A Phase 3, Double-Blind, Randomized, Vehicle-Controlled, Efficacy and Safety Study of Ruxolitinib Cream in Participants With Prurigo Nodularis
Phase: PHASE3
Conditions: Prurigo Nodularis
Sponsor: Incyte Corporation

Official Title: 
A Phase 3, Double-Blind, Randomized, Vehicle-Controlled, Efficacy and Safety 
Study of Ruxolitinib Cream in Participants With Prurigo Nodularis 
NCT Number: 
NCT05764161 
Document Date: 
Protocol INCB 18424-320 Am 2 Version 3 21 FEB 2024 
 
 
 

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Protocol INCB 18424-320 Am 2 
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Clinical Study Protocol 
 
TITLE PAGE 
INCB 18424-320 
A Phase 3, Double-Blind, Randomized, Vehicle-Controlled, Efficacy 
and Safety Study of Ruxolitinib Cream in Participants With 
Prurigo Nodularis 
 
Topical Ruxolitinib Evaluation in Prurigo Nodularis (TRuE-PN2) 
 
Product: 
Ruxolitinib Cream 
IND Number: 
77101 
EU CT Number: 
2022-502461-23-00 
Phase of Study: 
3 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 USA 
Original Protocol: 
01 DEC 2022 
Amendment 1: 
21 JUN 2023 
Amendment 2: 
21 FEB 2024 
 
This study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki (Brazil 2013) and conducted in adherence to the study Protocol, applicable Good Clinical Practices, and 
applicable laws and country-specific regulations, including WMO (Medical Research Involving Human Participants 
Act) and Clinical Trials Regulation (EU) No. 536/2014, in which the study is being conducted. 
The information in this document is confidential. No part of this information may be duplicated, referenced, or 
transmitted in any form or by any means (electronic, mechanical, photocopy, recording, or otherwise) without prior 
written consent. 

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INVESTIGATOR'S AGREEMENT 
I have read the INCB 18424-320 Protocol Amendment 2 (dated 21 FEB 2024) and agree to 
conduct the study as outlined. I agree to maintain the confidentiality of all information received 
or developed in connection with this Protocol. 
 
 
 
 
 
(Printed Name of Investigator) 
 
 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 

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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR'S AGREEMENT ................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF ABBREVIATIONS ..........................................................................................................8 
1. 
PROTOCOL SUMMARY ..........................................................................................11 
2. 
INTRODUCTION ......................................................................................................21 
2.1. 
Background .................................................................................................................21 
2.1.1. 
Ruxolitinib Cream ......................................................................................................21 
2.1.2. 
Prurigo Nodularis ........................................................................................................21 
2.2. 
Study Rationale ...........................................................................................................22 
2.2.1. 
Scientific Rationale for Study Design ........................................................................23 
2.2.2. 
Justification for Dose ..................................................................................................23 
2.2.3. 
Justification for Vehicle Control ................................................................................24 
2.3. 
Benefit/Risk Assessment ............................................................................................24 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................25 
4. 
STUDY DESIGN .......................................................................................................27 
4.1. 
Overall Design ............................................................................................................27 
4.2. 
Overall Study Duration ...............................................................................................27 
4.3. 
Study Termination ......................................................................................................27 
5. 
STUDY POPULATION .............................................................................................28 
5.1. 
Inclusion Criteria ........................................................................................................28 
5.2. 
Exclusion Criteria .......................................................................................................29 
5.3. 
Lifestyle Considerations .............................................................................................32 
5.4. 
Screen Failures ............................................................................................................32 
5.5. 
Replacement of Participants .......................................................................................33 
5.6. 
Data Monitoring Committee .......................................................................................33 
6. 
STUDY TREATMENT ..............................................................................................34 
6.1. 
Study Treatments Administered .................................................................................34 
6.2. 
Preparation, Handling, and Accountability ................................................................35 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................36 
6.4. 
Study Treatment Compliance .....................................................................................37 

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6.5. 
Dose Modifications .....................................................................................................37 
6.5.1. 
Criteria and Procedures for Dose Interruptions and Adjustments of Study 
Cream ..........................................................................................................................37 
6.5.2. 
Criteria for Permanent Discontinuation of Study Cream ...........................................39 
6.6. 
Concomitant Medications and Procedures .................................................................39 
6.6.1. 
Permitted Medications and Procedures ......................................................................40 
6.6.2. 
Restricted Medications and Procedures ......................................................................40 
6.6.3. 
Prohibited Medications and Procedures .....................................................................41 
6.7. 
Treatment After the End of the Study .........................................................................41 
7. 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
WITHDRAWAL ........................................................................................................42 
7.1. 
Discontinuation of Study Treatment ...........................................................................42 
7.1.1. 
Reasons for Discontinuation .......................................................................................42 
7.1.2. 
Discontinuation Procedures ........................................................................................43 
7.2. 
Participant Withdrawal From the Study .....................................................................43 
7.3. 
Lost to Follow-Up.......................................................................................................44 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................45 
8.1. 
Administrative and General Procedures .....................................................................45 
8.1.1. 
Informed Consent Process ..........................................................................................45 
8.1.2. 
Screening Procedures ..................................................................................................46 
8.1.3. 
Interactive Response Technology Procedure ..............................................................46 
8.1.4. 
Distribution of Reminder Cards and/or eDiaries ........................................................46 
8.1.5. 
Demography and Medical History ..............................................................................46 
8.1.5.1. 
Demographics and General Medical History .............................................................46 
8.1.5.2. 
Disease Characteristics and Treatment History ..........................................................47 
8.1.6. 
Exit Interviews ............................................................................................................47 
8.2. 
Efficacy Assessments .................................................................................................48 
8.2.1. 
Worst-Itch Numeric Rating Scale ...............................................................................48 
8.2.2. 
Investigator's Global Assessment ...............................................................................48 
8.2.2.1. 
Investigator Global Assessment for Stage of Chronic Prurigo (IGA-CPG-S) ...........48 
8.2.2.2. 
Investigator Global Assessment for Activity of Chronic Prurigo 
(IGA-CPG-A) .............................................................................................................48 
8.2.3. 
Prurigo Activity Score ................................................................................................49 

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8.2.4. 
Body Surface Area ......................................................................................................49 
8.2.5. 
Photography ................................................................................................................49 
8.3. 
Patient-Reported Outcomes ........................................................................................50 
8.3.1. 
Electronic Diary Assessments: Worse-Itch Numeric Rating Scale and Skin 
Pain Numeric Rating Scale .........................................................................................50 
8.3.2. 
Skin Pain Numeric Rating Scale.................................................................................50 
8.3.3. 
Dermatology Life Quality Index ................................................................................50 
8.3.9. 
Health Economics .......................................................................................................52 
8.3.9.1. 
EQ-5D-5L ...................................................................................................................52 
8.3.9.2. 
Work Productivity and Activity Index .......................................................................53 
8.4. 
Safety Assessments .....................................................................................................53 
8.4.1. 
Adverse Events ...........................................................................................................53 
8.4.2. 
Physical Examinations ................................................................................................54 
8.4.3. 
Vital Signs ..................................................................................................................54 
8.4.4. 
Electrocardiograms .....................................................................................................54 
8.4.5. 
Laboratory Assessments .............................................................................................54 
8.4.5.1. 
Pregnancy Testing ......................................................................................................57 
8.4.5.2. 
HIV Testing ................................................................................................................57 
8.4.5.3. 
Hepatitis Testing .........................................................................................................57 
8.5. 
Pharmacokinetic Assessments ....................................................................................58 
8.7. 
Unscheduled Visits .....................................................................................................59 
8.8. 
End of Treatment and/or Early Termination ..............................................................60 
8.9. 
Follow-Up ...................................................................................................................60 
8.9.1. 
Safety Follow-Up ........................................................................................................60 

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9. 
ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ......................61 
9.1. 
Definition of Adverse Event .......................................................................................61 
9.2. 
Definition of Serious Adverse Event ..........................................................................62 
9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse Events .........63 
9.4. 
Reporting of Serious Adverse Events .........................................................................65 
9.5. 
Potential Drug-Induced Liver Injury ..........................................................................67 
9.6. 
Events of Clinical Interest ..........................................................................................67 
9.7. 
Emergency Unblinding of Treatment Assignment .....................................................67 
9.8. 
Pregnancy ...................................................................................................................67 
9.9. 
Warnings and Precautions ..........................................................................................68 
9.10. 
Product Complaints ....................................................................................................68 
9.11. 
Treatment of Overdose ...............................................................................................68 
10. 
STATISTICS ..............................................................................................................69 
10.1. 
Sample Size Determination ........................................................................................69 
10.2. 
Populations for Analysis .............................................................................................69 
10.3. 
Level of Significance ..................................................................................................70 
10.4. 
Statistical Analyses .....................................................................................................70 
10.4.1. 
Primary Analysis ........................................................................................................70 
10.4.2. 
Key Secondary Analysis .............................................................................................72 
10.4.3. 
Secondary Analyses ....................................................................................................73 
10.4.4. 
Safety Analyses ..........................................................................................................73 
 
 
10.5 
Interim Analysis ..........................................................................................................74 
11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................75 
11.1. 
Investigator Responsibilities .......................................................................................75 
11.1.1. 
Identification of the Coordinating Principal Investigator ...........................................76 
11.2. 
Data Management .......................................................................................................76 
11.3. 
Data Quality Assurance ..............................................................................................78 
11.4. 
Data Privacy and Confidentiality of Study Records ...................................................79 
11.5. 
Financial Disclosure ...................................................................................................79 
11.6. 
Publication Policy .......................................................................................................80 

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11.7. 
Study and Site Closure................................................................................................80 
12. 
REFERENCES ...........................................................................................................81 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS AND DEFINITIONS ............................................84 
APPENDIX B. COVID-19 PANDEMIC MITIGATION STRATEGIES AND 
INSTRUCTIONS .......................................................................................................86 
APPENDIX C. PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................89 
 
LIST OF TABLES 
Table 1: 
Primary and Key Secondary Objectives and Endpoints .............................................11 
Table 2: 
Key Study Design Elements .......................................................................................12 
Table 3: 
Schedule of Activities for the Double-Blind Vehicle-Controlled Period ...................14 
Table 4: 
Schedule of Activities for the Open-Label Extension Period .....................................18 
Table 5: 
Objectives and Endpoints ...........................................................................................25 
Table 6: 
Study Treatment Information .....................................................................................35 
Table 7: 
Guidelines for Interruption of Study Cream for Treatment-Related Adverse 
Events and Restarting of Study Cream .......................................................................38 
Table 8: 
IGA-CPG-S.................................................................................................................48 
Table 9: 
IGA-CPG Activity ......................................................................................................49 
Table 10: Required Laboratory Analytes ....................................................................................56 
Table 11: Interpretation and Management of HBV Serologic Test Results ...............................57 
Table 12: Powering for Key Secondary Endpoints .....................................................................69 
Table 13: Populations for Analysis .............................................................................................70 
Table 14: Summary of Primary Analysis....................................................................................71 
Table 15: Summary of Key Secondary Analyses .......................................................................73 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema .................................................................................................13 
 

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LIST OF ABBREVIATIONS 
Abbreviations and 
Special Terms 
Definition 
AD 
atopic dermatitis 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BID 
twice daily 
BSA 
body surface area 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CMH 
Cochran-Mantel-Haenszel 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
coronavirus disease 2019 
CP 
conditional power 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DBVC 
double-blind, vehicle-controlled 
DLQI 
Dermatology Life Quality Index 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
EASI 
Eczema Area and Severity Index 
EASI75 
75% reduction from baseline in Eczema Area and Severity Index 
EC 
Executive Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eDiary 
electronic diary 
EOT 
end of treatment 
ET 
early termination 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 

