defined as the time from the first study intervention 
administration through the End of Study visit.  
• The post treatment period is defined as the time starting after the treatment-emergent 
period. 
9.4.4.1 Assignment to treatment and study phase  
Safety data will be assigned to study phase as following: 
• Blinded Period, if the TEAE onset was between the first administration (Day 1) of any 
study intervention in the Blinded Period and the first administration of study intervention 
(PRN473 Gel, 5%) in the Open-Label Period (scheduled Day 15). 
• Open-Label Period, if the TEAE onset was after the first administration of study 
intervention (PRN473 Gel, 5%) in the Open-Label Period (scheduled Day 15).  
Adverse events which are possibly related to study intervention and have onset date after the first 
dose of PRN473 will be considered possibly related to PRN473, unless they are documented as 
possibly related to the study intervention formulation of the placebo-treated lesion and not 
possibly related to the study intervention formulation of the PRN473 Gel, 5%-treated lesion. 
Table 8 - Safety analysis  
Safety Measures 
Statistical Analysis Methods 
Adverse events  
• 
AEs  
• 
TEAEs  
• 
SAEs  
• 
AEs leading to study intervention or study 
discontinuation  
• 
AEs leading to death  
• 
PCSAs 
 
Treatment-emergent adverse event incidence tables 
will be presented by System Organ Class, high-level 
group term, high-level term, and Preferred Term for 
each study period and overall, showing the number (n) 
and percentage (%) of patients experiencing a TEAE.  
Multiple occurrences of the same event in the same 
patient will be counted only once in the tables. The 
denominator for computation of percentages will be the 
corresponding safety population. In addition, TEAEs 
will be described according to maximum intensity 
and relation to the study intervention.  
Adverse events that occur outside the treatment 
emergent period will be listed separately. 
Proportion of patients with at least 1 TEAE, 
treatment-emergent SAE, TEAE leading to death, 
and TEAE leading to definitive treatment 
discontinuation will be tabulated by study period 
and overall.  
The incidence of PCSAs occurring during the TE 
period will be summarized overall and by baseline 
status. 
Abbreviations: AE = adverse event; PCSA = potentially clinically significant abnormality; SAE = serious adverse event; 
TEAE = treatment-emergent adverse event. 
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9.4.4.2 Analyses of adverse events  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA; 
version in use by the Sponsor at the time of database lock). Clinical judgment should be used to 
determine the severity of AEs. 
Adverse events will be classified into predefined standard categories according to chronological 
criteria: 
• Pre-treatment AEs: AEs that occurred, worsened, or became serious during the 
pre-treatment period. 
• Treatment-emergent AEs: AEs that occurred, worsened, or became serious during the TE 
period. 
• Post-treatment AEs: AEs that occurred, worsened, or became serious during the 
post-treatment period. 
If the onset date (or time) of an AE (occurrence, worsening, or becoming serious) is incomplete or 
missing, the AE will be considered as a TEAE unless a partial date (or time) shows it as a pre- or 
post-treatment event. 
All AEs reported in the study will be listed, sorted by patient, onset date, and time. 
Main summary will be per study period (Blinded Period, Open-Label Period) and overall.  
If selected TEAEs from the Blinded Period can be clearly assigned to one of the study 
intervention treated lesions, they may be presented additionally assigned to the treatment of the 
corresponding lesion.  
Any TEAEs which may occur between the first administration of placebo and the first 
administration of PRN473 Gel, 5% will be presented separately. 
9.4.4.3 Local cutaneous tolerability  
Signs of local cutaneous intolerability as incidence and severity of application-site 
burning/stinging, itching, and erythema will be summarized for the Blinded Period by treatment 
(PRN473 Gel, 5% or placebo) and overall for the open-label phase.  
9.4.4.4 Extent of study treatment exposure and compliance  
A summary table presenting the exposure of treatment (ie, the number of days or weeks 
of administration) will be provided by treatment group for the Safety population. 
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9.4.4.5 Laboratory data  
Descriptive statistics of all laboratory data variables (values and changes from Baseline) will be 
calculated for each scheduled visit (Baseline and post-Baseline timepoints). Frequencies for 
PCSAs will be presented. 
9.4.4.6 Vital signs  
Descriptive statistics of all vital signs variables (values and changes from Baseline) will be 
calculated for each scheduled visit (Baseline and post-Baseline timepoints). Frequencies for 
PCSAs will be presented. 
9.4.4.7 Electrocardiogram  
Descriptive statistics (including number, mean, median, standard deviation, minimum, 
and maximum) of all ECG variables (values and changes from Baseline), will be calculated for 
each visit (Baseline and post-Baseline timepoints). Frequencies for PCSAs will be presented. 
9.4.5 Analysis of pharmacokinetic data  
Due to the negligible amount of systemic absorption observed following topical administration of 
PRN473 Gel to healthy subjects, the PK sampling scheme is designed to be semi-sparse. For that 
reason, plasma PRN473 concentrations, but not plasma PRN473 PK parameters, will be reported. 
9.4.5.1 Pharmacokinetic parameters  
Not applicable. 
9.4.5.2 Analysis of pharmacokinetic concentrations  
For PK concentrations, the arithmetic mean, SD, median, minimum, maximum, percent 
coefficient of variation (CV%), geometric mean, geometric coefficient of variation (geometric 
CV%), and the number of observations below the limit of quantification (BLQ) values will be 
presented by timepoint. For the purpose of calculating summary statistics, plasma concentrations 
(and applicable metabolites) that are BLQ will be set to 0 if taken before first study intervention , 
and to missing elsewhere. Additional analyses will be performed as deemed necessary upon 
review of the data. 
Graphical displays of concentrations over time may also be presented.   
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9.4.6 Other analyses  
9.4.6.1 Biomarkers  
Changes from baseline in biomarkers using blood samples, skin tape stripping and skin biopsy 
will be analyzed between treatments within patients. Statistical analyses of biomarkers will be 
exploratory in nature and will be detailed in a Biomarker SAP. 
9.4.6.2 Further exploratory endpoint(s)  
Details on the analysis of further endpoints will be provided in the SAP. 
9.5 
INTERIM ANALYSIS  
An interim analysis for internal decision making may be implemented with approximately 25 or 
more of the planned participants who have completed the Blinded Period (Day 14). Available data 
of the Open Label Period may be included in the analysis as appropriate. The outcome is meant 
for internal decision making and may lead to early termination of the study in case of unfavorable 
signals or continuation without any changes. 
The Sponsor team that will analyze the data will include: a Medical Monitor, a biostatistician, a 
programmer, and a safety designee. Only the biostatistician and the programmer will have the 
access to unblinded individual data at the time of the analysis, which will not be provided to other 
Sponsor team members reviewing the data. Details of the analysis will be specified in a dedicated 
analysis plan, and results will be provided in a restricted way following a dissemination plan, 
issued before any treatment code release for the analysis established upfront before the 
unblinding. The blinding will be preserved notably toward the Investigator, other site staff 
involved in the conduct of the trial, and participants.  
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and ethical considerations  
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines. 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines. 
• Applicable laws and regulations. 
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate hazard to study 
patients. 
Protocols and any substantial amendments to the protocol will require health authority approval 
prior to initiation except for changes necessary to eliminate an immediate hazard to study patients. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC. 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, and all other applicable local regulations. 
10.1.2 Financial disclosure  
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
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responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3 Informed consent process  
The Investigator or his/her representative will explain the nature of the study to the patient 
and answer all questions regarding the study. 
Patients must be informed that their participation is voluntary. Patients will be required to sign 
a statement of informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the patient was enrolled in the study and the date the written consent was obtained. The authorized 
person obtaining the informed consent must also sign the ICF. 
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
A copy of the signed ICF must be provided to the patient. 
Patients who are rescreened are required to sign a new ICF. 
10.1.4 Data protection  
Patients will be assigned a unique identifier by the Sponsor. Any patient records or datasets that 
are transferred to the Sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred. 
The patient must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to the 
patient, who will be required to give consent for data to be used as described in the informed 
consent. 
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5 Data quality assurance  
All patient data relating to the study will be recorded on printed or electronic eCRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF. 
Guidance on completion of eCRFs will be provided. 
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The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Quality tolerance limits (QTLs) may be used to identify systematic issues that can impact patient 
safety and/or reliability of study results. Data quality parameters will be monitored during the 
study and important deviations tracked, and remedial actions taken will be summarized in the 
clinical study report. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the Monitoring Plan. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
The Sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations). 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator until at least 2 years after the last approval of a marketing application 
in an ICH region and until there are no pending or contemplated marking applications in an ICH 
region or at least 2-years have elapsed since the formal discontinuation of clinical development 
unless local regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the Sponsor. No records 
may be transferred to another location or party without written notification to the Sponsor. 
10.1.6 Source documents  
Source documentation provides evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documentation is kept at the Investigator's site. 
Data reported on the eCRF or entered in the eCRF that are transcribed from source documentation 
must be consistent with the source documentation or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available. 
Definition of what constitutes source data can be found in Monitoring Plan. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
Study monitors will perform ongoing source data verification to confirm that data entered into the 
eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documentation; that the safety and rights of patients are being protected; and that the study 
is being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
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10.1.7 Study and site start and closure  
10.1.7.1 Trial Stopping Rules  
The trial will be terminated if major safety concerns related to PRN473 or placebo emerge. Trial 
safety stopping criteria are:  
• More than one PRN473-related death  
• Three or more life-threatening (Common Terminology Criteria for Adverse Events 
[CTCAE], Grade 4) PRN473-related treatment-emergent adverse events (TEAEs)  
• Sponsor chooses to terminate the study  
10.1.7.2 Study/Site termination  
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
For study termination: 
• Discontinuation of further study intervention development. 
For site termination: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines. 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of patients by 
the Investigator. 
• Total number of patients included earlier than expected. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigator, the IECs/IRBs, the regulatory authorities, and any Contract Research Organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the patients and should assure 
appropriate therapy and/or follow-up. 
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10.1.8 Publication policy  
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication 
of multicenter studies only in their entirety and not as individual site data. In this case, 
a coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CONTRACEPTIVE AND BARRIER GUIDANCE  
10.2.1 Definition  
A woman is considered WOCBP (fertile) from the time of menarche until becoming 
postmenopausal (see below) unless permanently sterile (see below). 
• A postmenopausal state is defined as the period of time after a woman has experienced no 
menses for 12 consecutive months without an alternative medical cause. 
• A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used 
to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT).  
• Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment. 
Permanent sterilization methods include: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
• For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator 
discretion should be applied to determining study entry eligibility. 
Note: Documentation can come from the site personnel’s review of the patient’s medical records, 
medical examination, or medical history interview. 
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If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first administration of study intervention, additional evaluation should be 
considered. 
Women in the following categories are considered WONCBP: 
1. Any female with permanent infertility due to one of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
- 
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), 
Investigator discretion should be applied to determining study entry. 
2. Postmenopausal female 
A postmenopausal state is defined as the period of time after a woman has experienced no 
menses for 12 consecutive months without an alternative medical cause. 
- 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT).  
- 
Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
Note: Documentation can come from the site personnel’s review of the patient’s medical records, 
medical examination, or medical history interview. 
10.2.2 Contraception guidance  
• If locally required, acceptable contraceptive methods are limited to those which inhibit 
ovulation as the primary mode of action 
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CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when used 
consistently and correctly. 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS)c 
• Bilateral tubal occlusion 
• Azoospermic partner (vasectomized or due to a to medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of 
the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days. 
Note: documentation of azoospermia for a male patient can come from the site personnel’s review of the 
patient’s medical records, medical examination, or medical history interview. 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used consistently 
and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc 
- 
oral 
- 
intravaginal 
- 
transdermal 
- injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
- 
oral 
- 
injectable 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the patient) 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those 
participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently 
and correctly. 
c Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with Clinical Trial 
Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those which inhibit ovulation as the primary 
mode of action. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhoea method (LAM) are not acceptable methods of contraception. Male condom and female condom should not be 
used together (due to risk of failure with friction) 
 