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Abbreviations and 
Special Terms 
Definition 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
HADS 
Hospital Anxiety and Depression Scale 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HCVAb 
hepatitis C virus antibody 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
human immunodeficiency virus 
HRQoL 
health related quality of life 
HRT 
hormone replacement therapy 
IB 
Investigator's Brochure 
ICF 
informed consent form  
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ID 
identification 
IEC 
Independent Ethics Committee 
IGA 
Investigator's Global Assessment 
IGA-CPG-A 
Investigator Global Assessment for Activity of Chronic Prurigo 
IGA-CPG-S-TS 
Investigator's Global Assessment for Stage of Chronic Prurigo Treatment 
Success is defined as an IGA-CPG-S score of 0 or 1 with ≥ 2-grade 
improvement from baseline 
IGA-CPG-S 
Investigator Global Assessment for Stage of Chronic Prurigo 
IL 
interleukin 
IRB 
institutional review board 
IRT 
interactive response technology  
ITT 
intent-to-treat 
JAK 
Janus kinase 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
numeric rating scale 
OLE 
open-label extension 
PAS 
Prurigo Activity Score 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic(s) 

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Abbreviations and 
Special Terms 
Definition 
PDE 
phosphodiesterase 
 
 
 
 
PK 
pharmacokinetic(s) 
PN 
prurigo nodularis 
PP 
per protocol 
PRO 
patient-reported outcome  
 
 
QALY 
quality-adjusted life-year 
RNA 
ribonucleic acid 
RSI 
Reference Safety Information 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SNRI 
serotonin and norepinephrine reuptake inhibitor 
SoA 
schedule of activities 
SOP 
standard operating procedure 
SPF 
sun protection factor 
SSRI 
selective serotonin reuptake inhibitor 
STAT 
signal transducer and activator of transcription 
TCI 
topical calcineurin inhibitors 
TCS 
topical corticosteroids 
TEAE 
treatment-emergent adverse event 
Th 
T helper  
TYK 
tyrosine kinase 
ULN 
upper limit of normal 
VAS 
visual analog scale 
WI-NRS 
Worst-Itch Numeric Rating Scale 
WI-NRS4 
≥ 4-point improvement in WI-NRS score 
WPAI 
Work Productivity Index 
WOCBP 
women of childbearing potential 

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1. 
PROTOCOL SUMMARY 
Protocol Title: 
A Phase 3, Double-Blind, Randomized, Vehicle-Controlled, Efficacy and Safety Study of 
Ruxolitinib Cream in Participants With Prurigo Nodularis 
Topical Ruxolitinib Evaluation in Prurigo Nodularis (TRuE-PN2) 
Protocol Number: INCB 18424-320 
Objectives and Endpoints: 
Table 1 presents the primary and major/key secondary objectives and endpoints. 
Table 1: 
Primary and Key Secondary Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To demonstrate the efficacy of ruxolitinib 1.5% 
cream BID in participants with PN. 
WI-NRS4 response at Week 12, defined as 
achieving a ≥ 4-point improvement (reduction) in 
WI-NRS score from baseline. 
Key Secondary 
To further demonstrate the treatment effects of 
ruxolitinib 1.5% cream BID in participants 
with PN. 
• 
WI-NRS4 response at Week 4. 
• 
Overall-TS at Week 12, defined as achieving 
both a WI-NRS4 response and an 
IGA-CPG-S-TS. 
(IGA-CPG-S-TS is defined as an IGA-CPG-S 
score of 0 or 1 with a ≥ 2 grade improvement 
from baseline.) 
• 
IGA-CPG-S-TS at Week 12. 
• 
WI-NRS4 response on Day 7. 
Overall Design: 
Table 2 presents the key study design elements. Further study details are presented after the 
table. 

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Table 2: 
Key Study Design Elements 
Study Phase 
Phase 3 
Clinical Indication 
Treatment of adults with PN 
Population 
Male and female participants at least 18 years of age who have a 
clinical diagnosis of PN for at least 3 months, IGA-CPG-S score of ≥ 2, 
≥ 6 pruriginous lesions on ≥ 2 different body areas, and PN-related 
WI-NRS score ≥ 7. Note: The total estimated BSA treatment area must 
be ≤ 20%. Treatment area is defined as the area affected by pruriginous 
lesions plus an ~ 1 cm area surrounding each lesion. 
Number of Participants 
Approximately 180 participants will be randomized 1:1 to 1 of 
2 treatment groups (ruxolitinib 1.5% cream BID or vehicle cream BID) 
stratified by baseline IGA-CPG-S score and geographic region. 
Participants with an IGA-CPG-S score of 2 will constitute up to 
approximately 20% of the overall study population. 
Study Design 
This is a randomized, 12-week, DBVC study with a 40-week OLE 
period with active treatment for participants who complete 12 weeks of 
treatment during the DBVC period followed by a 30-day post-treatment 
safety follow-up visit.  
Estimated Duration of 
Study Participation 
Up to approximately 60 weeks, including up to 4 weeks for screening, 
up to 52 weeks for treatment, and 30 days for safety follow-up. 
DMC 
No (see Section 5.6) 
Coordinating Principal 
Investigator 
To be determined 
Treatment Groups and Duration: 
Approximately 180 adults with PN (≥ 6 pruriginous lesions [defined as: papules, nodules, 
plaques, umbilicated lesions, and linear lesions] on ≥ 2 different body areas) will be randomized 
1:1 to either ruxolitinib 1.5% cream or vehicle cream. The total estimated BSA treatment area 
must be ≤ 20%. Treatment area is defined as the area affected by pruriginous lesions plus an 
~ 1 cm area surrounding each lesion. During the DBVC period, eligible participants will apply 
either ruxolitinib 1.5% cream or vehicle cream (both BID) to all pruriginous lesions identified at 
baseline (including ~ 1 cm area surrounding each lesion). The BID applications should continue 
through the end of the DBVC period (Week 12) unless the participant meets criteria for stopping 
study cream. 
At Week 12, participants who have completed 12 weeks of treatment with no safety concerns 
will enter the 40-week OLE period. Affected areas will be treated intermittently based on the 
presence of pruriginous lesions and/or PN-related itch. The investigator will assess whether the 
participant requires continuation of therapy (IGA-CPG-S score ≥ 1 and/or the presence of 
PN-related itching). During the OLE period, all participants will apply ruxolitinib 1.5% cream 
BID, to PN affected areas only plus an ~ 1 cm area around each pruriginous lesion and/or to 
areas of PN-related itching. 
The safety follow-up period should occur 30 days (+ 7-day visit window) after the 
Week 52/EOT2 or ET visit (or 30 days after the last application of study cream if the 

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Week 52/EOT2 or ET visit was not performed). If the participant is in the OLE period and has 
been in an observation/no-treatment cycle with an IGA-CPG-S score of 0 and a WI-NRS score 
of 0 for at least 30 days prior to the Week 52/EOT2 visit, then the Week 52/EOT2 visit will also 
count as the safety follow-up visit. 
Figure 1 presents the study design schema, and Table 3 and Table 4 present the SoA. Adherence 
to the study design requirements, including those specified in the SoA, is essential and required 
for study conduct. 
Figure 1: 
Study Design Schema 

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Table 3: 
Schedule of Activities for the Double-Blind Vehicle-Controlled Period 
Visit Day (Range) 
Screening 
DBVC Period 
Notes 
Days −28 to −1 
Baseline/Day 1 
Week 2 
(± 3 d) 
Week 4 
(± 3 d) 
Week 8 
(± 3 d) 
Week 12/EOT1 
(± 3 d) 
Administrative procedures 
Informed consent (including photographic 
and skin tape ICF, as applicable) 
X 
 
 
 
 
 
Section 8.1.1  
Informed consent for optional qualitative 
exit interviews 
Note: A subgroup of participants at 
sponsor-selected sites will be included 
in a substudy involving exit interviews 
X 
 
 
 
 
 
Section 8.1.6 
If consent to provide exit 
interviews was not obtained at 
screening, it can be obtained at 
any visit prior to Week 12. 
Contact IRT 
X 
X 
X 
X 
X 
X 
Section 8.1.3 
Inclusion/exclusion criteria review 
X 
X 
 
 
 
 
Section 5.1, Section 5.2 
Demography and medical history (general 
and disease, including Fitzpatrick Skin 
Type) 
X 
 
 
 
 
 
Section 8.1.5 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
Section 6.6 
Apply study cream in clinic under site 
supervision 
 
X 
 
 
 
X 
Section 6.1 
Weigh/dispense study cream 
 
X 
X 
X 
X 
X 
Section 6.1 
Distribute reminder cards 
X 
X 
X 
X 
X 
X 
Section 8.1.4 
Collect/weigh study cream 
 
 
X 
X 
X 
X 
Section 6.2 
Issue eDiary 
X 
 
 
 
 
 
Section 8.1.4, Section 8.3.1  
Assess eDiary study cream application 
compliance 
 
X 
X 
X 
X 
X 
Section 6.4 
Assess eDiary PRO compliance 
X 
X 
X 
X 
X 
X 
Section 8.3, Section 8.3.1 
Contact participant 1 week prior to each 
study visit to confirm compliance with 
WI-NRS assessment 
 
X 
X 
X 
X 
X 
Section 8.2.1, Section 8.3.1 

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Table 3: 
Schedule of Activities for the Double-Blind Vehicle-Controlled Period (Continued) 
Visit Day (Range) 
Screening 
DBVC Period 
Notes 
Days −28 to −1 
Baseline/Day 1 
Week 2 
(± 3 d) 
Week 4 
(± 3 d) 
Week 8 
(± 3 d) 
Week 12/EOT1 
(± 3 d) 
Safety assessments 
AE assessments 
X 
X 
X 
X 
X 
X 
Section 8.4.1 
If an AE is noted, that body 
system should be physically 
examined 
Comprehensive physical examination 
X 
 
 
 
 
 
Section 8.4.2 
Targeted physical examination (as needed 
based on AEs) 
 
X 
X 
X 
X 
X 
Section 8.4.2 
Height and body weight 
X 
 
 
 
 
 
Section 8.4.2  
Vital signs 
X 
X 
X 
X 
X 
X 
Section 8.4.3 
12-lead ECG 
X 
 
 
 
 
 
Section 8.4.4 
Efficacy assessments 
WI-NRS 
eDiary is completed each evening from screening through the last application of study cream. 
Section 8.2.1 
%BSA of estimated treatment area*† 
X 
X 
X 
X 
X 
X 
Section 8.2.4 
*Total estimated BSA 
treatment area (excluding the 
scalp) must be ≤ 20% to be 
eligible for study entry and 
continued participation 
†Treatment area is defined as 
the area affected by pruriginous 
lesions plus an ~ 1 cm area 
surrounding each lesion 
IGA-CPG-S 
X 
X 
X 
X 
X 
X 
Section 8.2.2.1 
IGA-CPG-A 
X 
X 
X 
X 
X 
X 
Section 8.2.2.2 
PAS 
X 
X 
X 
X 
X 
X 
Section 8.2.3 
Photography 
 
X 
X 
X 
X 
X 
Section 8.2.5 

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Table 3: 
Schedule of Activities for the Double-Blind Vehicle-Controlled Period (Continued) 
Visit Day (Range) 
Screening 
DBVC Period 
Notes 
Days −28 to −1 
Baseline/Day 1 
Week 2 
(± 3 d) 
Week 4 
(± 3 d) 
Week 8 
(± 3 d) 
Week 12/EOT1 
(± 3 d) 
Patient-reported outcomes 
Skin Pain NRS 
eDiary is completed each evening from screening through the last application of study cream. 
Section 8.3.2 
DLQI 
 
X 
X 
X 
X 
X 
Section 8.3.3 
EQ-5D-5L 
 
X 
X 
X 
X 
X 
Section 8.3.9.1 
Laboratory assessments 
Chemistry assessments 
X 
X* 
 
 
 
X 
Section 8.4.5 
*Not necessary if screening 
assessment is performed within 
14 days of Day 1 
Hematology assessments 
X 
X* 
 
 
 
X 
FSH 
X 
 
 
 
 
 
Section 8.4.5 
Women of nonchildbearing 
potential only 
Serum pregnancy test 
X 
 
 
 
 
 
Section 8.4.5.1 
WOCBP only; positive urine 
test to be confirmed by serum 
test 
Urine pregnancy test 
 
X 
 
X 
X 
X 
HIV serology 
X 
 
 
 
 
 
Section 8.4.5.2 
Hepatitis testing 
X 
 
 
 
 
 
Section 8.4.5.3 
Participants who enrolled prior 
to Protocol Amendment 1 
should have hepatitis testing 
performed at the next 
scheduled or unscheduled visit. 
Thyroid test 
X 
 
 
 
 
 
Section 8.4.5 

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Table 3: 
Schedule of Activities for the Double-Blind Vehicle-Controlled Period (Continued) 
Visit Day (Range) 
Screening 
DBVC Period 
Notes 
Days −28 to −1 
Baseline/Day 1 
Week 2 
(± 3 d) 
Week 4 
(± 3 d) 
Week 8 
(± 3 d) 
Week 12/EOT1 
(± 3 d) 
Note: All Week 12 assessments must be completed before the participant can continue into the OLE period. Study cream will not be applied in the clinic at Week 12 for 
participants not continuing into the OLE period. 
Note: Patient-reported outcomes (with the exception of the WI-NRS and Skin Pain NRS) must be conducted before any other assessments. 
Note: Blood draw for clinical laboratory tests must be performed before the in-clinic study cream application. 
Note: Pharmacokinetic assessments must be performed before study cream application. 