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10.2.3 Collection of pregnancy information  
Male patients with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male patient’s 
female partner who becomes pregnant while the male patient is in this study. This applies 
only to male patients who receive the IMP. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
Female patients who become pregnant 
• The Investigator will collect pregnancy information on any female patient who becomes 
pregnant while participating in this study. The initial information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a patient's 
pregnancy.  
• The patient will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on the patient and the neonate and the information will 
be forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date. Any termination of pregnancy will be 
reported, regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
• Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be reported as an AE or SAE.  
• A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at 
>22 weeks gestational age) is always considered to be an SAE and will be reported as 
such.  
• Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.5. While the Investigator is not obligated to actively seek this information in 
former study patients, he or she may learn of an SAE through spontaneous reporting. 
• Any female patient who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
 
 
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10.3 
APPENDIX 3: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND 
FOLLOW UP ASSESSMENTS AND STUDY INTERVENTION RECHALLENGE 
GUIDELINES  
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 8.3.1.3 is met. 
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Thrombocytopenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 8.3.1.3 is met. 
  
 
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*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation.  
Note: 
“Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the baseline 
visit. The algorithm does not apply to the instances of increase in ALT during screening. 
See Section 8.3 for guidance on safety reporting. 
 
Normalization is defined as ≤ULN or baseline value, if baseline value is >ULN. 
ALT > 3 ULN
Monitor LFTs every 72 hours
ALT ≤ 5 ULN
ALT > 3 ULN &
Total Bilirubin > 2 ULN 
Permanent Discontinuation of IMP
ALT > 5 ULN 
In ANY CASE, FOLLOW the instructions listed in the box below: 
1.
INFORM the Site Monitor who will forward the information to the Study Manager
2.
INVESTIGATE specifically for malaise with or without loss of consciousness, dizziness, and/or 
hypotension and/or episode of arrhythmia in the previous 72 hours; rule out muscular injury
3.
PERFORM the following tests:
- LFTs: AST, ALT, alkaline phosphatase, total and conjugated bilirubin and prothrombin time / INR
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM, (HBV-DNA if clinically indicated), anti-HCV and HCV RNA, anti-
CMV IgM and anti-HEV IgM antibodies
- Depending on the clinical context, check for recent infection with EBV, herpes viruses, and toxoplasma
- Hepatobiliary ultrasonography (or other imaging investigations if needed)
4.
CONSIDER Auto-antibodies: antinuclear, anti-DNA, anti-smooth muscle, anti-LKM
5.
CONSIDER consulting with hepatologist
6.
CONSIDER patient hospitalisation if INR>2 (or PT<50%) and/or central nervous system disburbances 
suggesting hepatic encephalopathy
7.
MONITOR LFTs after discontinuation of IMP:
- As closely as possible (or every 48 hours) until stabilization, then every 2 weeks until return to 
normal/baseline or clinical resolution.
8.
FREEZE serum sample (5ml x 2)
9.
In case of SUSPICION of GILBERT Syndrome, a DNA diagnostic test should be done
COMPLETE the specific CRF forms 
for „ALT Increase” and inform the 
Monitoring Team within 24 hours
Confirm ALT > 3 ULN
Retest within 72 hours of initial sample*
IMP administration can be continued as 
long as – under close monitoring –
conditions for permanent 
discontinuation or temporary 
interruption per protocol are not met
INCREASE IN ALT
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10.4 
APPENDIX 4: ADDITIONAL APPENDICES  
10.4.1 Grading of application site tolerability symptoms  
 
Grade 
Burning/Stinging 
Pruritus 
Erythema 
0 (none) 
No stinging/burning 
No pruritus 
No detectable erythema; skin 
of normal color 
1 (mild) 
Slight warm, tingling 
sensation; not really 
bothersome 
Occasional, slight 
itching/scratching 
Slight pinkness present 
2 (moderate) 
Definite warm, tingling 
sensation that is somewhat 
bothersome 
Constant or intermittent 
itching/scratching that is not 
disturbing sleep 
Definite redness, easily 
recognized 
3 (severe) 
Hot, tingling/stinging 
sensation that has caused 
definite discomfort 
Bothersome itching/scratching 
that is disturbing sleep 
Intense redness 
Adapted from: Zane 2016. 
 
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10.4.2 Validated investigator global assessment-atopic dermatitis (vIGA-AD)  
 
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10.4.3 Lesion Total Sign Score (TSS)  
 
Scale  
Erythema 
Induration/Papulation 
Excoriation 
Lichenification 
0 (none) 
None 
None 
None 
None 
1  
Mild 
Mild 
Mild 
Mild 
2  
Moderate 
Moderate 
Moderate 
Moderate 
3  
Severe 
Severe 
Severe 
Severe 
 
 
10.4.4  
Hanifin and rajka criteria  
The patient must have 3 of the major criteria and 3 of the minor criteria to be eligible for the 
study. 
 
Major Criteria 
1. Pruritus 
2. Typical morphology and distribution 
 
Flexural lichenification in adults 
 
Facial and extensor eruptions in infants and children 
3. Chronic or chronically relapsing dermatitis 
4. Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis) 
Minor Criteria 
1. Xerosis 
2. Ichthyosis/palmar hyperlinearity, keratosis pilaris 
3. Immediate (type 1) skin-test reactivity 
4. Raised serum IgE 
5. Early age of onset 
6. Tendency toward cutaneous infections (especially 
Staphylococcus aureus and herpes simplex), 
impaired cell-mediated immunity 
7. Tendency toward non-specific hand or foot 
dermatitis 
8. Nipple eczema 
9. Cheilitis 
10. Recurrent conjunctivitis 
11. Dennie-Morgan infraorbital fold 
12. Keratoconus 
13. Anterior subcapsular cataracts 
14. Orbital darkening 
15. Facial pallor, facial erythema 
16. Pityriasis alba 
17. Anterior neck folds 
18. Itch when sweating 
19. Intolerance to wool and lipid solvents 
20. Perifollicular accentuation 
21. Food intolerance 
22. Course influenced by environmental or emotional 
factors 
23. White dermographism, delayed blanch 
Source: Hanifin 1980. 
 
  
 
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10.5 
APPENDIX 5: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment (amended 
protocol 02) is located directly before the Table of Contents.  
Amendment 01 (15 June 2021) 
This amended protocol 01 (amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
This protocol is being amended to incorporate feedback from health authorities as well as other 
clarifications deemed necessary by the Sponsor. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
Updated protocol version and date. 
Administrative. 
Protocol amendment summary of changes 
table 
Inserted table to include the document 
history related to the initial Clinical 
Study Protocol and the Amended 
Clinical Study Protocol.  
Inserted for the current Amended 
Clinical Study Protocol text related to 
the overall rationale and protocol 
amendment summary of changes 
table. 
New section per Sanofi protocol 
template and process. 
Section 1.1 synopsis; Section 4.1 overall 
design; Section 4.3 justification of dose; 
Section 5.1 inclusion criteria #7; Section 
6.2 
Preparation/handling/storage/accountability 
Updated the investigational skin 
lesion from “10*10 cm” to “100cm2” 
To provide flexibility for the lesional 
area. 
Section 1.1 synopsis; Section 1.2 schema; 
Section 4.1 overall design; Section 5.1 
inclusion criteria #5,#6; Section 6.7.3 
rescue medicine 
Added “genital” in the excluded 
treatable areas for PRN473 Gel 
administration.  
To respond the FDA’s comment of 
considering exclusion of mucosal 
sites such as the genitalia. 
Section 1.1 synopsis; Section 1.2 schema; 
Section 4.1 overall design 
Added the following text to clarify the 
administration of study intervention 
during Open Label period “…and 
should continue to treat the assigned 
areas throughout the Open Label 
Period.” 
For clarity.   
Section 1.1 synopsis, Section 4.1 overall 
design 
Updated the text from” To evaluate 
the PK (plasma concentrations) and 
biomarkers of PRN473, blood 
samples will be collected throughout 
the study” to “…will be collected at 
For clarity. 
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Section # and Name 
Description of Change 
Brief Rationale 
study visits accordingly to the SoA 
(Section 1.3).” 
Section 1.1 synopsis; Section 5.1 inclusion 
criteria 
Replaced the eligibility regarding 
patient’s vIGA-AD score at 
“screening” instead of “baseline “in 
inclusion #5 
To correct a typo. 
 
Introduced a new inclusion criterion 
as “inclusion #8” for male 
contraception/abstinence 
requirements. And renumbered the 
following inclusion criteria.  
To introduce the male 
contraception/abstinence requirements 
in patient eligibility 
 
Updated the inclusion #9 with Sanofi 
common text language on female 
contraception/abstinence and 
pregnancy testing requirements 
following decision tree.  
To align with Sanofi common text and 
safety guidance.  
Section 1.1 synopsis; Section 5.2 exclusion 
criteria 
Updated the exclusion #17 of any 
malignancy history to “History of any 
malignancy except skin basal cell or 
squamous cell carcinomas in situ that 
have been removed and completely 
resolved at least 5 years ago”  
To respond the FDA’s comment. 
 
Introduced a new exclusion criterion 
for laboratory abnormalities as 
exclusion #18 
To align with Sanofi common text and 
safety guidance. 
 
Introduced a new exclusion criterion 
for QT intervals as exclusion #19 
To align with Sanofi common text and 
safety guidance. To respond the FDA’s 
comment to add subject stopping 
criteria based on ECG abnormalities. 
 
Introduced the diagnostic 
assessments for HIV HBV and HCV 
as exclusion #20, #21, and #22 
respectively.  
To align with Sanofi common text and 
safety guidance. To respond the FDA’s 
comment to obtain HIV test prior to 
study enrollment. 
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Section # and Name 
Description of Change 
Brief Rationale 
 
Added the exclusion #23 on medical 
condition of tuberculosis as “Evidence 
of active or latent tuberculosis (TB) as 
documented by medical history and 
examination, chest X-rays (posterior 
anterior and lateral), and TB testing: 
either a positive tuberculin skin test 
(TST; defined as a skin induration ≥ 5 
mm at 48 to 72 hours, regardless of 
Bacillus Calmette-Guerin (BCG) or 
other vaccination history) or a positive 
(not indeterminate) TB test such as 
QuantiFERON®-TB Gold Plus test. 
NOTE: The choice to perform a TST 
or a QuantiFERON-TB Gold Plus test 
will be made by the investigator 
according to local licensing and 
standard of care. The QuantiFERON-
TB Gold Plus test can only be used in 
countries where it is licensed, and the 
use of this test is dependent on 
previous treatment(s). This test may 
not be suitable if previous 
treatment(s) produced significant 
immunosuppression” 
To align with Sanofi common text and 
safety guidance. To respond the FDA’s 
comment to obtain Mantoux TST test 
prior to study enrollment. 
 
Introduced the history of serious 
infection or currently active infection 
(including COVID-19) as 
exclusion #24 
To align with Sanofi common text and 
safety guidance. 
 
Introduced the receipt of COVID-19 
vaccine as exclusion #25 
To align with COVID-19 vaccine safety 
profile.   
Section 1.3 SoA 
Updated the assessment item from 
“Evaluation of BSA involvement” to 
“Evaluation of treatable BSA” 
For clarity. 
 
Added FSH test and footnote f to 
clarify it is for post-menopausal 
women of non-childbearing potential 
only. Renumbered the footnote 
thereafter.  
To align with Table 6. 
 
Added Urinalysis test. 
To align with inclusion #10 and Table 6 
 
Removed the footnote b from PP-
NRS assessment  
To correct an error and be consistent 
within protocol.  
 
Day 15 has been included in footnote 
q of biomarker collection.  
To correct an omission 
 
Revised the footnote i with “The vIGA-
AD will be conducted on all treated 
lesions at screening and Day 15, 29 
and 43 during Open Label period.  
To clarify the vIGA-AD is for all treated 
lesions and the scheduled study visit. 
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Section # and Name 
Description of Change 
Brief Rationale 
 
Added “predose at Day 15” at the end 
of footnote j . 
To correct an omission. 
 
Newly added footnote k “The lesional 
vIGA-AD will be administered predose 
separately on each of the 2 target 
lesions only during Blinded Period 
and predose at Day 15” and crossed 
link to Lesional vIGA assessment. 
Renumber the footnote thereafter.  
To clarify the lesional vIGA-AD is only 
for 2 target lesions and the scheduled 
study visit. 
Section 1.3 SoA, Section 8.9 lesion 
photography 
Added “to document biopsy location 
and” for the purpose of photograph in 
footnote j and section 8.9. 
For clarity.   
Section 1.3 SoA, Table 6 
Introduced the diagnostic 
assessments for Serology (HIV, 
hepatitis B and C) and TB test in 
screening visit. 
To align with Sanofi common text and 
safety guidance. To respond the FDA’s 
comment to obtain HIV test prior to 
study enrollment. 
Section 4.1 overall design 
Added the text clarifying study 
duration.  
For clarity and align with synopsis.  
Section 4.3 justification for dose 
Added the following text “Patients will 
measure the dose by the fingertip unit 
method and the expected dose 
variability when the compound is 
topically self-applied by this method 
may be up to two-fold excess of 
compound which is reasonably below 
the safety margin.” 
To introduce the guidance for patient 
self-administration of study intervention 
in open-label period.  
Section 4.4 end of study definition  
Updated the definition for patient 
completed the study to “A patient is 
considered to have completed the 
study if he/she has completed all 
phases of the study including the Day 
43 and Day 56 safety follow up phone 
call.” 
For clarity. 
Section 6.7.1 COVID-19 vaccination 
Introduced a new section for the 
guidance and requirements of use 
COVID-19 vaccination. 
To clarify the guidance of COVID-19 
vaccination during study in the context 
of its approval.   
Section 6.7.2 prohibited medications, 
Table 5 
Added any live vaccines in excluded 
medications and treatments list. 
To align with vaccine safety profile.   
Section 6.7.4 rescue medicine 
Updated the text to “Rescue topical 
medications use will be at the 
discretion of the Investigator after 
discussion with the Medical Monitor if 
the patient is flaring above 14% 
treatable BSA ( excluding scalp, 
palms, soles and genitalia) during the 
last two weeks of the Open Label 
Period. Investigators should make 
every attempt to conduct efficacy and 
safety assessments (eg, disease 
To respond the FDA’s comment to 
provide a plan for patients who flare 
and have >14% treatable BSA during 
the open label period.  
 
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Section # and Name 
Description of Change 
Brief Rationale 
severity scores, safety labs) 
immediately before administering any 
rescue treatment. An unscheduled 
visit may be used for this, if 
necessary. Patients who receive 
rescue treatment will be asked to 
continue with study treatment and 
procedures.” 
Section 7.1 discontinuation of the study 
intervention  
Section has been updated to include 
subject stopping criteria based on 
liver chemistry and ECG 
abnormalities. In addition, introduced 
a new sub-section 7.1.4 for 
hematology stopping criteria.  
To align with Sanofi common text and 
safety guidance. 
Section 8.2.3 electrocardiograms 
Added the following text “Refer to 
Section 7.1.3 for QTc withdrawal 
criteria and any additional QTc 
readings that may be necessary.”  
For clarity. To respond the FDA’s 
comment to add subject stopping 
criteria based on ECG abnormalities. 
Section 8.2.4.1 clinical laboratory tests 
Table 6 
Corrected the clinical chemistry 
assessment from “Urate/Urea” to 
“Blood urea nitrogen (BUN)” 
For clarity.  
 
Added “Details of liver chemistry 
stopping criteria and required actions 
and follow-up are given in Section 
7.1.2 Liver Chemistry Stopping 
Criteria and Appendix 5 Liver and 
other safety: suggested actions and 
follow-up assessments. All events 
which may indicate severe liver injury 
(possible Hy’s Law) must be reported 
to Sponsor in an expedited manner 
(excluding studies of hepatic 
impairment or cirrhosis).” as footnote 
a and renumbered the following 
footnotes. 
To align with Sanofi common text and 
safety guidance. To respond the FDA’s 
comment to add subject stopping 
criteria based on liver chemistry. 
Section 8.2.5 Pregnancy testing; Section 
8.3.6 Pregnancy  
Whole section been updated.  
To align with Sanofi common text and 
safety guidance. 
Section 8.3.5 Regulatory reporting 
requirements for SAEs 
Included the regulatory requirement of 
reporting SUSAR as one of the listed 
bullet points.  
To align with Sanofi common text and 
safety guidance. 
Section 8.3.7 Expedited reporting 
requirements   
Added the time window for expedited 
reporting of AE.  
To align with Sanofi common text and 
safety guidance. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.4.3 analysis of efficacy data 
Included the following text “Where 
appropriate, supplemental analyses 
will be presented excluding 
observations after administration of 
rescue medication. Imputation would 
then be performed for missing 
observations including those due to 
withdrawal due to lack of efficacy, as 
will be specified in the SAP.” 
To include efficacy data after the use of 
rescue medication.  
Section 9.4.4 analysis of safety data 
Included the following text “Where 
appropriate, supplemental analyses 
will be presented excluding 
observations after administration of 
rescue medication.”  
To include safety data after the use of 
rescue medication. 
Section 10 supporting documentation and 
operational considerations 
Added a new subsection 10.1.7.1 for 
trial stopping rules in Appendix 1 
To align with Sanofi common text and 
safety guidance. 
 
Included the contraceptive and barrier 
guidance, laboratory decision trees for 
neutropenia and thrombocytopenia as 
Appendix 2. 
To align with Sanofi common text and 
safety guidance. 
 
Included neutropenia and 
thrombocytopenia decision trees in 
Appendix 3 
To align with Sanofi common text and 
safety guidance. 
 
Grouped the original appendices 1 to 
4 as the subsection of Appendix 4 of 
additional appendices. 
For clarity.  
 