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Table 4: 
Schedule of Activities for the Open-Label Extension Period 
Visit Day (Range) 
OLE Period 
Safety 
Follow-Up 
Notes 
Week 14 
(± 3 d) 
Week 16, 
20, 24 
(± 3 d) 
Week 28, 
32, 36 
(± 3 d) 
Week 40, 
44, 48 
(± 3 d) 
Week 52/EOT2, 
ET 
(± 3 d) 
30 Days 
(+ 7 d) After 
Last Dose 
Administrative procedures 
Contact IRT 
X 
X 
X 
X 
X 
 
Section 8.1.3 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
Section 6.6 
Weigh/dispense study cream 
X 
X 
X 
X 
 
 
Section 6.1 
Distribute reminder cards 
X 
X 
X 
X 
X 
 
Section 8.1.4 
Collect/weigh study cream 
X 
X 
X 
X 
X 
 
Section 6.2 
Assess eDiary study cream application compliance 
X 
X 
X 
X 
X 
 
Section 6.4 
Assess eDiary PRO compliance 
X 
X 
X 
X 
X 
 
Section 8.3, 
Section 8.3.1 
Contact participant 1 week prior to each study visit to 
confirm compliance with WI-NRS assessment  
X 
X 
X 
X 
X 
 
Section 8.2.1, 
Section 8.3.1 
Safety assessments 
AE assessments* 
X 
X 
X 
X 
X 
X 
Section 8.4.1 
*If an AE is noted, that 
body system should be 
physically examined 
Comprehensive physical examination 
 
 
 
 
 
X 
Section 8.4.2 
Targeted physical examination (as needed; based on AEs) 
X 
X 
X 
X 
X 
X 
Section 8.4.2 
Vital signs 
X 
X 
X 
X 
X 
X 
Section 8.4.3 

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Table 4: 
Schedule of Activities for the Open-Label Extension Period (Continued) 
Visit Day (Range) 
OLE Period 
Safety 
Follow-Up 
Notes 
Week 14 
(± 3 d) 
Week 16, 
20, 24 
(± 3 d) 
Week 28, 
32, 36 
(± 3 d) 
Week 40, 
44, 48 
(± 3 d) 
Week 52/EOT2, 
ET 
(± 3 d) 
30 Days 
(+ 7 d) After 
Last Dose 
Efficacy assessments 
WI-NRS 
eDiary is completed each evening from screening through the last 
application of study cream. 
 
Section 8.2.1  
%BSA of treatment area* 
X 
X 
X 
X 
X 
X 
Section 8.2.4 
Total estimated BSA 
treatment area (excluding 
the scalp) must be ≤ 20% 
for continued participation 
*Treatment area is defined 
as the area affected by 
pruriginous lesions plus an 
~ 1 cm area surrounding 
each lesion 
IGA-CPG-S 
X 
X 
X 
X 
X 
X 
Section 8.2.2.1 
IGA-CPG-A 
X 
X 
X 
X 
X 
X 
Section 8.2.2.2 
PAS 
X 
X 
X 
X 
X 
X 
Section 8.2.3 
Photography 
X 
X* 
X† 
X‡ 
X 
 
Section 8.2.5 
*Week 20 only 
†Weeks 28 and 36 only 
‡Week 44 only 
Patient-reported outcomes 
Skin Pain NRS 
eDiary is completed each evening from screening through the last 
application of study cream. 
 
Section 8.3.2 
DLQI 
X 
X 
X 
X 
X 
X 
Section 8.3.3  
EQ-5D-5L 
X 
X 
X 
X 
X 
 
Section 8.3.9.1 

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Table 4: 
Schedule of Activities for the Open-Label Extension Period (Continued) 
Visit Day (Range) 
OLE Period 
Safety 
Follow-Up 
Notes 
Week 14 
(± 3 d) 
Week 16, 
20, 24 
(± 3 d) 
Week 28, 
32, 36 
(± 3 d) 
Week 40, 
44, 48 
(± 3 d) 
Week 52/EOT2, 
ET 
(± 3 d) 
30 Days 
(+ 7 d) After 
Last Dose 
Laboratory assessments 
Chemistry assessments 
 
X 
 
 
X 
X 
Section 8.4.5 
Hematology assessments 
 
X 
 
 
X 
X 
Section 8.4.5 
Urine pregnancy test 
X 
X 
X 
X 
X 
X 
Section 8.4.5.1 
WOCBP only; positive 
urine test to be confirmed 
by serum test 
Note: Participants who withdraw from the study early should complete the ET and safety follow-up visits. 
Note: Patient-reported outcomes must be conducted before any other assessments. 
Note: For participants in the OLE period who have been in an observation/no-treatment cycle with an IGA-CPG-S score of 0 and a WI-NRS score of 0 for at least 30 days prior to 
the Week 52/EOT2 visit, then the Week 52/EOT2 visit will also count as the safety follow-up visit. 

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2. 
INTRODUCTION 
2.1. 
Background 
2.1.1. 
Ruxolitinib Cream 
Ruxolitinib cream is a topical formulation of ruxolitinib phosphate under development for a 
variety of dermatological conditions. Ruxolitinib (1.5%) cream is approved by the US FDA for 
the topical short-term and noncontinuous chronic treatment of mild to moderate AD in 
nonimmunocompromised patients 12 years of age and older whose disease is not adequately 
controlled with topical prescription therapies or when those therapies are not advisable. More 
recently, ruxolitinib has been approved for the topical treatment of nonsegmental vitiligo in adult 
and pediatric patients 12 years of age and older (Opzelura™ 2022). Ruxolitinib phosphate is an 
inhibitor of the JAK family of protein TYKs. Inflammatory cytokines are strongly implicated in 
the pathogenesis of a number of inflammatory dermatoses. Because JAKs serve to translate 
extracellular signals from a number of relevant cytokines and growth factors upregulated in these 
inflammatory diseases, JAK inhibitors represent potential therapeutic agents for these disease 
states (Chapman et al 2022). 
2.1.2. 
Prurigo Nodularis 
Prurigo nodularis is a chronic inflammatory skin disorder characterized by symmetrically 
distributed severely pruritic nodules most commonly found on the extensor surface of the arms 
and legs and on the trunk (Huang et al 2020b). Typically, the upper back is spared, as this is an 
area that patients cannot reach (Watsky 2021). Prurigo nodularis presents as firm, dome-shaped, 
itchy nodules (also referred to as lesions) ranging in size from a few millimeters to several 
centimeters with pruritus lasting ≥ 6 weeks and signs of repeated scratching, picking, or rubbing 
(Pereira et al 2018). In addition to pruritus, patients may experience burning, stinging, and pain 
sensation (Elmariah et al 2021). The exact pathogenesis of PN remains unknown; however, there 
is evidence of a significant interaction and dysregulation between immune cells (eg, T cells, mast 
cells, and eosinophilic granulocytes; Almeida et al 2004, Zeidler et al 2018) and nerve fibers 
leading to a cutaneous reaction pattern causing endless cycles of chronic itch followed by 
repeated scratching (Kwatra 2020). The itch generally precedes the nodules, and in a subset of 
patients with chronic pruritus, PN occurs as a result of continuous scratching. 
Kwatra (2022) describes classic PN as a unique inflammatory skin disease. Transcriptomic 
studies have supported this by finding that PN has a unique transcriptome compared with both 
psoriasis and AD, with dysregulation of cutaneous fibroproliferative and neurovascular function 
(Kwatra 2022, Sutaria et al 2022). The exact incidence and prevalence of PN are not known; 
however, based on insurance claims data, PN has an estimated prevalence of 72 per 100,000 
among 18- to 64-year-old people in the United States (Huang et al 2020b). In England, a 
retrospective data analysis gathered from the English National Health Service showed an 
estimated prevalence of 3.27 per 10,000, equating to 18,471 patients living with PN in 2018 
(Morgan et al 2022). Reports vary on whether it is more prevalent in women versus men (Huang 
et al 2020b) or occurs equally in men and women (Elmariah et al 2021, Pereira et al 2018). An 
epidemiologic study of 7095 patients with PN in the United States showed that older adults 

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(mean age, 50.9 years) are affected by the disease with a slightly higher diagnosis in women 
(53.1%) versus men (46.9%; Huang et al 2020b). Furthermore, Black patients are substantially 
more likely to have PN than White patients (McColl et al 2021). In particular, 1 study found that 
African American patients were 3.4 times more likely to have PN than White patients (Boozalis 
et al 2018). 
Prurigo nodularis has substantial negative effects on quality of life (Kwatra 2020) and is 
associated with sleep disturbance, impact on job performance, and avoidance of social activities 
(Todberg et al 2020). In addition, the burden of systemic comorbidities in PN often exceeds that 
of other inflammatory skin disorders (ie, AD or psoriasis). Prurigo nodularis is associated with 
increased rates of mental health (specifically anxiety and depression) and endocrine, 
cardiovascular, and renal disorders as well as HIV and malignancy (Dazzi et al 2011, Huang 
et al 2020a, Kowalski et al 2019). Approximately half of all patients with PN report a history 
of AD (Iking et al 2013). 
In SEP 2022, Dupixent® was approved by the FDA for the treatment of adult patients with PN 
(Dupixent 2022). The overall goal in treating PN, topically or systemically, is to stop the 
itch-scratch cycle and reduce the pruritus to allow flattening of the skin nodules/lesions. Current 
therapies focus on targeting the immunological and/or the neural mechanism of the disease 
(Williams et al 2021). Based on clinical experience and small observational studies, superpotent 
topical corticosteroids (eg, clobetasol) and intralesional steroids (eg, triamcinolone) are 
considered first-line therapy (Williams et al 2020) with some limited success in targeting the 
itch. Other topical treatments including capsaicin, TCIs (eg, tacrolimus, pimecrolimus), and 
topical vitamin D analogs (eg, calcipotriol, tacalcitol) are also used for the treatment of PN. 
Sedating antihistamines (eg, hydroxyzine, diphenhydramine) administered at bedtime may be 
useful in controlling nocturnal pruritus. Both selective serotonin reuptake inhibitors and tricyclic 
antidepressants are also used for treatment of chronic pruritus, especially when a component of 
depression is present (Watsky 2021). 
Patients with widespread disease may be given phototherapy (Kowalski et al 2019). Patients with 
recalcitrant PN may be given systemic treatments including systemic immunosuppressants, 
thalidomide, lenalidomide, and anticonvulsants (Tsianakas et al 2016). However, long-term use 
can be associated with potential significant toxicity, and their efficacy in patients with 
recalcitrant PN has not been established (Elmariah et al 2021, Watsky 2021). 
2.2. 
Study Rationale 
Inflammatory cells, including T cells, eosinophils, and mast cells, are increased in patients with 
PN and secrete neurotrophins that promote neurogenic inflammation (Kwatra 2020, Perez 
et al 1993). Central to the pathogenesis of PN is a robust inflammatory response and intense itch 
associated with release of mediators such as IL-31, tryptase, eosinophil cationic protein, 
histamine, prostaglandins, and neuropeptides (Almeida et al 2004, Zeidler et al 2018). 
Although the exact initial pathogenesis or itch trigger in PN remains unknown, there is evidence 
of Th1 and Th2 cytokine involvement (Watsky 2021). Ruxolitinib cream, a JAK1/JAK2 
inhibitor, mediates the production of key proinflammatory cytokines involved in inflammation 
and transmission of itch at the intracellular level (Kim et al 2020). The role of Th1 and Th2 
cytokines in the pathogenesis of PN also has been evaluated by examining the cytokine 
signatures in the epidermis in 22 cases of PN, using STAT1, STAT3, and STAT6 