Protocol amendment history added as 
Appendix 5 per Sanofi template. 
Administrative update. 
Throughout document 
Replaced “study drug” with “study 
intervention”.  
To align with Sanofi protocol template 
terminology recommendation.   
Throughout document 
Other minor editorial changes 
(eg, grammatical, stylistic, and minor 
typographical error corrections) 
Minor, therefore, have not been 
summarized 
 
 
 
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11 
REFERENCES  
Ahmed A, Solman L, Williams HC. Magnitude of benefit for topical crisaborole in the treatment 
of atopic dermatitis in children and adults does not look promising: a critical appraisal. Brit J 
Dermatol. 2018;178:659-62. 
Bieber T. Atopic dermatitis. Ann Dermatol. 2010;22(2):125-37. 
Bieber T, D'Erme AM, Akdis CA, Traidl-Hoffmann C, Lauener R, Schäppi G, et al. Clinical 
phenotypes and endophenotypes of atopic dermatitis: Where are we, and where should we go? J 
Allergy Clin Immunol. 2017;139(4S):S58-S64. 
Boguniewicz M, Alexis AF, Beck LA, Block J, Eichenfield LF, Fonacier L, et al. Expert 
Perspectives on Management of Moderate-to-Severe Atopic Dermatitis: A Multidisciplinary 
Consensus Addressing Current and Emerging Therapies. J Allergy Clin Immunol Pract. 
2017;5(6):1519-31. 
Boguniewicz M, Leung DY. Atopic dermatitis: a disease of altered skin barrier and immune 
dysregulation. Immunol Rev. 2011;242(1):233-46. 
Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting BTK with 
Ibrutinib in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2013;369:32-42. 
Chang BY, Huang MM, Francesco M, Chen J, Sokolove J, Magadala P, et al. The Bruton tyrosine 
kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector 
cells. Arthritis Res Ther. 2011;13:R115. 
Crofford LJ, Nyhoff LE, Sheehan JH, Kendall PL. The role of Bruton’s tyrosine kinase in 
autoimmunity and implications for therapy. Expert Rev Clin Immunol. 2016;12(7):763-73. 
Di Paolo JA, Huang T, Balazs M, Barbosa J, Barck KH, Bravo BJ, et al. Specific Btk inhibition 
suppresses B cell- and myeloid cell-mediated arthritis. Nat Chem Biol. 2011;7:41-50.  
Eichenfield LF, Tom WL, Berger TG, Krol A, Paller AS, Schwarzenberger K, et al. Guidelines of 
care for the management of atopic dermatitis: section 2. Management and treatment of atopic 
dermatitis with topical therapies. J Am Acad Dermatol. 2014;71(1):116-32. 
Futatani T, Watanabe C, Baba Y, Tsukada S, Ochs HD. Brutons tyrosine kinase is present 
in normal platelets and its absence identifies patients with X-linked agammaglobulinaemia 
and carrier females. Br J Hematol. 2001;114(1):141-9. 
Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol Suppl 
(Stockh). 1980;92:44-7. 
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Product Name: PRN473 (SAR444727) 
Clinical Study Protocol PRN473-0005 (ACT17131) 
Principia Biopharma, Inc. 
 
100 of 100 
Confidential and Proprietary 
 
01-Mar-2022 Final 
Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B, et al. The Bruton tyrosine 
kinase inhibitor PCI-32765 blocks B cell activation and is efficacious in models of autoimmune 
disease and B cell malignancy. Proc Natl Acad Sci USA. 2010;107:13075-80. 
Hutcheson J, Vanarsa K, Bashmakov A, Grewal S, Sajitharan D, Chang BY, et al. Modulating 
proximal cell signaling by targeting Btk ameliorates humoral autoimmunity and endorgan disease 
in murine lupus. Arthritis Res Ther. 2012;14:R243. 
Kim KH, Maderna A, Schnute ME, Hegen M, Mohan S, Miyashiro J, et al. Imidazo[1,5-
a]quinoxalines as irreversible BTK inhibitors for the treatment of rheumatoid arthritis. Bioorg 
Med Chem Lett. 2011;21(21):6258-63.  
Mohamed AJ, Yu L, Backesjo CM, Vargas L, Faryal R, Aints A, et al. Bruton's tyrosine kinase 
(Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol 
Rev. 2009;228:58-73. 
Oliveira S, Rosowski EE, Huttenlocher A. Neutrophil migration in infection and wound repair: 
going forward in reverse. Nat Rev Immunol. 2016;16(6):378-91.  
Rip J, Van der Ploeg EK, Hendriks RW, Corneth O. The role of Bruton’s Tyrosine Kinase in 
immune cell signaling and systemic autoimmunity. Crit Rev Immunol. 2018;38(1):17-62. 
Silverberg JI. Public Health Burden and Epidemiology of Atopic Dermatitis. Dermatol Clin. 
2017;35(3):283-9. 
Werfel T, Allam JP, Biedermann T, Eyerich K, Gilles S, Guttman-Yassky E, et al. Cellular 
and molecular immunologic mechanisms in patients with atopic dermatitis. J Allergy Clin 
Immunol. 2016;138(2):336-49. 
Weidinger S, Beck LA, Bieber T, Kabashima K, Irvine AD. Atopic dermatitis. Nat Rev Dis 
Primers. 2018;4(1):1. 
Xu D, Kim Y, Postelnek J, Vu MD, Hu DQ, Liao C, et al. RN486, a selective Bruton's tyrosine 
kinase inhibitor, abrogates immune hypersensitivity responses and arthritis in rodents. 
J Pharmacol Exp Ther. 2012;341:90-103. 
Zane LT, Hughes MH, Shakib S. Tolerability of crisaborole ointment for application on sensitive 
skin areas: A randomized, double-blind, vehicle-controlled study in healthy volunteers. Am J Clin 
Dermatol. 2016;17:519-26. 
 
 
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SAP_001.pdf: 


Statistical Analysis Plan  
14-Sep-2022 
SAR444727-ACT17131 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 4 
VERSION HISTORY ....................................................................................................................................... 5 
1 
INTRODUCTION .............................................................................................................................. 6 
1.1 
STUDY DESIGN .............................................................................................................................. 6 
1.2 
OBJECTIVE AND ENDPOINTS ...................................................................................................... 6 
2 
ANALYSIS POPULATIONS ............................................................................................................ 8 
3 
STATISTICAL ANALYSES ............................................................................................................. 9 
3.1 
GENERAL CONSIDERATIONS ...................................................................................................... 9 
3.2 
PRIMARY ENDPOINT(S) ANALYSIS .............................................................................................. 9 
3.2.1 
Definition of endpoint(s) ................................................................................................................... 9 
3.2.2 
Main analytical approach ................................................................................................................. 9 
3.2.3 
Sensitivity analysis ......................................................................................................................... 10 
3.2.4 
Supplementary analyses ................................................................................................................ 10 
3.3 
SECONDARY ENDPOINT(S) ANALYSIS ..................................................................................... 10 
3.4 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS .............................................................. 10 
3.5 
MULTIPLICITY ISSUES ................................................................................................................ 14 
3.6 
SAFETY ANALYSES ..................................................................................................................... 14 
3.6.1 
Extent of exposure ......................................................................................................................... 15 
3.6.2 
Adverse events .............................................................................................................................. 15 
3.6.3 
Additional safety assessments ....................................................................................................... 18 
3.6.3.1 
Vital signs, electrocardiograms (ECGs) and laboratory variables ................................................. 18 
3.6.3.2 
Local cutaneous tolerability ............................................................................................................ 19 
3.7 
OTHER ANALYSES....................................................................................................................... 20 
3.7.1 
Other variables and/or parameters ................................................................................................ 20 
3.7.1.1 
PK analyses ................................................................................................................................... 20 
3.7.1.2 
Biomarkers analyses ...................................................................................................................... 20 
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3.8 
INTERIM ANALYSES .................................................................................................................... 20 
3.8.1 
General considerations for the interim analysis ............................................................................. 20 
3.9 
CHANGES TO PROTOCOL-PLANNED ANALYSES .................................................................... 21 
4 
SAMPLE SIZE DETERMINATION ................................................................................................ 22 
5 
SUPPORTING DOCUMENTATION .............................................................................................. 23 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS ..................................................................................... 23 
5.2 
APPENDIX 2 PARTICIPANT DISPOSITION ................................................................................. 24 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS .................................................................................................. 25 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS ........................................................................ 26 
 
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Page 4 
LIST OF TABLES  
Table 1 - Objectives and endpoints ................................................................................................................. 6 
Table 2 - Populations for analyses .................................................................................................................. 8 
Table 3 - Sorting of AE tables ....................................................................................................................... 16 
Table 4 - Analyses of adverse events ........................................................................................................... 17 
Table 5 - Selections for AESIs ...................................................................................................................... 18 
Table 6 - Analyses window definition ............................................................................................................ 27 
 
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Statistical Analysis Plan  
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Version number: 1 
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Page 5 
VERSION HISTORY  
This statistical analysis plan (SAP) for study ACT17131 is based on the Amended Clinical Trial 
Protocol 02 dated 01 March 2022. 
This SAP is approved before the database lock or before the first interim analysis. 
Major changes in statistical analysis plan 
SAP Version 
Approval Date 
Changes 
Rationale 
1 
14-Sep-2022 
Not applicable 
Original version 
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Statistical Analysis Plan  
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Page 6 
1 
INTRODUCTION  
1.1 
STUDY DESIGN  
PRN473 is also known as SAR444727 and both terminologies are used in an interchangeable way 
in this document. For the reporting “SAR444727” will be used. 
Study ACT17131 is a Phase 2a that consists of a randomized, double-blind, intra-patient placebo-
controlled treatment period and an open-label uncontrolled treatment period.  
The objective of the study is to evaluate the safety, tolerability, pharmacokinetics (PK) and 
preliminary efficacy of topically administered SAR444727 in up to 40 participants with mild to 
moderate atopic dermatitis (AD). 
On Day 1 (Baseline) of the Blinded Period, 2 target lesions of 100 cm2 area each with a difference 
no greater than 1 point in lesional Total Sign Score (TSS) are randomly assigned to treatment in 
an intra-participant 1:1 manner, with one lesion assigned to SAR444727 Gel 5% and the other to 
matching placebo (ie, same inactive ingredients). SAR444727 Gel 5% and matching placebo (ie, 
same inactive ingredients) are applied twice a day (BID, morning and evening) at a quantity of 
2.5 mg/cm2 to a 100 cm2 area of each target lesion on Days 1-14 (Blinded Period). On Days 15-42 
(Open-Label Period), participants are instructed to apply SAR444727 Gel, 5% BID to all AD-
affected areas in a thin layer (excluding the scalp, palms, soles and genitals), and should continue 
to treat the assigned areas throughout the Open-label Period. 
Participation will take approximately 13 weeks, including up to a 5-week screening period, a 
6-week treatment period (2-week blinded and 4-week open label), end of study assessments 1 day 
after last dose, and a safety follow-up phone call 2 weeks after last dose. 
1.2 
OBJECTIVE AND ENDPOINTS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
 