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(Fukushi et al 2011). In 19 of 22 cases, the entire epidermis stained with anti-pSTAT6, a marker 
for the Th2 cytokines IL-4, IL-5, and IL-13. Only 8 cases showed scattered staining with 
anti-pSTAT1, a marker for the Th1 cytokines interferon gamma and IL-27. These findings 
suggest that Th2 cytokines play a principal role in the pathogenesis of PN (Watsky 2021). 
Ruxolitinib cream in 2 Phase 3 studies (INCB 18424-303 and INCB 18424-304) showed 
anti-inflammatory and rapid antipruritic effects with superior efficacy versus vehicle cream in 
participants with mild to moderate AD (Papp et al 2021). Given that JAKs and Th1 and/or 
Th2 cytokines play an important role in PN, ruxolitinib (1.5%) cream may be a good candidate 
for the treatment of this disease, particularly the itch component. 
2.2.1. 
Scientific Rationale for Study Design 
This Phase 3 study will investigate the efficacy and safety of ruxolitinib 1.5% cream BID versus 
vehicle cream BID in participants with PN (IGA-CPG-S score of ≥ 2, ≥ 6 pruriginous lesions on 
≥ 2 different body areas, and PN-related WI-NRS score ≥ 7). The total estimated BSA treatment 
area must be ≤ 20%. This design will provide a well-controlled assessment of the efficacy of 
ruxolitinib 1.5% cream in participants with PN while minimizing the treatment duration for 
participants assigned to vehicle cream. Further, the 40-week OLE period will provide the 
participants who are initially randomized to vehicle cream the opportunity to receive ruxolitinib 
1.5% cream, and it is an adequate duration to assess the safety and efficacy of intermittent dosing 
with ruxolitinib 1.5% cream.  
Based on 2 Phase 3 pivotal studies (INCB 18424-303 and -304) in participants ≥ 12 years of age 
with mild to moderate AD affecting 1% to 20% BSA (excluding the scalp), ruxolitinib 1.5% 
cream BID was statistically significantly superior to vehicle cream after 8 weeks of treatment for 
the primary endpoint, IGA-TS (IGA score of 0 or 1 with ≥ 2-grade improvement from baseline). 
Furthermore, statistically significant improvement was observed on the key secondary endpoints, 
including EASI75 and ≥ 4-point improvement in Itch NRS score (Papp et al 2021). 
In PN, disease healing is characterized by flattening of the lesions, with the base of the lesions 
remaining unchanged. A white or colored scar may remain after lesion clearance. In a static 
assessment of lesions, the stage of elevation or flattening for multiple lesions cannot be 
compared with previous visits. 
Zeidler (2021) reported that for chronic prurigo, the number of lesions is representative of the 
stage of the disease. The presence of excoriation to the lesion(s) reflect(s) scratching activity, 
which is an early sign of CPG improvement (ie, the resolution of crusts and erosions from the top 
of the lesions). Two IGAs were validated to assess the stage (number of lesions) and the 
scratching activity of chronic prurigo, IGA-CPG stage, and IGA-CPG activity. 
2.2.2. 
Justification for Dose 
Study data from the 2 Phase 3 registrational studies (INCB 18424-303 and -304) in participants 
≥ 12 years of age with AD supports the selection of the 1.5% BID regimen in this study. Overall, 
ruxolitinib 1.5% cream was found to be more efficacious than the 0.75% strength, while the 
safety and tolerability profiles of both treatment regimens were comparable and 
nondifferentiating. Of note, the Phase 3 efficacy and safety findings were consistent with and 
confirmatory of the outcomes of the earlier Phase 2 (INCB 18424-206) dose range–finding 
study. Given these data, and the fact that high potency topical corticosteroids are recommenced 

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as first line therapy over less potent corticosteroids, ruxolitinib 1.5% cream BID was selected as 
the treatment regimen for this study. 
2.2.3. 
Justification for Vehicle Control 
The comparison to vehicle cream is relevant to better understand the effect of ruxolitinib cream 
in the treatment of PN. The use of vehicle cream is justified considering: the 12-week duration of 
the DBVC period; the recent approval of Dupixent by the FDA, which was based on a 
population with more severe prurigo nodularis (≥ 20 nodular lesions); there are no other 
approved PN-specific therapies to be used as a comparator; and delaying treatment does not pose 
excessive harm to patients (Millum and Grady 2013). After the 12-week, vehicle-controlled 
period, all participants who complete visits (through Week 12) will receive ruxolitinib cream 
1.5% for up to 40 weeks in the OLE period. 
2.3. 
Benefit/Risk Assessment 
In the Phase 3 AD studies, ruxolitinib 1.5% cream BID rapidly and effectively improved both the 
signs and symptoms of AD in adults and adolescents. The antipruritic effect of ruxolitinib 1.5% 
cream BID showed a rapid onset, with evidence of a treatment effect on daily Itch NRS scores as 
early as Day 1 (ie, within 12 hours after the first application of study cream). The disease course 
(assessed by IGA scores and %BSA affected by AD at study visits during Weeks 8 through 52) 
was well-controlled throughout the entirety of the long-term safety period of the study. The 
treatment effects of ruxolitinib 1.5% cream BID on IGA-TS, EASI75, and Itch NRS score were 
consistently observed across both adult and adolescent subgroups. 
Safety data from the Phase 3 AD studies demonstrated that use of ruxolitinib 1.5% cream BID 
continuously for 8 weeks followed by prolonged (44 weeks) intermittent use was safe and 
well-tolerated. The TEAEs were generally Grade 1 or 2 in severity and were most often events of 
nasopharyngitis and upper respiratory tract infection. Frequencies of these events were within the 
expected range for the general AD population. There were no meaningful differences in the 
TEAE profile of ruxolitinib 1.5% cream BID between the adult and adolescent subgroups. 
Results from dermal safety studies in healthy adult participants (INCB 18424-104, -105, -106, 
-107, and -108) to evaluate local tolerability demonstrated that ruxolitinib 1.5% cream did not 
cause sensitization and was only slightly irritating under exaggerated testing conditions 
(occlusive application). In addition, ruxolitinib 1.5% cream was not phototoxic and did not 
induce photosensitization. This was further confirmed by the Phase 3 (INCB 18424-303 and 
-304) safety data, which showed that ruxolitinib 1.5% cream BID was well-tolerated at the 
application sites with infrequently reported application site reactions. The most frequently 
reported application site reaction events were application site pain (lowest-level terms were 
primarily application site burning or application site stinging) and application site pruritus; each 
of these events occurred in a lower proportion of participants in the ruxolitinib 1.5% cream BID 
treatment group (application site pain, 0.7%; application site pruritus, 0.6%) compared with the 
vehicle cream treatment group (application site pain, 4.8%; application site pruritus, 2.8%) 
during the 8-week, vehicle-controlled period, which may be attributable to worsening of the 
underlying disease in the absence of active cream treatment. 
The overall benefit/risk assessment of ruxolitinib 1.5% cream BID favors its use in both 
adolescent and adult patients with PN affecting areas up to and including 20% BSA.  

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Furthermore, given that PN has an itch component to the disease, it is likely that participants 
with PN will benefit from treatment with ruxolitinib cream for itch. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of ruxolitinib cream may be found in the IB. 
3. 
OBJECTIVES AND ENDPOINTS 
Table 5 presents the objectives and endpoints. 
Table 5: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To demonstrate the efficacy of ruxolitinib 1.5% cream 
BID in participants with PN. 
• WI-NRS4 response at Week 12, defined as achieving 
a ≥ 4-point improvement (reduction) in WI-NRS 
score from baseline. 
Key Secondary 
To further demonstrate the treatment effects of 
ruxolitinib 1.5% cream BID in participants with PN. 
• WI-NRS4 response at Week 4. 
• Overall-TS at Week 12, defined as achieving both a 
WI-NRS4 response and an IGA-CPG-S-TS. 
(IGA-CPG-S-TS is defined as an IGA-CPG-S score 
of 0 or 1 with a ≥ 2 grade improvement from 
baseline) 
• IGA-CPG-S-TS at Week 12. 
• WI-NRS4 response on Day 7. 
Secondary 
To further demonstrate the treatment effects of 
ruxolitinib 1.5% cream BID in participants with PN. 
• WI-NRS4 response at each postbaseline visit. 
• Change from baseline in WI-NRS score at each 
postbaseline visit. 
• Time to ≥ 2-point improvement from baseline in 
WI-NRS score. 
• Time to ≥ 4-point improvement from baseline in 
WI-NRS score. 
• Achieving a ≥ 2-point improvement (reduction) in 
Skin Pain NRS score from baseline. 
• Change from baseline in Skin Pain NRS score at 
each postbaseline visit. 
• IGA-CPG-S-TS at each postbaseline visit. 
• IGA-CPG-A score of 0 or 1 with at least a 2 grade 
improvement (reduction) at each postbaseline visit. 
• Achieving > 75% healed lesions from PAS at each 
postbaseline visit. 

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Table 5: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
To evaluate the effect of ruxolitinib 1.5% cream BID 
on QOL. 
• Change from baseline in DLQI score at each 
postbaseline visit. 
• Change from baseline in EQ-5D-5L score at each 
postbaseline visit. 
To evaluate the safety and tolerability of ruxolitinib 
1.5% cream BID in participants with PN. 
The type, frequency, and severity of AEs, including 
changes in vital signs and clinical laboratory blood 
samples. 
Exploratory 

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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 3, multicenter, randomized, DBVC, parallel-group study in adults with PN 
(IGA-CPG-S score of ≥ 2; ≥ 6 pruriginous lesions on ≥ 2 different body areas; and PN-related 
WI-NRS score ≥ 7). The total estimated BSA treatment area must be ≤ 20%. Treatment area is 
defined as the area affected by pruriginous lesions plus an ~ 1 cm area surrounding each lesion. 
Eligible participants will be randomized 1:1 to ruxolitinib 1.5% cream or vehicle cream. 
Participants will apply either ruxolitinib 1.5% cream or vehicle cream (both BID) through 
Week 12 to all pruriginous lesions identified at baseline plus an ~ 1 cm surrounding area each 
lesion. 
At Week 12, participants who have completed 12 weeks of treatment with no safety concerns 
will enter the 40-week OLE period. The investigator will assess whether the participant requires 
continuation of therapy (IGA-CPG-S score ≥ 1 and/or the presence of PN-related itching). 
During the OLE period, all participants will apply ruxolitinib 1.5% cream BID to PN affected 
areas plus an ~ 1 cm area surrounding each pruriginous lesion and/or areas of PN-related itching. 
After the last application of study cream, participants will be followed for safety; the safety visit 
will occur at least 30 days after the last application of study cream. 
The treatment assignment a participant received during the DBVC period will be blinded to 
investigators and participants until after all participants have completed treatment or 
discontinued treatment and completed the safety follow-up period. 
Figure 1 presents the study design schema. The SoA for the DBVC and OLE periods are 
presented in Table 3 and Table 4, respectively. 
The COVID-19 global pandemic may present challenges to the normal conduct of this study 
(including AE and laboratory assessments), requiring the outline of potential mitigation 
strategies described in Appendix B. Participants do not need to stop treatment in the study to 
receive a COVID-19 vaccine. 
4.2. 
Overall Study Duration 
The study begins when the first participant signs the study ICF. The end of the study is defined 
as the date of the last visit of the last participant in the study or the last scheduled procedure 
shown in the SoA for the last participant in the study globally. Estimated total duration of 
participation for an individual is up to approximately 60 weeks, including up to 4 weeks for 
screening, up to 52 weeks for treatment, and 30 days for safety follow-up. 
4.3. 
Study Termination 
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study site contract. The investigator is to notify the IRB/IEC of the study's 
completion or early termination in writing, send a copy of the notification to the sponsor or 
sponsor's designee, and retain 1 copy for the site study regulatory file. 
The sponsor may terminate the study electively if, for example, required by regulatory decision. 
If the study is terminated prematurely, the sponsor will notify the investigators, the IRBs and 
IECs, and the regulatory bodies of the decision and reason for termination of the study. 

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5. 
STUDY POPULATION 
Deviations from eligibility criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or participant safety. Therefore, 
adherence to the criteria as specified in this Protocol is essential. Prospective approval of 
Protocol deviations to recruitment and enrollment criteria, also known as Protocol waivers or 
exemptions, are not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Ability to comprehend and willingness to sign a written ICF for the study. 
2. Age ≥ 18 years at the time of signing the ICF. 
Note: For Korea, participants age ≥ 19 years. 
3. Clinical diagnosis of PN ≥ 3 months before screening. 
4. There are ≥ 6 pruriginous lesions on ≥ 2 different body areas (such as right and left leg) at 
screening and baseline. Note: The total estimated BSA treatment area must be ≤ 20%. 
5. IGA-CPG-S score of ≥ 2 at screening and baseline. 
6. Baseline PN-related WI-NRS score ≥ 7. Baseline WI-NRS score is defined as the 7-day 
average of WI-NRS scores before Day 1 (data from a minimum of 4 out of 7 days prior to 
Day 1 is needed). 
7. Removed during Protocol Amendment 2. 
8. Willingness to avoid pregnancy or fathering children based on the criteria below. 
a. Male participants with reproductive potential must agree to take appropriate 
precautions to avoid fathering children from screening through 90 days 
(a spermatogenesis cycle) after the last application of study cream and must refrain 
from donating sperm during this period. Permitted methods in preventing pregnancy 
(see Appendix A) should be communicated to the participants and their understanding 
confirmed. 
b. Female participants who are WOCBP must have a negative serum pregnancy test at 
screening and negative urine pregnancy test before the first application of study 
cream on Day 1 and must agree to take appropriate precautions to avoid pregnancy 
from screening through 30 days (1 menstrual cycle) after the last application of study 
cream and must refrain from donating oocytes during this period. Permitted methods 
in preventing pregnancy (see Appendix A) should be communicated to the 
participants and their understanding confirmed. 
c. A female participant not considered to be of childbearing potential as defined in 
Appendix A is eligible. 

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5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Acute or chronic pruritus due to a condition other than PN. (Conditions such as: scabies, 
insect bite, lichen simplex chronicus, psoriasis, acne, folliculitis, habitual picking, 
lymphomatoid papulosis, chronic actinic dermatitis, dermatitis herpetiformis, 
sporotrichosis, bullous disease, excoriation syndrome, venous stasis; systemic 
hematologic disorders [iron-deficiency anemia, polycythemia rubra vera, lymphoma, 
leukemia]; gastrointestinal disorders [celiac disease, gastric malignancy, obstructive 
biliary disease; α-1 antitrypsin deficiency]; infections [HIV, hepatitis B and C, 
mycobacterial]; endocrine disorders [hyperthyroidism]; psychosocial disorders 
[depression, anxiety], and chronic renal failure.) 
2. Total estimated BSA treatment area (excluding the scalp) > 20%. 
3. Neuropathic and psychogenic pruritus, such as but not limited to notalgia paresthetica, 
brachioradial pruritus, small fiber neuropathy, skin picking syndrome, or delusional 
parasitosis. 
4. Active AD lesions (signs and symptoms other than dry skin) within 6 months of 
screening and baseline. 
5. Uncontrolled hypothyroidism or hyperthyroidism at screening as determined by the 
investigator. Note: If the participant has a history of thyroid disease and is on treatment, 
the participant must be on a stable thyroid regimen for at least 6 weeks prior to Day 1. 
6. Concurrent conditions and history of other diseases: 
a. Any other concomitant skin disorder (eg, generalized erythroderma such as 
Netherton's syndrome), pigmentation, or extensive scarring that in the opinion of the 
investigator may interfere with the evaluation of pruriginous lesions or assessments of 
efficacy or compromise participant safety. 
b. Immunocompromised (eg, lymphoma, acquired immunodeficiency syndrome, 
Wiskott-Aldrich syndrome). 
c. Chronic or acute infection requiring treatment with systemic antibiotics, antivirals, 
antiparasitics, antiprotozoals, or antifungals within 2 weeks before baseline. 
d. Active acute bacterial, fungal, or viral skin infection (eg, herpes simplex, herpes 
zoster, chickenpox, clinically infected AD, or impetigo) within 1 week before 
baseline.  
e. Unstable asthma or COPD requiring systemic treatment (such as intravenous steroids) 
or hospital admission or treatment in the emergency department within 3 months of 
baseline 
or 
Stable asthma or COPD requiring the dose equivalent of budesonide more than 
720 µg/day (2 puffs BID of a 180-μg dose) or fluticasone more than 440 μg/day 
(2 puffs BID of a 110-μg dose) or other equivalent inhaled corticosteroids. 

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f. Acute or chronic active HBV or HCV infection (see Section 8.4.5.3). Participants 
who have recovered or have been successfully treated with no evidence of active 
HBV or HCV infection and those who are immune due to HBV vaccination can 
enroll. 
g. Any underlying condition known to be associated with the clinical presentation of PN 
that is not under control (stable) prior to the baseline visit. 
7. Any serious illness or medical, physical, or psychiatric condition(s) that, in the 
investigator's opinion, would interfere with full participation in the study, including 
application of study cream and attending required study visits; pose a significant risk to 
the participant; or interfere with interpretation of study data. For example: 
a. Clinically significant or uncontrolled cardiovascular disease, including unstable 
angina, acute myocardial infarction or stroke within 6 months from Day 1, New York 
Heart Association Class III or IV congestive heart failure, and arrhythmia requiring 
therapy or uncontrolled hypertension (blood pressure > 150/90 mmHg) unless 
approved by the medical monitor/sponsor. 
b. Participants with or a history of malignancy in the 5 years preceding the baseline 
visit, except for adequately treated, nonmetastatic nonmelanoma skin cancer. 
c. Current and/or history of arterial or venous thrombosis, including deep vein 
thrombosis and pulmonary embolism. 
d. Current and/or history of active tuberculosis or current and/or history of latent 
tuberculosis unless adequately treated. 
e. History of severe anemia, severe thrombocytopenia, or severe neutropenia. 
8. Any of the following clinical laboratory test results at screening: 
a. Cytopenias, defined as follows: 
− Hemoglobin < 100 g/L (ie, 10 g/dL) 
− Absolute neutrophil count < 1.5 × 109/L (ie, 1500/µL)  
− Platelet count < 1 × 1011/L (ie, 100,000/µL) 
b. Liver function tests: 
− AST or ALT ≥ 2.5 × ULN 
− Total bilirubin > 1.5 × ULN unless Gilbert's syndrome 
c. Estimated glomerular filtration rate < 30 mL/min/1.73 m2 (using the CKD-EPI 2021 
Creatinine Equation). 
d. Positive serology test results at screening for HIV antibody. 
e. Any other clinically significant laboratory result that, in the opinion of the 
investigator, poses a significant risk to the participant. 

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9. Use of any of the following treatments within the indicated washout period before the 
baseline visit: 
a. Five half-lives or 12 weeks, whichever is longer – biologic agents (eg, dupilumab). 
For biologic agents with washout periods longer than 12 weeks (eg, rituximab), 
consult the medical monitor. 
b. Current treatment or treatment within 30 days or 5 half-lives (whichever is longer) 
before baseline with another investigational medication or current enrollment in 
another investigational drug protocol. 
c. Four weeks for any topical or systemic JAK or TYK2 inhibitor (eg, abrocitinib, 
baricitinib, deucravacitinib, filgotinib, lestaurtinib, pacritinib, ruxolitinib, tofacitinib, 
or upadacitinib). 
d. Four weeks – systemic or intralesional corticosteroids or adrenocorticotropic 
hormone analogs, cyclosporine, methotrexate, azathioprine, or other systemic 
immunosuppressive or immunomodulating agents (eg, mycophenolate or tacrolimus). 
e. Four weeks for opioid antagonists (eg, naloxone and naltrexone).  
f. Four weeks for gabapentin, pregabalin, or thalidomide. 
g. Four weeks for the following: 
− Paroxetine, fluvoxamine, or other SSRIs 
− SNRIs 
− Tricyclic antidepressants 
h. Four weeks – recreational or medicinal use (topical, inhaled, oral, sublingual, or any 
other route) of cannabis or cannabinoids (eg, THC, CBD). 
i. Two weeks – systemic antibiotics and immunizations with live-attenuated vaccines. 
Note: Live-attenuated vaccines are prohibited during the DBVC period. COVID-19 
vaccination is permitted.  
j. Two weeks – sedating antihistamines. 
k. Two weeks or 5 half-lives, whichever is longer – strong systemic CYP3A4 inhibitors. 
l. Two weeks – any topical treatments for PN (other than bland emollients, eg, Aveeno® 
creams, ointments, sprays, and soap substitutes), such as corticosteroids, calcineurin 
inhibitors, topical antipruritics (eg, doxepin cream), PDE4 inhibitors, coal tar 
(shampoo), topical antibiotics, and antibacterial cleansing body wash/soap. 
m. One week – nonsedating antihistamines used for the treatment of PN. 
10. Current use of a medication known to cause pruritus. 
11. History of treatment failure (as assessed by the investigator through study participant 
interview) for PN or any inflammatory condition with any systemic or topical JAK 
inhibitors (eg, abrocitinib, baricitinib, deucravacitinib, filgotinib, lestaurtinib, pacritinib, 
ruxolitinib, tofacitinib, or upadacitinib). 

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12. Psoralen and ultraviolet A or ultraviolet B therapy within 4 weeks before baseline 
or 
Ultraviolet light therapy or prolonged exposure to natural or artificial sources of 
ultraviolet radiation (eg, sunlight or tanning booth) within 2 weeks before baseline and/or 
intention to have such exposure during the study that is thought by the investigator to 
potentially impact the participant's PN. 
13. Pregnant or lactating, or considering pregnancy during study participation. 
14. History of alcoholism or drug addiction within 1 year before screening or current alcohol 
or drug use that, in the opinion of the investigator, will interfere with the participant's 
ability to comply with the application schedule and study assessments. 
15. Removed during Protocol Amendment 1. 
16. Known allergy or reaction to any of the components of the study cream. 
17. In the opinion of the investigator, unable or unlikely to comply with the application 
schedule and study evaluations. 
18. Committed to a mental health institution by virtue of an order issued either by the judicial 
or the administrative authorities. 
19. Employees of the sponsor or investigator or otherwise dependents of them. 
20. The following participants are excluded in France: 
a. Vulnerable populations according to article L.1121-6 of the French Public Health 
Code. 
b. Adults under legal protection or who are unable to express their consent per article 
L.1121-8 of the French Public Health Code. 
c. Individuals not affiliated with the social security system. 
5.3. 
Lifestyle Considerations 
Participants should be cautioned to avoid exposure to artificial sunlight (including tanning 
booths, sun lamps, etc). If sunscreen or other cosmetics have been applied to the areas to be 
treated, participants should follow the guidance in Section 6.6 regarding concomitant 
medications. 
It is recommended that bathing, showering, excessive sweating, or swimming should not take 
place within 2 hours before and after the planned study cream application. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study treatment. Tests with results that fail eligibility 
requirements may be repeated once during screening if the investigator believes the result to be 
in error. Additionally, a participant who fails screening may repeat the screening process 1 time 
if the investigator believes that there has been a change in eligibility status. Participants who 
rescreen must reconsent and be assigned a new participant number. 

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5.5. 
Replacement of Participants 
No participants will be replaced at any time during this study. However, as noted in the 
COVID-19–related guidance (see Appendix B), due to the evolving situation of the COVID-19 
pandemic, the sponsor may decide to recruit additional participants in the study beyond the 
expected number (eg, if a substantial number of participants withdraw early from the study). 
5.6. 
Data Monitoring Committee 
A DMC or Data Safety Monitoring Board will not be used in this study because the primary 
objective is to evaluate relief of itch due to PN, which does not involve the treatment any of the 
following: a life-threatening disease; the reduction of risk of a major adverse health outcome; or 
a comparison of the rates of mortality or major morbidity. The primary endpoint analysis will be 
conducted after all participants complete Week 12. The long-term safety of ruxolitinib 1.5% 
cream was assessed in 2 indications approved by the FDA (Sections 2.2.1 and 2.2.2). In this 
study, the population is not a medically fragile population and may include elderly participants. 
The exclusion criteria excludes participants at with any serious illness or medical, physical, or 
psychiatric condition(s) that, in the investigator's opinion, would pose a significant risk to the 
participant. For example, elevated risk of death or other serious outcomes. Moreover, this 
multicenter study is not large (n = 180) and the duration of the study (ie, primary endpoint) is 
12 weeks (FDA 2006, EMA 2005). 