Safety: 
To assess the safety and tolerability of PRN473 Gel, 5% 
versus placebo administered BID up to 6 weeks in 
participants with mild to moderate AD 
Safety: 
• 
Incidence and severity of AEs 
• 
Changes in vital signs, ECGs, and laboratory tests 
• 
Assessment of local cutaneous tolerability: incidence and 
severity of application-site events such as 
burning/stinging, itching, and erythema   
Secondary 
 
PK: To evaluate the plasma PK of PRN473 following 
administration of multiple topical doses of PRN473 Gel, 5% 
for 42 days in participants with mild to moderate AD 
• 
PK: Plasma PRN473 concentrations at specified 
timepoints 
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Objectives 
Endpoints 
Exploratory 
• 
Biomarker: To evaluate blood and skin changes in 
protein expression, lymphocyte infiltration, and epidermal 
thickness following treatment with PRN473 Gel, 5% at 
Days 8 and 15 
• 
Biomarker: Change from Baseline in biomarkers using 
blood samples, skin tape stripping, and skin biopsy 
• 
Efficacy: To assess the preliminary efficacy following 
double-blind treatment with PRN473 Gel, 5% compared 
to placebo at Days 8 and 15 
Efficacy During Blinded Period: 
• 
Change from Baseline in lesion TSS at Days 8 and 15 
• 
Change from Baseline in daily lesional PP-NRS score up 
to Day 15 
• 
Change from Baseline in lesional validated IGA score at 
Days 8 and 15 
• 
Lesional validated IGA response (proportion of 
participants with a validated IGA score of 0 or 1 and 
≥2-grade improvement from Baseline) at Days 8 and 15 
• 
Efficacy: To  assess the preliminary efficacy following 
open-label treatment with PRN473 Gel, 5% at Days 29 
and 43 
Efficacy During Open-Label Period 
• 
Change from Baseline in TSS for the 2 target lesions at 
Days 29 and 43. 
For EASI: 
• 
Percent change from Baseline in EASI at Days 29 and 
43 
• 
Percent change from Day 15 in EASI to Days 29 and 43 
• 
Proportion of patients with EASI 50, EASI 75, 
and EASI 90 from Day 15 to Days 29 and 43 
For PP-NRS: 
• 
Change in PP-NRS from Day 15 to Days 29 and 43 
• 
Proportion of participants achieving at least 3-point 
reduction from Day 15 in PP-NRS at Days 29 and 43 
• 
Proportion of participants achieving at least a 4-point 
reduction from Day 15 in PP-NRS at Days 29 and 43 
 
• 
Change from Day 15 in weekly mean of PP-NRS at Days 
29 and 43 
For vIGA-AD: 
• 
Proportion of participants achieving at least 2 grade 
reduction in vIGA-AD to clear (vIGA-AD 0) or almost 
clear (vIGA-AD 1) from Day 15 to Days 29 and 43 
Other endpoints: 
• 
Change from Day 15 in SCORAD at Days 29 and 43 
• 
Change from Day 15 in percentage of treatable BSA at 
Days 29 and 43  
• 
Change from Baseline in POEM at Days 15, 29, and 43 
• 
Proportions of participants with a reduction in POEM ≥4 
from Baseline at Days 15, 29 and 43 in participants with 
POEM≥4 at Baseline 
• 
Proportions of participants with a reduction in POEM ≥4 
from Day 15 at Days 29 and 43 in participants with 
POEM≥4 at Baseline 
• 
Change from Baseline in DLQI at Days 15, 29, and 43 
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2 
ANALYSIS POPULATIONS  
The following populations for analyses are defined: 
Table 2 - Populations for analyses  
Participants Analysis Set 
Description 
Screened 
All participants who signed the informed consent form (ICF). 
Enrolled/Randomized 
All participants from the screened population who have been allocated to 
a randomized intervention for each target lesion by interactive response technology 
(IRT) regardless of whether the intervention was received. 
Safety 
All randomized participants who receive any amount of study drug (SAR444727 
or placebo) will be included in the Safety population. The Safety population will be 
based on the intervention actually received and will be used for the summaries of all 
safety assessments.  
Pharmacokinetic 
All participants who received any amount of active study drug (SAR444727) and have 
at least one pharmacokinetics (PK) sample taken will be included in the PK population. 
The PK population will be used for the summaries of all PK data. 
Efficacy 
- 
For double blind period 
All randomized participants who did actually receive at least 80% of prescribed study 
drug in the Blinded Period (for both lesion)  and with at least 1 post-study drug 
administration efficacy (TSS) measurement.  
- 
For open label period 
All randomized participants who did actually receive at least 80% of prescribed study 
drug in the Blinded Period (for both lesion) and at least 80% of prescribed study drug 
in the Open-Label Period and at least 1 post-study drug administration efficacy (TSS) 
measurement. 
Participants will be analyzed according to the intervention they actually received.  
Biomarker 
All randomized participants with no important deviations impacting Biomarker 
measurements, for whom the Biomarker data are considered sufficient 
and interpretable.  
Note: “Screened” means a participant's, or their legally acceptable representative’s, agreement to 
participate in a clinical study following completion of the informed consent process.  
Participants exposed to study intervention before or without being randomized will not be 
considered randomized and will not be included in any analysis population.  The safety 
experience of these participants will be reported separately. 
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3 
STATISTICAL ANALYSES  
3.1 
GENERAL CONSIDERATIONS  
In general, unless otherwise specified, continuous data will be summarized using the number of 
observations available, mean, Standard Deviation (SD), median, range (minimum and maximum). 
Categorical and ordinal data will be summarized using the count and percentage of participants, as 
appropriate. 
The baseline value is defined as the last available value before the first dose of Investigational 
Medicinal Product (IMP). For participants randomized but not treated, the baseline value is defined 
as the last available value before randomization. 
Unless otherwise specified, analyses will be performed by intervention group (and overall, for 
baseline and demographics characteristics). 
Observation period  
The observation period will be divided into 3 segments:  
• The pre-treatment period is defined as the period up to first IMP administration. 
• The treatment-emergent (TE) period is defined as the period from the first IMP 
administration to the end of study (EOS) visit (EOS day included).  
• The post-treatment period is defined as the period from the end of the TE period (starting 
the day after date of EOS visit). 
Double blind analysis period is defined as the period from the date of first IMP up to the Day 15 
(administration of first open label IMP) Visit or date of IMP discontinuation which ever comes 
first. 
3.2 
PRIMARY ENDPOINT(S) ANALYSIS  
The primary endpoints detailed in this section are safety and tolerability of SAR444727 in 
participants with mild to moderate AD. Details are given in Section 3.6. 
3.2.1 Definition of endpoint(s)  
The primary endpoints are incidence and severity of the adverse events (AEs) defined in 
Section 3.6.2, the standard clinical parameters (vital signs and electrocardiograms [ECGs]), the 
laboratory parameters defined in Section 3.6.3.1 and the assessment of local cutaneous tolerability 
defined in Section 3.6.3.2.  
3.2.2 Main analytical approach  
All the safety analyses will be performed based on the safety population defined in Table 2.  
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The safety evaluation will be based upon the review of the individual values (clinically significant 
abnormalities), descriptive statistics (summary tables and figures). No statistical significance tests 
will be performed on safety data. No imputation will be performed. 
Safety measures include AEs, Treatment-Emergent AEs (TEAEs), Serious AEs (SAEs), AEs 
leading to study intervention, treatment discontinuation (permanent or not), study discontinuation, 
and death. Overall AEs, TEAEs, and SAEs incidence tables will be presented by System Organ 
Class (SOC), high level group term (HLGT), high level term (HLT), and preferred term (PT for 
each study period and overall, showing the number (n) and percentage (%) of participants 
experiencing an AE. They will be described according to maximum intensity and relation to the 
study intervention.  
Proportion of participants with at least 1 TEAE, treatment emergent SAE, TEAE leading to death, 
and TEAE leading to definitive treatment discontinuation will be tabulated by study period 
and overall.  
For the changes in vital signs, ECGs and laboratory tests, the incidence of potentially clinically 
significant abnormalities (PCSAs) occurring during the TE period will be summarized overall and 
by baseline status. 
For analysis local cutaneous tolerability see Section 3.6.3.2. 
3.2.3 Sensitivity analysis  
Not applicable. 
3.2.4 Supplementary analyses  
Not applicable. 
3.3 
SECONDARY ENDPOINT(S) ANALYSIS  
The secondary endpoints are the Plasma SAR444727 concentrations at specified timepoints 
defined in Section 3.7.1.1.  
3.4 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS  
There are two type of exploratory endpoints. The first exploratory endpoint is biomarker to 
evaluate changes in blood samples, skin tape strippings, and skin biopsies. Details are given in 
Section 3.7.1.2. 
The second exploratory endpoints are efficacy endpoints during double-blind period and Open-
label period based on the efficacy population. For the double-blind period, treatment differences 
or ratios will be assessed for SAR444727 Gel, 5% versus placebo at Day 8 and Day 15, and data 
will be presented by treatment for the blinded period, for scores assessed per lesion, and overall 
otherwise. During the Open-Label Period, efficacy will be assessed mainly at Days 29 and 43, 
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overall. For  TSS, data will be described over the full course of the study presented by treatment 
received during the double-blind Period. 
More specifically, the following endpoints will be assessed: 
During double-blind period 
• Change from Baseline in lesional TSS for the 2 target lesions at Day 8 and Day 15  
• Change from Baseline in daily lesional Peak Pruritus Numeric Rating Scale (PP-NRS) 
score for the 2 target lesions up to Day 15 and at Day 15 
• Change from Baseline in lesional validated Investigator Global Assessment for AD 
(v-IGA-AD) score for the 2 taget lesions at Days 8 and 15 
• Lesional v-IGA-AD response (proportion of participants with a lesional v-IGA-AD score 
of 0 [clear] or 1 [almost clear] and ≥2-grade improvement from Baseline) at Days 8 and 15 
During Open-label period 
• For lesional TSS 
- 
Change from Baseline in lesional TSS for the 2 target lesions at Days 29 and 43 
- 
Change from Day 15 in lesional TSS for the 2 target lesions at Days 29 and 43 
• For PP-NRS 
- 
Change in daily global PP-NRS from Day 15 to Days 29 and 43 
- 
Change in weekly average of PP-NRS from Day 15 to Days 29 and 43 
- 
Proportion of participants achieving at least 3-point reduction from Day 15 in daily 
global PP-NRS at Days 29 and 43 in participants with PP-NRS≥3 at Day 15 
- 
Proportion of participants achieving at least a 4-point reduction from Day 15 in daily 
global PP-NRS at Days 29 and 43 in participants with PP-NRS≥4 at Day 15 
• For Eczema Area and Skin Severity Index (EASI) 
- 
Percent change from Baseline in EASI at Days 29 and 43 
- 
Percent change from Day 15 in EASI at Days 29 and 43 
- 
Proportion of participants with at least a reduction ≥50% in EASI (EASI-50), with at 
least a reduction ≥75% in EASI (EASI-75), with at least a reduction ≥90% in EASI 
(EASI-90), and with at least a reduction ≥100% in EASI (EASI-100), from Baseline to 
Days 15, 29 and 43 
- 
Proportion of participants with EASI-50, EASI-75, EASI-90, and EASI-100 from 
Day 15 to Days 29 and 43 
• For v-IGA-AD  
- 
Proportion of participants achieving vIGA-AD of 0 (clear) or 1 (almost clear) at 
Day 29 
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- 
 Proportion of participants achieving a vIGA-AD of 0 (clear) or 1 (almost clear) at 
Day 43  
- 
Proportion of participants achieving vIGA-AD of 0 (clear) or 1 (almost clear) and a 
reduction of ≥2 points from Day 15 to Day 29 
- 
Proportion of participants achieving vIGA-AD of 0 (clear) or 1 (almost clear) and a 
reduction of ≥2 points from Day 15 to Day 43 
• For Body Surface Area (BSA) 
- 
Change from Day 15 in percentage of treatable BSA at Days 29 and 43 
• For Scoring Atopic Dermatitis (SCORAD) 
- 
Percent change from Day 15 in SCORAD index at Days 29 and 43 
• For Patient Oriented Eczema Measure (POEM) 
- 
Change from Baseline in POEM at Days 15, 29, and 43 
- 
Change from Day 15 in POEM at Days 29 and 43 
- 
Proportions of participants with a reduction in POEM ≥4 from Baseline at Days 15, 29 
and 43 in participants with POEM≥4 at Baseline 
- 
Proportions of participants with a reduction in POEM ≥4 from Day 15 at Days 29 and 
43 in participants with POEM≥4 at Day 15 
• For Dermatology Quality of Life Index (DLQI) 
- 
Change from Baseline in DLQI at Days 15, 29, and 43. 
- 
Change from Day 15 in DLQI at Days 15, 29, and 43 
- 
Proportions of participants with a reduction in DLQI ≥4 from Baseline at Days 15, 29 
and 43 in participants with DLQI≥4 at Baseline 
- 
Proportions of participants with a reduction in DLQI ≥4 from Day 15 at Days 29 and 
43 in participants with DLQI≥4 at Day 15 
Analyses for binary endpoints 
The binary endpoints will be descriptively summarized using number, percentage and 95% 
confidence interval (CI) of percentage at each time point. 
The proportion of subjects meeting the binary endpoint during the Open label period and 
corresponding exact 95% and 80% CI (95% CI and 80% CI respectively calculate with Wilson 
score method) will be summarized.  
For the intra-participant comparison of SAR444727 vs placebo during the double blind period, 
binary endpoints (only for lesional v-IGA-AD response) will be analyzed for Day 8 and Day 15 
separately, using a logistic regression model with intervention (SAR444727, placebo) as fixed 
effects. Odds ratio and difference in proportions as well as the corresponding 95% CI will be 
provided. 
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Analyses for continuous endpoints 
The descriptive statistics (mean, SD, SEM, median, Q1, Q3, and range) for all continuous 
endpoints collected will be provided by treatment and time point on raw data, absolute changes or 
percent changes from baseline using the baseline efficacy population. Boxplots will also be 
provided by treatment and time point. Absolute or percent change from baseline and ratio from 
Baseline (mean ± SEM and/or median with interquartile range) will also be produced by 
treatment for the double blind period. 
For the intra-participant comparison of SAR444727 vs placebo, a linear mixed model (using 
restricted maximum likelihood) with repeated measurements will be fitted to estimate the 
difference in mean change in lesional TSS from Baseline to Day 15; and from Baseline to Day 8.  
In addition to the visit, treatment, and visit-by-treatment interaction terms, the model includes the 
participant-specific baseline lesional TSS score covariate. Repeated measurements for visit are 
taken within participant and an unstructured covariance matrix will be used to model the within-
subject variance-covariance errors. Baseline lesional TSS will be defined as the mean TSS from 
the two treated lesions at Baseline. 
Change from baseline TSS= Intercept + TSSbase + VISIT + TRT + VISIT*TRT +  Error 
Least square means will be calculated for change from Baseline to Day15 for both treatments and 
differences of means for SAR444727 versus placebo with two-sided 95% CI will be derived from 
the model framework. 
The model may be simplified if there are convergence issues. 
SAS Statement 
proc mixed data= method=reml;  
 