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6. 
STUDY TREATMENT 
6.1. 
Study Treatments Administered 
Ruxolitinib 1.5% cream or matching vehicle cream will be applied as a thin film BID on each 
pruriginous lesion and the surrounding area of the lesion (~ 1 cm), with applications at least 
8 hours apart in the morning and in the evening at least 1 hour before bedtime. 
On Day 1 and at Week 12 (if applicable), the participant will apply a thin film of study cream to 
the treatment area under the supervision of site staff. The treatment area is defined as the area 
affected by pruriginous lesions plus an ~ 1 cm area surrounding each lesion. During the DBVC 
period, all other applications of study cream will be applied by the participant to the treatment 
area identified at baseline. The total BSA treatment area must be ≤ 20%. Participants should not 
apply the application of study cream at home prior to clinic visits at Week 2, Week 12/EOT1, 
and Week 52/EOT2 (see Section 8.5). 
At the baseline visit, an estimate of the %BSA treatment area will be used by the IRT system to 
calculate the number of tubes of study cream to be dispensed. All areas identified at baseline 
should continue to be treated through the end of the DBVC period (Week 12) unless the 
participant meets criteria for stopping study cream (see Section 6.5.2). If there are new 
pruriginous lesions to be treated, after consultation with the investigator, study cream should be 
applied to these lesions in addition to the areas treated at baseline (total BSA treatment area must 
be ≤ 20%), and the percentage of BSA to be treated will be recalculated and increased. This new 
estimate will be entered into the IRT system to calculate the number of tubes of study cream to 
be dispensed. 
During the OLE period starting at the Week 12 visit, pruriginous lesions will be evaluated by the 
investigator to confirm whether the participant still requires continuation of therapy 
(ie, IGA-CPG-S score ≥ 1 and/or the presence of itching related to PN). Participants with an 
IGA-CPG-S score of 0 may continue or restart therapy if there is itch associated with underlying 
PN, or they can otherwise (re)enter the observation/no-treatment cycle (ie, IGA score of 0 and 
WI-NRS score of 0). At Week 12, the IRT system will dispense a prespecified number of tubes 
according to the assessment of total BSA treatment area. 
Between OLE study visits, participants will treat all areas identified with pruriginous lesions 
and/or itch associated with PN (total BSA treatment area must be ≤ 20%). If all signs and 
symptoms of PN resolve between study visits, the participant will contact the investigator to 
confirm that study cream applications should be stopped 3 days after the lesions and itch have 
disappeared. If this 3-day window is during a study visit, and the IGA-CPG-S score is 0 and itch 
has resolved, as assessed by the investigator, treatment is to be stopped at the study visit. 
If a participant has stopped treatment during the OLE period, treatment may be restarted after 
consultation with the investigator that the participant has an IGA-CPG-S score ≥ 1 and/or the 
presence of PN-related itching (WI-NRS score > 0). In the event that new pruriginous lesions are 
outside of the usual location and/or are more widespread than at the prior visit, the participant is 
required to contact the site for approval. Approval to treat additional areas may occur via 
telephone or other modes of communication during the OLE period; however, the investigator, at 
their discretion, may ask the participant to return for an unscheduled visit. 

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The amount of study cream used per application will be determined by weighing a tube 
(including the cap) before and after the participant applies study cream to the affected areas at 
Day 1. All tubes (including caps) of study cream will be weighed before being dispensed. All 
returned tubes (including caps) of study cream will also be weighed. 
Application instructions will be provided by the site staff, and the participant will record their 
daily applications in the eDiary. Refer to the Pharmacy Manual for participant instructions for 
handling study cream. 
Table 6 presents the study treatment information. 
Table 6: 
Study Treatment Information 
 
Ruxolitinib 
Vehicle 
Mechanism of action 
JAK1/2 inhibitor 
Not applicable 
Dosage formulation 
Cream 
Cream 
Unit dose strength(s)/dosage 
level(s) 
1.5% 
Not applicable 
Application instructions 
DBVC period: Apply a thin film to pruriginous lesions 
identified at baseline (plus an ~ 1 cm area surrounding each 
lesion) in the morning and at least 1 hour before bedtime with 
applications at least 8 hours apart for 12 weeks. 
OLE period: Apply a thin film to pruriginous lesions (plus an 
~ 1 cm area surrounding each lesion) in the morning and at least 
1 hour before bedtime with applications at least 8 hours apart as 
needed for 40 weeks. 
Packaging and labeling 
Ruxolitinib or vehicle cream will be provided in a 60-g tube. 
Each tube will be labeled as required per country requirement. 
Storage 
15°C-30°C (59°F-86°F) 
Status of treatment in 
participating countries 
Investigational  
6.2. 
Preparation, Handling, and Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatments received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only participants enrolled in the study may receive study treatment, and only authorized site 
staff may supply or administer study treatment. All study treatment 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. 

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The investigator or designee is responsible for study treatment accountability, reconciliation, and 
record maintenance (ie, receipt, reconciliation, and final disposition records). Inventory and 
accountability records must be maintained and readily available for inspection by the study 
monitor and are open to inspection at any time by any applicable regulatory authorities. The 
investigator or designee must maintain records that document the following: 
• Delivery of study cream to the study site 
• Inventory of study cream at the site 
• Participant use of the study cream, including tube counts and weight from each 
supply dispensed 
• Return of study cream to the investigator or designee by participants 
The investigational product must be used only in accordance with the Protocol. The investigator 
or designee will also maintain records adequately documenting that the participants were 
provided the specified study cream. These records should include dates, quantities, and any 
available batch or serial numbers or unique code numbers assigned to the investigational product 
and study participants. 
Completed accountability records will be archived by the site. The investigator or designee will 
be expected to collect and retain all used, unused, and partially used containers of study cream 
until verified by the study monitor (unless otherwise agreed to by the sponsor). At the conclusion 
of the study, the investigator or designee will oversee the destruction of any remaining study 
cream according to institutional SOPs. If, however, local procedures do not allow on-site 
destruction, shipment of the study cream back to the sponsor is allowed. In this case, the site 
should (where local procedures allow) maintain the investigational supply until the study monitor 
inspects the accountability records in order to evaluate compliance and accuracy of 
accountability by the investigative site. At sites where the study cream is destroyed before 
monitor inspection, the monitors rely on documentation of destruction per the site SOP. 
Further guidance and information for the final disposition of unused study treatments are 
provided in the study materials provided to sites. 
The COVID-19 global pandemic may present challenges to the normal conduct of this study, 
requiring the outline of potential mitigation strategies described in Appendix B. Participants do 
not need to interrupt study cream to receive the COVID-19 vaccine. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
All participants will be centrally assigned to study treatment using an IRT system. The IRT 
system will assign in a 1:1 ratio, stratified by baseline IGA-CPG-S score (2 or ≥ 3), and 
geographic region (North America or outside of North America), the participant study number; 
track participant visits; randomize according to the defined parameters; maintain the blinding; 
and manage study cream inventory. Enrollment for participants with an IGA-CPG-S score 
of 2 will be up to approximately 20% of the overall study population. Full details will be 
provided in the IRT Manual. 
Participants, investigators, and the sponsor will remain blinded to each participant's treatment 
assignment throughout the DBVC period. During the OLE period, participants and investigators 

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will remain blinded to the treatment assignment during the DBVC period. Emergency unblinding 
will occur if an AE requires the investigator to be made aware of the participant's treatment 
assignment (see Section 9.7; refer to the IRT Manual). The investigator has the right to unblind 
the study treatment in the case of a medical emergency. 
6.4. 
Study Treatment Compliance 
Compliance with all study-related treatments should be emphasized to the participant by the site 
personnel, and appropriate steps should be taken to optimize compliance during the study. 
Compliance will be assessed for frequency of application of study cream by reviewing the 
participants' eDiaries. Participants will also be questioned regarding study cream application 
technique, missed applications, and use of any additional topical or systemic prescriptions of 
other products or over-the-counter products. Compliance with study cream will be evaluated by 
the participant's adherence to the BID application regimen (evaluation of actual number vs 
prescribed number of applications), documented by the site staff, and monitored by the 
sponsor/designee. 
Qualified clinical staff will review the eDiary entries for compliance. Participants will be 
considered compliant with the treatment regimen if they apply and report at least 80% of the 
prescribed number of applications during participation in the DBVC period of the study. 
Participants who are noncompliant during the DBVC and/or OLE periods (if on a treatment 
cycle) will be reinstructed by the investigator (or designee); the sponsor should be consulted by 
the investigator for instruction on the proper handling of the participant who fails to comply with 
study treatment despite re-enforcement. 
Study cream accountability will be assessed by documenting the quantities of study cream used 
between study visits (tube counts and weighing). At the first clinic visit, the amount of study 
cream to be applied is to be determined by weighing a tube (including the cap) before and after 
the participant applies a thin film of study cream to the affected areas. Participants will be 
instructed to bring all study cream with them to the study visits in order for site staff to assess 
study cream accountability. 
6.5. 
Dose Modifications 
There are no application adjustments or modifications allowed (decrease or increase in study 
cream strength or frequency of application) except for interruption or permanent discontinuation 
if needed (eg, for management of an AE). Temporary interruption could be due to an AE during 
the DBVC or OLE period (see Section 6.5.1) or due to IGA-CPG-S score of 0 and no itch related 
to PN during the OLE period (see Section 6.1). 
6.5.1. 
Criteria and Procedures for Dose Interruptions and Adjustments of Study 
Cream 
Safety concerns should be discussed with the sponsor immediately upon occurrence or awareness 
to determine whether the participant should continue or discontinue study treatment. 
In some circumstances, it may be necessary to temporarily interrupt treatment as a result of AEs 
or laboratory abnormalities that may have an unclear relationship to study cream. In the event 
that an AE is present at a specific site of study cream application, treatment may be temporarily 

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withheld only at that application site and continued elsewhere. This should be recorded as a dose 
interruption on the AE eCRF page. Except in cases of emergency, it is recommended that any 
findings of concern (eg, AE) be confirmed and that the investigator consult with the medical 
monitor before interrupting study cream applications. Additionally, the investigator must obtain 
approval from the medical monitor before restarting study cream. Participants who experience a 
recurrence of the initial AEs upon restarting the study cream may need to permanently 
discontinue treatment with the study cream. 
Participants should be closely monitored for the development of signs and symptoms of infection 
during treatment with the study cream and up to the safety follow-up visit. Study cream should 
be interrupted if a participant develops a serious infection, an opportunistic infection, or sepsis. 
Study cream application should not be resumed until the infection is controlled. 
Instructions for application interruptions of study cream related to laboratory abnormalities are 
outlined in Table 7. 
Table 7: 
Guidelines for Interruption of Study Cream for Treatment-Related Adverse 
Events and Restarting of Study Cream 
Adverse Event 
Action Taken 
Any Grade 3a laboratory 
abnormality 
• Laboratory abnormalities should be confirmed with repeat 
testing within 48 hours whenever possible, and immediate 
delivery of the laboratory results should be requested. 
• Interrupt study cream, based on clinical judgment in 
consultation with the medical monitor (whenever possible), 
taking into account the relatedness of the AE to the study 
cream and the participant's underlying condition.  
• Interruption may occur after the initial test result or may be 
delayed until or unless the repeat test confirms the laboratory 
abnormality; however, if the repeat test does confirm the 
laboratory abnormality, the study cream must be interrupted 
unless the medical monitor approves continuation. 
• At the discretion of the investigator, after consultation with the 
sponsor, study cream application may be restarted once the 
laboratory abnormalities have resolved or returned to the 
baseline level. 
Any Grade 4a laboratory 
abnormality 
• Laboratory abnormalities should be confirmed with repeat 
testing within 48 hours whenever possible, and immediate 
delivery of the laboratory results should be requested. 
• Discontinue study cream permanently if laboratory 
abnormalities are confirmed, laboratory abnormalities are 
considered related to study cream, and no alternative cause is 
found. 
a Adverse event grades are based on CTCAE v5.0. 