class VISITNUM USUBJID TRT; 
 
model CHGSC=BASESC TRT VISITNUM TRT*VISITNUM/solution ddfm=kr ; 
 
repeated VISITNUM*TRT/type=UN subject=USUBJID; 
 
lsmeans VISITNUM*TRT /slice=VISITNUM  cl; 
estimate "SAR versus Plbo D15" TRT -1 1 VISITNUM*TRT 0 0 -1 1 /cl; 
estimate "SAR versus Plbo D8" TRT -1 1 VISITNUM*TRT -1 1 0 0 /cl; 
run; 
Participants with missing data at Baseline will not be included in the analysis. Participants with 
one or more post-dose timepoints will be included. Mixed model for repeated measures (MMRM) 
to account for missing data is used for the primary analysis under the missing at random (MAR) 
framework. Parameters will be estimated using restricted maximum likelihood method with the 
Newton-Raphson algorithm. Denominator degrees of freedom will be estimated using Kenward-
Roger adjustment. All efficacy data after discontinuation of treatment will not be considered.  
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The same analysis will be conducted for lesional v-IGA-AD score at Days 8 and 15 and lesional 
PP-NRS. For the other efficacy parameters, only descriptive analyses will be provided. 
The weekly average PP-NRS scores will be defined as the average of daily non-missing scores 
within the week preceding the given visit and will be calculated if there is a minimal amount of 
4 non-missing scores. 
The POEM score is a 5-point scale: 0 (“No days”), 1 (“1-2 days”), 2 (“3-4 days”), 3 (“5-6 days”) 
and 4 (“Every day”). The POEM score is calculated by summing the values for the 7 items. 
If two or more questions are left unanswered the questionnaire is not scored. 
The DLQI is a 4-point scale: 0 (“Not relevant”/“Not at all”), 1 (“A little”), 2 (“A lot”), 3 (“Very 
much”). For Question 7, “Prevented work or studying” is scored at 3. The DLQI is calculated by 
summing the score of each question. 
The EASI-50/75/95/100 response is defined as a participant achieved a decrease by at least 
50%/ 75%/ 95%/100% of EASI from Day 15. 
Change in lesional TSS, PP-NRS (daily global and weekly average), EASI, BSA, SCORAD, 
POEM, DLQI during the Open label period will be analyzed descriptively. Estimations with 95% 
and 80% CIs may be derived. Sub-score of EASI by localization will also be provided.  
Supplemental analyses 
Where appropriate, supplemental analyses may be presented excluding observations after 
administration of rescue medication. No imputation will be made. 
3.5 
MULTIPLICITY ISSUES  
No adjustment will be made for multiple analyses. 
3.6 
SAFETY ANALYSES  
All safety analyses will be performed on the safety population as defined in Section 2, during double 
blind and Open-label period separately and overall unless otherwise specified, using the following 
common rules: 
• The analysis of the safety variables will be essentially descriptive, and no testing is planned.  
• Safety data in participants who do not belong to the safety population (eg, exposed but not 
randomized) will be provided separately. 
Safety data will be assigned to study phase as following: 
• Blinded Period, if the TEAE onset was between the first administration (Day 1) of any 
study intervention in the Blinded Period and the first administration of study intervention 
(SAR444727 Gel, 5%) in the Open-Label Period (scheduled Day 15 morning). 
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• Open-Label Period, if the TEAE onset was after the first administration of study 
intervention (SAR444727 Gel, 5%) in the Open-Label Period (scheduled Day 15 
morning). 
3.6.1 Extent of exposure  
The extent of IMP exposure will be assessed by the duration of IMP exposure and compliance and 
will be summarized in the safety population for the double-blind period and the Open-label 
period. 
Duration of IMP exposure 
For each study period, duration of IMP exposure is defined as last IMP administration date – first 
IMP administration date + 1 days, regardless of unplanned intermittent discontinuation(s). If the 
date of the last dose of IMP is missing, the duration of IMP will be left as missing. 
For each study period, duration of IMP exposure will be summarized quantitatively and 
categorically:  
• Double-blind period: 1 day to ≤7 days, > 8 to <15 days, and ≥15 days  
• Open-label period: 15 days to  ≤29 days,  > 29 to ≤43 days, and >43 days  
Additionally, the cumulative duration of treatment exposure defined as the sum of the duration of 
treatment exposure over each study period for all participants will be provided. 
Treatment compliance 
Percentage of treatment compliance for a participant will be defined as the number of 
administrations/days that the participant was compliant divided by the total number of 
administrations/days that the participant was planned to take from the first administration of IMP 
up to the actual last administration of IMP. 
Treatment compliance will be summarized over each study period, quantitatively and categorically: 
<80%, ≥80% by treatment (SAR444727 Gel, 5% or placebo) and overall for the Open-label phase. 
3.6.2 Adverse events  
General common rules for adverse events 
All AEs will be coded to a LLT, PT, HLT, HLGT, and associated primary SOC using the Medical 
Dictionary for Regulatory Activities (MedDRA) version currently in effect at Sanofi at the time of 
database lock. 
The AEs will be analyzed in the following 3 categories: 
• Pre-treatment AEs: AEs that developed, worsened or became serious during the pre-
treatment period. 
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• TEAEs: AEs that developed, worsened or became serious during the TE period 
• Post-treatment AEs: AEs that developed, worsened or became serious during the post-
treatment period  
Similarly, the AE leading to deaths will be analyzed in the pre-treatment, TE and post-treatment 
periods.  
The primary focus of AE reporting will be on TEAEs. Pre-treatment and post-treatment AEs will 
be described separately. Main summary will be per study period (Blinded Period, Open-Label 
Period) and overall. 
If selected TEAEs from the Blinded Period can be clearly assigned to one of the study interventions 
treated lesions, they may be presented additionally assigned to the treatment of the corresponding 
lesion. 
An AE with incomplete or missing date/time of onset (occurrence, worsening, or becoming 
serious) will be classified as a TEAE unless there is definitive information to determine it is a pre-
treatment or a post-treatment AE.  
If the assessment of the relationship to IMP is missing for an AE, this AE will be assumed as 
related to IMP. If the severity/grade is missing for an AE, the severity/grade will be left as 
missing. AEs which are possibly related to study intervention and have onset date after the first 
dose of SAR444727 will be considered possibly related to SAR444727, unless they are 
documented as possibly related to the study intervention formulation of the placebo-treated lesion 
and not possibly related to the study intervention formulation of the SAR4447272 Gel, 5%-treated 
lesion. 
The AE tables will be sorted as indicated in Table 3.  
Table 3 - Sorting of AE tables  
AE presentation 
Sorting rules 
SOC and PT 
By the internationally agreed SOC order and decreasing frequency of PTsa, b 
PT 
By decreasing frequency of PTsa 
a Sorting will be based on the overall incidence 
b The table of all TEAEs presented by SOC and PT will define the presentation order for all other tables (eg, treatment-emergent SAE) 
presented by primary SOC and PT, unless otherwise specified. 
Analysis of all adverse events 
The overview of TEAEs with the details below will be generated: 
• Any TEAE  
• Any severe TEAE 
• Any treatment emergent SAE 
• TEAE leading to death, if any 
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• Any TEAE leading to permanent intervention discontinuation 
• Any TEAE leading to permanent study discontinuation 
• Any treatment emergent AE of special interest (AESI) (Expedited reports as described in 
section 8.3.7 of the protocol will be considered as AESIs) 
The AE summaries of Table 4 will be generated with number (%) of participants experiencing at 
least one event and sorted by the internationally agreed SOC order and decreasing frequency of 
PTs. Sorting will be based on experimental study drug intervention group (see Table 3).  
Table 4 - Analyses of adverse events  
Type of AE 
MedDRA levels 
All TEAE 
Primary SOC and PT 
TEAE related to IMP as per Investigator’s judgment 
Primary SOC, and PT 
Treatment emergent SAE 
Primary SOC, and PT 
Treatment emergent SAE related to IMP as per Investigator’s 
judgment [optional] 
Primary SOC, and PT 
TEAE leading to permanent intervention discontinuation [optional] 
Primary SOC, and PT 
TEAE leading to death (death as an outcome of the AE as reported 
by the Investigator in the AE page) [optional] 
Primary SOC and PT 
AESI 
Primary SOC and PT 
In addition, the all TEAE summary by Primary SOC and PT will be performed by trial impact 
(disruption) due to COVID-19 (coronavirus disease 19). The number (%) of participants 
experiencing at least one treatment emergent COVID-19 related AE by primary SOC and PT, if 
applicable.  
Optional tables mentioned in Table 4 are to be done in case of sufficient number of events. 
Deaths, serious, and other significant adverse events 
Deaths and SAEs will be listed.  
Adverse events leading to intervention/study discontinuation 
AE leading to intervention or study discontinuation will be listed.  
Analysis of adverse events of special interest (AESIs)  
AESIs will be selected for analyses as indicated in Table 5. Number (%) of participants 
experiencing at least one event will be provided for each event of interest, by PT if applicable. 
Tables will be sorted as indicated in Table 3.  
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Table 5 - Selections for AESIs  
AESIs  
Selection 
Increase in alanine transaminase (ALT) 
e-CRF specific tick box on the AE page 
Pregnancy 
Specific page 
Symptomatic overdose (serious or 
nonserious) with IMP 
Specific page 
 
3.6.3 Additional safety assessments  
3.6.3.1 Vital signs, electrocardiograms (ECGs) and laboratory variables  
The following variables will be analyzed. They will be converted into standard international units. 
• Vital signs (see Section 8.2.2 of the protocol): heart rate, systolic and diastolic blood 
pressure, weight, temperature 
• ECG variables (see Section 8.2.3 of the protocol): heart rate, PR, QRS, QT, and corrected 
QTc (according to Bazett/Fridericia) 
•  Laboratory variables (see Section 8.2.4.1 of the protocol): hematology, clinical chemistry, 
coagulation, urinalysis  
For laboratory parameters, out-of-normal range definitions will be listed. 
Data below the Lower Limit Of Quantitation/detection limit (LLOQ) will be replaced by half of 
the LLOQ, data above the Upper Limit Of Quantification (ULOQ) will be replaced by ULOQ 
value. 
Quantitative analyses 
When relevant, vital signs, ECG variables above and for laboratory variables, descriptive statistics 
for results and changes from Baseline as appropriate will be provided for each planned visit and 
time/analysis window.  
For vital signs, ECG and laboratory variables, mean changes from Baseline with the 
corresponding standard error deviation will be plotted over time.  
Analyses according to PCSA 
PCSA analyses will be performed based on the PCSA list currently in effect at Sanofi at the time 
of the database lock. For laboratory parameters for which no PCSA criteria are defined, similar 
analyses will be done using out-of-normal ranges, if applicable. For parameters defined as 
efficacy/pharmacodynamic endpoints, PCSA summaries will not be provided. 
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Analyses according to PCSA will be performed based on the worst value during the TE period, 
using all measurements (either local or central, either scheduled, nonscheduled or repeated). 
For laboratory variables above, the incidence of participants with at least one PCSA during the TE 
period will be summarized regardless of the baseline level and according to the following baseline 
status categories: 
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 
Summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum and 
maximum) of all ECG variables (raw values and changes from Baseline) will be calculated for 
each planned visit by intervention group. In addition, mean changes from Baseline with the 
corresponding standard errors will be plotted over time in each intervention group.   
For ECGs, the incidence of participants with at least one abnormal ECG during the TE period will 
be summarized regardless of the baseline level and according to the following Baseline status 
categories:  
• Normal/missing 
• Abnormal 
Listing of participants with QTc >480 msec and/or change from baseline QTc >60 msec 
If any, an intext listing of participants with QTc >480 msec and/or change from Baseline 
QTc >60 msec will be provided. 
3.6.3.2 Local cutaneous tolerability  
The local cutaneous tolerability is assessed by the incidence and severity (grade) of application-site 
events such as burning/stinging, itching, and erythema.  
Grading of application site local tolerability symptoms will be recorded using the grading scale (cf 
Protocol Appendix 4, Section 10.4.1) following each dosing during the blinded period. During the 
Open Label period symptom grading will record worst symptom observed on the lesional areas 
treated within approximately 30 min after dosing. 
For each lesion, number and proportion of participants with at least one application-site event 
(such as burning/stinging, itching, and erythema) over the 2-week double-blind period, the 4-week 
Open label period, overall and by type of sign will be summarized. For each lesion, and by type of 
sign, the distribution of corresponding worst grade (intensity) will be summarized. The 
localization of the lesion on the body with an application-site event of local untolerability will be 
reported. 
Burning/stinging sub-score assessments over time by lesion during blinded period and overall 
during Open-label period will be also summarized. 
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Overview of AEs linked to local cutaneous tolerability will be presented by SOC, PT for each 
study period and overall. 
No analysis of the total score will be performed. 
3.7 
OTHER ANALYSES  
3.7.1 Other variables and/or parameters  
3.7.1.1 PK analyses  
For PK concentrations, the arithmetic mean, SD, median, minimum, maximum, percent 
coefficient of variation (CV%), geometric mean, geometric coefficient of variation (geometric 
CV%), and the number of observations below LLOQ values will be presented by timepoint. For 
the purpose of calculating summary statistics, plasma concentrations (and applicable metabolites) 
that are below the LLOQ will be set to 0 for both pre-dose and post-dose samples excepted for the 
geometric mean and associated coefficient of variation for which they will be considered as 
missing. Additional analyses will be performed as deemed necessary upon review of the data. 
Graphical displays of concentrations over time may also be presented. 
3.7.1.2 Biomarkers analyses  
Statistical analyses of biomarkers (RNAseq data, proteomic data…) will be exploratory in nature 
and will be detailed in a Biomarker SAP and results may be analysed separately. 
3.8 
INTERIM ANALYSES  
An interim analysis (IA) for internal decision making will be implemented when approximately 
25 or more of the planned participants have completed the Blinded Period (Day 15). Available 
data of the Open Label Period may be included in the analysis as appropriate.  
The outcome is meant for internal decision making and may lead to early termination of the study 
only in case of unfavorable signals, or continuation without any changes. 
3.8.1 General considerations for the interim analysis  
The Sponsor team that will analyze the data will include: a Medical Monitor, a biostatistician, a 
programmer, and a safety designee (global safety officer, [GSO]). Only the biostatistician and the 
programmer will have the  access to unblinded individual data at the time of the analysis, which 
will not be provided to other Sponsor team members reviewing the data. Results will be provided 
in a restricted way following a dissemination plan, issued before any treatment code release for 
the analysis established upfront before the unblinding. The blinding will be preserved notably 
toward the Investigator, other site staff involved in the conduct of the trial, and participants. 
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The results of this IA will be considered preliminary results as they will not be based on final 
data. Final analysis will be conducted after database lock for the clinical study report. 
Analyses methods and conventions described in the other sections of this SAP will be applied for 
all analyses as applicable.  
3.9 
CHANGES TO PROTOCOL-PLANNED ANALYSES  
No major statistical changes were included in the protocol amendment(s). 
One major statistical change in SAP to the current amended protocol has been made and is 
summarized in the section below: 
Major statistical changes in SAP to (current) amended protocol 
Current 
Amended 
Protocol 
Number 
Section 
Changes 
Rationale 
 