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6.5.2. 
Criteria for Permanent Discontinuation of Study Cream 
The occurrence of unacceptable severity of an AE, such that it would interfere with study cream 
treatment or study procedures, may require that the study cream be permanently discontinued. 
Unacceptable severity is defined as follows: 
• Occurrence of an AE that is related to treatment with the study cream that, in the 
judgment of the investigator or the sponsor's medical monitor, compromises the 
participant's ability to continue study-specific procedures or is considered to not be in 
the participant's best interest.  
• Worsening of PN that requires treatment with a prohibited concomitant medication. 
• An AE requiring an interruption of study cream for more than 2 weeks. 
• Grade 4 laboratory abnormalities deemed related to study cream and confirmed on 
repeat testing (see Table 7). 
See Section 7.1.1 for reasons for discontinuation. 
6.6. 
Concomitant Medications and Procedures 
All concomitant medications and treatments (including over-the-counter or prescription 
medicines, vitamins, vaccines, and/or herbal supplements) must be recorded in the eCRF. Any 
prior medication (other than PN medications) received up to 28 days before the first application 
of study treatment will be recorded in the eCRF. Any prior PN treatments received at least 1 year 
before the first application of study cream will be recorded, including the reason for stopping the 
treatment (eg, inadequate response or intolerance or contraindication). All medications received 
from the first application of study cream through 30 days after the last application of study cream 
will be recorded in the eCRF. Any addition, deletion, or change in the dose/regimen of these 
medications will also be recorded. 
Other relevant medications or procedures received more than 28 days before the first application 
of study cream may be recorded in the eCRF at the discretion of the investigator or at the request 
of the sponsor based on emerging events during the study. 
Concomitant medications administered within 30 days after the last application of study cream 
should be recorded for SAEs. Concomitant treatments/procedures that are required to manage a 
participant's medical condition during the study will also be recorded in the eCRF. The medical 
monitor should be contacted if there are any questions regarding concomitant or prior therapy. 

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6.6.1. 
Permitted Medications and Procedures 
The following are permitted during the study: 
• Participants may use/continue to use bland emollients (eg, Aveeno® creams, 
ointments, sprays, or soap substitutes). Participants may not change or introduce a 
new emollient within 4 weeks of the baseline visit through the end of the study. 
• Note: Emollients should not be used within 4 hours before and 30 minutes after study 
cream application. 
• If sunscreen is needed, a mineral-based sunscreen (such as zinc oxide or titanium 
oxide–based) with an SPF of at least 30 is preferred and may be used not less than 
4 hours before and at least 1 hour after study cream application.  
• Participants may use nonsedating, over-the-counter antihistamines except for the 
treatment of PN. 
• Use of inhaled corticosteroids for bronchial asthma or COPD is allowed with the dose 
equivalent of budesonide (not to exceed 720 µg/day or 2 puffs BID of a 180-μg dose) 
or fluticasone (not to exceed 440 μg/day or 2 puffs BID of a 110-μg dose) or other 
equivalent inhaled corticosteroids. 
6.6.2. 
Restricted Medications and Procedures 
The use of the following medications and procedures is restricted as specified below: 
• Use of any over-the-counter, nonprescription preparations (including vitamins, 
minerals, and phytotherapeutic, herbal, or plant-derived preparations) within 7 days 
before the baseline visit through the safety follow-up visit unless deemed acceptable 
by the investigator. 
• Use of any prescription medication within 7 days before the baseline visit through the 
safety follow-up visit unless deemed acceptable by the investigator. 
• Use of topical anti-infectives applied to pruriginous lesions to treat concurrent 
infection should be limited to 5 days or less. Furthermore, the use of topical 
anti-infectives should not be used for at least 4 hours before and 1 hour after 
application of study cream. 

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6.6.3. 
Prohibited Medications and Procedures 
The following are not permitted during the study:  
• Any investigational medication other than the study cream. 
• Systemic or topical agents for PN (except bland emollients as noted in Section 6.6.1). 
• Treatment known to affect the course of PN. 
• Any topical or systemic JAK or TYK2 inhibitor other than ruxolitinib cream 
(eg, ruxolitinib, tofacitinib, baricitinib, filgotinib, lestaurtinib, pacritinib, abrocitinib, 
brepocitinib). 
• Systemic immunosuppressive or immunomodulating biologic drugs (eg, adalimumab, 
dupilumab, etanercept, infliximab, golimumab, certolizumab, ustekinumab, 
secukinumab, brodalumab, ixekizumab, risankizumab, guselkumab, bimekizumab, 
iscalimab, bermekimab, rituximab, anakinra). 
• Systemic immunosuppressive or immunomodulating small-molecule drugs (eg, oral, 
injectable, or intralesional corticosteroids; methotrexate; cyclosporine; dapsone; 
azathioprine). 
• Any opioid antagonist. 
• Gabapentin, pregabalin, and thalidomide. 
• Paroxetine, fluvoxamine, or other SSRIs. 
• SNRIs. 
• Tricyclic antidepressants. 
• Sedating antihistamines. 
• Nonsedating antihistamines for the treatment of PN. 
• Recreational or medicinal use (topical, inhaled, oral, sublingual or any other route) of 
cannabis or cannabinoids (eg, THC, CBD). 
• Topical corticosteroids, tacrolimus, pimecrolimus, and PDE4 inhibitors (Eucrisa®). 
• Systemic corticosteroids, methotrexate, cyclosporine A, azathioprine and biological 
therapies, or other immunosuppressant agents. 
• Phototherapy or tanning beds. 
• Immunizations with live-attenuated vaccines during the DBVC period. 
• Note: COVID-19 vaccination is permitted. 
• Strong systemic CYP3A4 inhibitors. 
6.7. 
Treatment After the End of the Study 
There will be no treatment provided after the end of the study. 

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7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT WITHDRAWAL 
7.1. 
Discontinuation of Study Treatment 
7.1.1. 
Reasons for Discontinuation 
Participants must be discontinued from study treatment for the following reasons: 
• The participant becomes pregnant.  
• Consent is withdrawn. 
Note: Consent withdrawn means that the participant has explicitly indicated that they 
do not want to be followed any longer; in this case no further data, except data in the 
public domain, may be solicited from or collected on the participant. Consent may 
also be partial. Participants may choose to discontinue study treatment and remain in 
the study to be followed for safety.  
• Further participation would be injurious to the participant's health or well-being, in 
the investigator's medical judgment. 
• Unacceptable toxicity as noted in Section 6.5.2. 
• Worsening PN and the need for treatment with a prohibited medication as noted in 
Section 6.6.3. 
• Worsening PN during either the DBVC period or the OLE period, in which the extent 
of PN to be treated (ie, all areas excluding the scalp plus 1 cm surrounding 
pruriginous lesion[s]) exceeds 20% BSA. 
• If a participant is found after randomization not to have met eligibility criteria at the 
time of enrollment. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
• Development of AD lesions. 
A participant may be discontinued from study treatment as follows: 
• If, after 2 consecutive study visits and reinforcement of study cream application by 
site staff, a participant's cream usage exceeds one 60-g tube every 4 days, a 
participant who again fails to meet compliance benchmarks at a subsequent visit may 
be considered for withdrawal from the study. The medical monitor should be 
consulted for instruction on handling the participant. 
• If a participant is noncompliant with study procedures or study cream application in 
the investigator's opinion, the sponsor should be consulted for instruction on handling 
the participant. 

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7.1.2. 
Discontinuation Procedures 
In the event that the decision is made to permanently discontinue the study treatment prior to the 
Week 52/EOT2 visit, the ET visit should be conducted. Reasonable efforts should be made to 
have the participant return for a follow-up visit. If a participant is in the OLE period and has 
been in an observation/no-treatment cycle with an IGA-CPG-S score of 0 and a WI-NRS score 
of 0 for at least 30 days prior to the Week 52/EOT2 visit, then the Week 52/EOT2 visit will also 
count as the safety follow-up visit. These visits are described in Table 3 and Table 4. The last 
date of the last application of study cream and the reason for discontinuation of study cream will 
be recorded in the eCRF. 
If a participant is discontinued from study treatment: 
• The study monitor or sponsor must be notified. 
• The reason(s) for discontinuation must be documented in the participant's medical 
record and the primary reason for discontinuation must be included in the eCRF. 
• The ET visit should be performed and date recorded. 
• The status of the participant should be updated to ET in the IRT. 
• Participants must be followed for safety until the time of the follow-up visit or until 
study cream–related toxicities resolve, return to baseline, or are deemed irreversible, 
whichever is longest. 
If the participant discontinues study treatment and actively withdraws consent for collection of 
follow-up data (safety follow-up or disease assessment), then no additional data collection 
should occur; however, participants will have the option of withdrawing consent for study 
treatment but continuing in the follow-up period of the study for safety/efficacy assessments. 
7.2. 
Participant Withdrawal From the Study 
A participant may withdraw from the study at any time at their own request or may be withdrawn 
at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. When a participant is withdrawn from the study, the ET visit procedures 
should be performed; if possible, the safety follow-up visit should also be conducted within 
30 days of the last application of study cream. 
If a participant withdraws from the study, they may request destruction of any samples taken and 
not tested, and the investigator must document this in the site study records. If the participant 
withdraws consent for disclosure of future information, the sponsor may retain and continue to 
use any data collected before such a withdrawal of consent. 
See Table 3 and Table 4 for data to be collected at the time of study withdrawal and follow-up 
and for any further evaluations that need to be completed. 

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7.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and are unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant's last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant's medical record. 
• Should the participant continue to be unreachable, they will be considered to have 
withdrawn from the study. 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
Administrative and General Procedures 
8.1.1. 
Informed Consent Process 
• The investigator or their representative will explain the nature of the study to the 
participant or their legally authorized representative and answer all questions 
regarding the study. 
− Informed consent must be obtained before any study-related procedures are 
conducted, unless otherwise specified by the Protocol. 
− Informed consent must be obtained using the IRB/IEC-approved version in a 
language that is native and understandable to the participant. An ICF template 
will be provided by the sponsor or its designee. The sponsor or its designee must 
review and acknowledge the site-specific changes to the ICF template, and all 
site-specific changes must be approved by the IRB/IEC and the sponsor or its 
designee. The ICF must include a statement that the sponsor or its designee and 
regulatory authorities have direct access to participant records. 
− The ICF must contain all required elements, including optional 
samples/procedures (eg, optional biopsy), and describe the nature, scope, and 
possible consequences of the study in a form understandable to the study 
participant. 
• Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of informed 
consent that meets the applicable requirements and regulations for the countries in 
which the study is being conducted as well as the IRB/IEC or study center. 
• The participant must be informed that their personal data collected for the study will 
be used by the sponsor and/or their designee(s) in accordance with local data 
protection laws. The level of disclosure must also be explained to the participant. 
• The participant must be informed that their 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. 
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
• Participants must provide consent to the most current version of the ICF during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the participant or the participant's legally 
authorized representative. 
• Participants who are rescreened are required to sign a new ICF. 