2- Analysis 
Populations 
Delete ITT population 
Redefine Efficacy population 
ITT population is not used in the analysis 
Efficacy population has been redefined to 
take into account compliance durin both 
periods (double-blind and open-label period) 
 
 
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4 
SAMPLE SIZE DETERMINATION  
No sample size calculations were performed due to the exploratory nature of this study. 
The sample size of up to 40 for this study with participants receiving both SAR444727Gel, 5% 
and placebo is based upon empirical clinical consideration. The sample size is considered 
adequate to evaluate the safety, tolerability, and PK of topically administered SAR444727.  
This study is signal seeking and neither aimed nor powered to provide formal inferential statistical 
analyses. 
 
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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
AD: 
atopic dermatitis 
AE: 
adverse event, adverse event 
AESIs: 
adverse events of special interest 
AUC: 
area under the curve 
BID: 
twice daily 
BLQ: 
below the limit of quantification 
BSA: 
body surface area 
CI: 
confidence interval 
Cmax: 
maximum plasma concentration 
COVID-19: 
coronavirus disease 19 
CV%: 
percent coefficient of variation 
DLQI: 
dermatology life quality index 
EASI: 
eczema area and skin severity index 
ECG: 
electrocardiogram 
EOS: 
end of study 
HLT: 
high level term 
ICF: 
inform consent form 
IMP: 
investigational medicinal product 
IRT: 
interactive responses technology 
LLOQ: 
lower limit of quantification 
LLT: 
lower-level term 
MedDRA: 
medical dictionary for regulatory activities 
PCSA: 
potentially clinically significant abnormality 
PK: 
pharmacokinetics 
POEM: 
patient oriented eczema measure 
PP-NRS: 
peak pruritus numeric rating scale 
PT: 
preferred term 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SCORAD: 
scoring atopic dermatitis 
SD: 
standard deviation 
SEM: 
standard error of the mean 
SOC: 
system organ class 
TE: 
treatment-emergent 
TEAE: 
treatment-emergent adverse event 
TSS: 
total sign score 
vIGA-AD: 
validated Investigator Global Assessment – Atopic Dermatitis 
WHO-DD: 
World Health Organization-drug dictionary 
 
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5.2 
APPENDIX 2 PARTICIPANT DISPOSITION  
The number (%) of participants included in each of the analysis populations listed in Table 2 will 
be provided.  
Screen failures are defined as participants who consent to participate in the study (ie, signed the 
informed consent form [ICF]) but are not subsequently randomized. The number (%) of screen 
failures and reasons for screen failures will be provided in the screened population. 
The number (%) of participants in the following categories will be provided:  
• Screen / screen-failed 
• Randomized participants 
• Randomized but not exposed participants  
• Randomized and exposed participants (ie, having a randomization number assigned and 
who received at least one administration of IMP 
• Participants who did not complete the study treatment period as per protocol and main 
reason for permanent intervention discontinuation  
• Participants who completed the study period as per protocol 
• Participants who did not complete the study period as per protocol and main reason for 
study discontinuation  
• Reason for study period withdrawal by subject 
Reasons for permanent study intervention and study discontinuation “AE” and “other reasons” 
will be split as related versus not related to COVID-19. 
The number (%) of exposed and not randomized participants will also be summarized, if 
applicable.  
Listings of participants with permanent study intervention discontinuation or with premature end 
of study (i.e. who did not complete the study period as per protocol) will be provided for the 
safety population along with the main reason of discontinuations and related to COVID-19 or not, 
respectively. 
A summary of visits impacted by COVID-19 pandemic will be provided along with the 
description of the impact (visit not done, visit partially done on site / by phone, visit done but 
delayed), if applicable. In addition, the number (%) for reasons for exclusion from COVID-19 
non-impacted population will be provided, if applicable. A listing of participants excluded from 
this population will be provided. 
Protocol deviations 
Critical and major protocol deviations (automatic or manual) will be listed in the randomized 
population. They will be displayed separately as related versus not related to COVID-19. The list 
of predefined protocol deviations can be found in the eTMF (Trial management Section). 
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5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS  
Demographics, baseline characteristics, medical surgical history  
The following demographics and baseline characteristics, medical and surgical history and disease 
characteristics at baseline will be summarized using descriptive statistics in the randomized 
population. 
Demographic and baseline characteristics 
• age in years as quantitative variable and in categories (18 to <65, ≥65) 
• gender (Male, Female) 
• race (White, Black or African American…)  
• ethnicity [(Hispanic or Latino, not Hispanic or Latino)] 
• weight, height, body mass index screening v-IGA-AD score 
• screening %BSA 
• EASI 
Target lesion baseline (lesional TSS, lesional PP-NRS, lesional v-IGA-AD) characteristics data 
will be summarized by treatment. 
Baseline safety and efficacy parameters (apart from those listed above) will be presented along 
with the safety and efficacy summaries. 
Specific disease history includes time from diagnosis, severity of the disease (v-IGA-AD) will be 
summarized. 
Medical and surgical history 
Additionally, all medical and surgical history will be coded to a LLT, PT, HLT, HLGT, and 
associated primary SOC using the MedDRA version currently in effect at Sanofi at the time of 
database lock. All medical history will be summarized by primary SOC and PT using a frequency 
table (number and % of participants) by study intervention group. 
Prior or concomitant medications 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock.  
• Prior medications are those the participant used prior to first IMP intake. Prior medications 
can be discontinued before first administration or can be ongoing during study intervention 
period. 
• Concomitant medications are any medications received by the participant during the TE 
period. 
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• Post-treatment medications are those the participant took after the TE period. 
A given medication can be classified as a prior medication and/or as a concomitant medication 
and/or as post-treatment medication. If it cannot be determined whether a given medication was 
taken prior or concomitantly or post, it will be considered as prior, concomitant, and post-
treatment medication. 
The prior and concomitant medications will be summarized for the safety population, by anatomic 
and therapeutic level. The summaries will be sorted by decreasing frequency of anatomic category 
(ATC) based on incidence in SAR444727 group. In case of equal frequency, alphabetical order 
will be used. Participants will be counted once in each ATC category (anatomic or therapeutic) 
linked to the medication.  
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS  
Double blind analysis period is defined from the date of first IMP up to Day15 or date of IMP 
discontinuation which ever comes first. 
Day15 of Open label period is defined as the first day the placebo is not used.  
For parameters with evaluations before administration and in cases of rechecked value(s) for one 
participant, only the last observation will be used as baseline in descriptive statistics and 
derivations of other parameter values. After baseline, only observations planned in the protocol 
will be used in descriptive statistics. 
For clinical laboratory parameters with non-numeric values, the imputed values used for the 
descriptive statistics and/or the flags will be determined by considering the following rules: 
• 
If database value is ‘ <X’, the value used will be X/2 
• 
If database value is ‘ >X’, the value used will be X 
• 
If database value is a range (eg, ‘X – Y’), the values used will be (Y + X)/2 
Pharmacokinetic analysis 
For ease of presentation, mean values will be arithmetic mean unless specified. Concentration 
values below the plasma assay limit will be treated as zero in all summary statistics. Mean values 
below LLOQ will be reported as LLOQ in the tables and not plotted in the figures if after 
maximal plasma concentration (Cmax). Mean calculations and their associated statistics will be 
generated from unrounded numbers and may differ slightly from those values that would be 
determined using the rounded numbers displayed in the tables. Values expressed in all tables will 
before ease of presentation and will not be meant to imply accuracy to more than 3 significant 
figures.  
Area under the curve (AUC) values extrapolated by more than 30% will be excluded from any 
pharmacokinetic statistical analysis. 
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Analysis windows for time points 
The following analysis windows will decide how the scheduled and/or unscheduled visits will be 
used in the by-visit analyses of efficacy. For participants with premature study discontinuation, 
follow-up measurements will be reallocated to the corresponding analysis window and reported 
together with other measurements. 
A measurement (scheduled or unscheduled) will be used if it is available and measurement date is 
within the analysis window.  
After applying these time windows, if multiple assessments are associated to the same time point, 
the closest from the targeted study day will be used. If the difference is a tie, the value after the 
targeted study day will be used. If multiple valid values exist within a same day, then the first 
value of the day will be selected when time is available, otherwise the scheduled exam will be 
used.  
If there is no measurement for a given parameter in an analysis window, data will be considered 
missing for the corresponding visit.  
Table 6 - Analyses window definition  
Study period 
Scheduled visit 
post baseline 
Targeted 
study day 
Analysis window in study days 
Double blind period 
Day 8 
8 
7 to 9 
 
Day 15 
15 
13 to 18 
Open label period 
Day 29  
29 
25 to 33 
 
Day 43  
43 
39 to 47 
Study days are calculated considering Day 1 as the day of first administration of intervention in blinded period. 
Unscheduled and end of treatment (EOT)/EOS visits 
Unscheduled visit measurements of efficacy, laboratory data, vital signs, PK and biomarkers will 
be used, in particular for computation of Baseline, the last on-treatment value, analysis according 
to PCSAs, and the shift summaries for safety. They will also be included in the by-visit 
summaries if they are re-allocated to scheduled visits. 
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