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8.1.2. 
Screening Procedures 
Screening is the interval between signing the ICF and the day the participant is randomized in the 
study (Day 1). Screening may not exceed 28 days. Assessments that are required to demonstrate 
eligibility may be performed over the course of 1 or more days during the screening process. 
Results from the screening visit evaluations will be reviewed to confirm eligibility before 
randomization or the application of study cream. Tests with results that fail eligibility 
requirements may be repeated once during screening if the investigator believes the results to be 
in error. For screening assessments that are repeated, the most recent available result before 
randomization will be used to determine eligibility. 
See Sections 5.4 and 5.5 for information regarding screen failures and replacement of 
participants, respectively. 
8.1.3. 
Interactive Response Technology Procedure 
Each participant will be identified in the study by a participant ID number, which is a 
combination of the country's abbreviation, the site ID, and the participant number. Site staff 
should contact the IRT to obtain the participant ID number during screening. Upon determining 
that the participant is eligible for randomization, the IRT will be contacted to obtain the 
treatment assignment. Additionally, the IRT will be contacted at the study visits indicated in 
Table 3 and Table 4 to update the study cream supply. Additional details will be provided in the 
IRT Manual. 
8.1.4. 
Distribution of Reminder Cards and/or eDiaries 
Participants will be provided with a reminder card at each visit except the safety follow-up visit. 
The reminder card will indicate the date/time of the next visit and will also remind the participant 
that they should not apply their application of study cream before the Week 2, Week 12/EOT1, 
and Week 52/EOT2 visits. Study cream will be applied after blood draws for PK and safety 
assessments have been completed on Week 2 and Week 12 (see Section 8.5). 
Participants will be instructed on the use of the eDiary at screening. The date and time of the last 
application of study cream preceding each PK sample collection visit (Week 2, Week 12/EOT1, 
and Week 52/EOT2/ET) will be recorded in the eDiary. Daily study cream application will be 
recorded in the eDiary and verified by the study investigator/designee at study visits as shown in 
Table 3 and Table 4. 
8.1.5. 
Demography and Medical History 
8.1.5.1. 
Demographics and General Medical History 
Demographic data and general medical history will be collected at screening by the investigator 
or qualified designee and will include year of birth/age, race, ethnicity, Fitzpatrick Skin Type, 
medical and surgical history, history of atopy (eg, AD, allergic rhinitis/rhinoconjunctivitis, 
asthma, or food allergy), and current illnesses. Medical history will include relevant medical and 
surgical treatments considered to be clinically significant by the investigator. 
As race and/or ethnicity data are not to be analyzed from a scientific or medical perspective, but 
rather are to be reported in a descriptive format only in the CSR, data on race and/or ethnicity 

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from France (or other countries as per local law) must not be collected as per GDPR and local 
data protection law and requirements. 
8.1.5.2. 
Disease Characteristics and Treatment History 
A PN-targeted medical and treatment history will be collected at screening. Details regarding the 
participant's PN, including date of diagnosis, relevant disease characteristics, and prior 
treatments with outcome (eg, inadequate response), and the reason for stopping treatments, 
including systemic treatments, surgical procedures, and phototherapy, will be recorded. A 
medical or surgical history of other conditions related to PN or relevant to the conduct of this 
clinical trial will also be collected at screening. 
In addition, information about prescription PN treatments (eg, name, start/end dates, regimen) 
used within 12 months prior to screening, and the reason for discontinuation (eg, inadequate 
response, intolerance) will be collected. 
Acceptable documentation for the use of prescription treatments (within 12 months prior to 
screening) include any of the following: 
• Medical records 
• Communication with the participant's treating physician 
• Investigator documentation based on any of the following: 
− An interview with the participant or legal representative 
− Review of participant- or legal representative–reported medication history 
8.1.6. 
Exit Interviews 
Up to 30 participants in a subset of sites will enroll in a cross-sectional, noninterventional, 
qualitative research study. Data collected will be used to illustrate how improvements in PN 
effect the participant's life; this treatment satisfaction will generate evidence of the perceived 
meaningful improvement. Interviews will be performed by a vendor via telephone contact on a 
one-on-one basis. (Note: Interviews will be approximately 60 minutes.) The interview process is 
described in the Qualitative Exit Interview Manual. 
Participants will be introduced to the substudy during the informed consent process. Interested 
participants will indicate their willingness to participate in the substudy; however, their consent 
to participate in the substudy will be recorded through a substudy ICF. Participants will be 
contacted and interviews scheduled by research staff using communication materials provided in 
the Qualitative Exit Interview Manual. 
Each substudy participant will be interviewed up to 2 times, once shortly after completing their 
Week 12 treatment period and, for participants who continue in the treatment extension period, 
once shortly after completing Week 52. Note: Although it is encouraged that the same 
participants be interviewed after Week 12 and Week 52 treatment periods, it is not required. 
With the participant's permission, ascertained via the consent form and confirmed verbally 
before the start of the interview, the interview(s) will be audio recorded. 

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During the interview, participants will be asked a set of open-ended questions with probes to 
explore their experience with PN and the meaningfulness of the change they experienced in 
PN-related symptom(s) during and after study participation. Interview discussion guides are 
provided in the Qualitative Exit Interview Manual. 
8.2. 
Efficacy Assessments 
8.2.1. 
Worst-Itch Numeric Rating Scale 
The WI-NRS is a PRO comprised of a single item rated on a scale from 0 ("No itch") 
to 10 ("Worst imaginable itch"). Each evening beginning on the day of screening through 
Week 52 or ET, the participant will assess their worst level of PN-related itch during the past 
24 hours on a scale of 0 to 10 in an eDiary (see Section 8.3.1). 
An average of the 7-day WI-NRS scores, prior to the baseline visit (minimum 4 out of 7 days' 
data required), will be used to determine if a participant meets the inclusion criteria. The study 
staff should contact the participant 1 week prior to each visit to confirm the participant's 
compliance with completion of the WI-NRS assessment. 
Detailed directions for the administration of an eDiary will be provided in the Study Manual. 
8.2.2. 
Investigator's Global Assessment 
The severity and the activity of PN will be assessed via the IGA-CPG-S and the IGA-CPG-A, 
respectively. 
8.2.2.1. 
Investigator Global Assessment for Stage of Chronic Prurigo (IGA-CPG-S) 
The IGA-CPG-S is an overall severity rating on a scale of 0 to 4 (see Table 8). 
The IGA-CPG-S will be performed at the visits noted in the SoA (see Table 3 and Table 4). 
Table 8: 
IGA-CPG-S 
Score 
Category 
Description: Stage (IGA-CPG-S) 
0 
Clear 
No lesions (0 lesions) 
1 
Almost clear 
Rare palpable pruriginous lesions (approximately 1-5 lesions) 
2 
Mild 
Few palpable pruriginous lesions (approximately 6-19 lesions) 
3 
Moderate 
Many palpable pruriginous lesions (approximately 20-100 lesions) 
4 
Severe 
Abundant palpable pruriginous lesions (over 100 lesions) 
Source: Zeidler et al 2021. 
For a participant to be eligible for enrollment, their IGA-CPG-S score must be ≥ 2 at screening 
and baseline. Note: The total BSA treatment area must be ≤ 20%. The IGA-CPG-S-TS is defined 
as an IGA-CPG-S score of 0 or 1 with ≥ 2 grade improvement from baseline. 
8.2.2.2. 
Investigator Global Assessment for Activity of Chronic Prurigo (IGA-CPG-A) 
The IGA-CPG-A is an overall severity rating on a scale of 0 to 4 (see Table 9). The IGA will be 
performed at the visits noted in the SoA (see Table 3 and Table 4). 

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Table 9: 
IGA-CPG Activity 
Score 
Category 
Description: Activity (IGA-CPG-A) 
0 
Clear 
No pruriginous lesions have excoriations or crusts 
1 
Almost clear 
Very small proportion of pruriginous lesions have excoriations or crusts 
(up to approximately 10% of all pruriginous lesions) 
2 
Mild 
Minority of pruriginous lesions have excoriations or crusts 
(approximately 11-25% of all pruriginous lesions) 
3 
Moderate 
Many pruriginous lesions have excoriations or crusts 
(approximately 26-75% of all pruriginous lesions) 
4 
Severe 
Majority of pruriginous lesions have excoriations or crusts 
(approximately 76-100% of all pruriginous lesions) 
Source: Zeidler et al 2021. 
8.2.3. 
Prurigo Activity Score 
The extent and severity of PN will also be assessed via the PAS (v1.2) and will be determined at 
the visits noted in the SoA (see Table 3 and Table 4). The first 3 items are descriptive of the type, 
predominant type, distribution, and quantity of pruriginous lesions. The remaining 2 items of the 
PAS will assess disease activity in terms of percentage (ie, 0%, 1%-25%, 26%-50%, 51%-75%, 
76%-100%) of pruriginous lesions with excoriations/crusts on top (to reflect active scratching), 
and the percentage (100%, 76%-99%, 51%-75%, 26%-50%, 0%-25%) of healed pruriginous 
lesions, in order to quantify change of PN skin lesions. In addition, the total number of 
pruriginous lesions in a representative area will be identified at screening and followed 
throughout the study. 
8.2.4. 
Body Surface Area 
Total estimation of the %BSA treatment area will be used to determine the number of tubes of 
study cream dispensed at each visit (see Section 6.1). Treatment area is defined as the area 
affected by pruriginous lesions plus an ~ 1 cm area surrounding each lesion. Total %BSA 
treatment area will be estimated at each visit as outlined in the SoA (see Table 3 and Table 4). 
Body surface area assessment will be approximated to the nearest 0.1% using the Palmar Method 
as a guide. The Palmar Method is the palm plus 5 digits, with fingers tucked together and thumb 
tucked to the side (handprint), which is considered as 1% BSA and, the thumb, as 0.1% BSA, 
respectively. 
8.2.5. 
Photography 
At select sites, 2-dimensional photographs of the upper and lower half of the participant's body 
will be obtained at the visits noted in Table 3 and Table 4. 

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8.3. 
Patient-Reported Outcomes 
For all patient-reported outcome assessments conducted at the study site, in order to avoid bias in 
the participants' responses to the questionnaires, assessments should be completed before any 
other evaluations or study procedures on the day of the study visit and prior to treatment-related 
discussions with the investigator or study site staff. 
8.3.1. 
Electronic Diary Assessments: Worse-Itch Numeric Rating Scale and Skin Pain 
Numeric Rating Scale 
Participants will either bring and use their own device or be issued a handheld device (eDiary) at 
the screening visit. Each participant will be instructed to complete the eDiary each evening 
beginning on the day of screening through Week 52 or treatment discontinuation. Compliance 
with the eDiary is calculated electronically in real time via the vendor portal. If the participant is 
frequently not completing the eDiary, the site staff will be informed so compliance can be 
addressed in a timely manner. Note: Completion of the WI-NRS a minimum of 4 out of 7 days 
before study visits is required for the analysis. 
Study sites will contact participants 1 week before the baseline visit to confirm compliance with 
eDiary assessments to ensure information is available to allow randomization if appropriate. The 
WI-NRS is depicted Section 8.2.1. 
8.3.2. 
Skin Pain Numeric Rating Scale 
Each evening, the participant will assess their worst level of PN-related skin pain during the past 
24 hours on a scale of 0 to 10. 
8.3.3. 
Dermatology Life Quality Index 
The DLQI is a simple, 10-question validated questionnaire to measure how much the skin 
problem has affected the participant over the previous 7 days and will be completed as outlined 
in the SoA (see Table 3 and Table 4; Finlay and Khan 1994). The participant will answer the 
questionnaire as follows: (1) very much, (2) a lot, (3) a little, or (4) not at all. 
The questionnaire is analyzed under 6 headings as follows: 
• Symptoms and feelings (Questions 1 and 2) 
• Daily activities (Questions 3 and 4) 
• Leisure (Questions 5 and 6) 
• Work and school (Question 7) 
• Personal relations (Questions 8 and 9) 
• Treatment (Question 10) 
Overall scoring ranges from 0 to 30, with a high score indicative of poor HRQoL. 

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8.3.9. 
Health Economics 
8.3.9.1. 
EQ-5D-5L 
Participants will complete the EQ-5D-5L questionnaire at the designated study visits listed in the 
SoA (see Table 3 and Table 4). The EQ-5D-5L questionnaire is a standardized, validated 
instrument for use as a measure of health outcome (Herdman et al 2011). The EQ-5D-5L 
questionnaire will provide data for use in economic models and analyses, including developing 
health utilities or QALYs. The EQ-5D-5L questionnaire consists of the following 2 sections: the 
EQ-5D descriptive system and the EQ VAS. The descriptive system comprises 5 dimensions: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. 
Each dimension has 5 levels: Level 1 = no problems, Level 2 = slight problems, 
Level 3 = moderate problems, Level 4 = severe problems, and Level 5 = extreme problems. This 
part of the EQ-5D-5L questionnaire provides a descriptive profile that can be used to generate a 
health state profile. For example, a participant in "health state 12345" would have no problems 
with mobility, slight problems with self-care (washing or dressing), moderate problems with 
doing usual activities, severe pain or discomfort, and extreme anxiety or depression. Each health 
state can potentially be assigned a summary index score based on societal preference weights for 
the health state. These weights, sometimes referred to as utilities, are often used to compute 
QALYs for use in health economic analyses. Health state index scores generally range from 
< 0 (where 0 is the value of a health state equivalent to dead; negative values represent values as 
worse than dead) to 1 (the value of full health), with higher scores indicating higher health 
utility. The health state preferences often represent national or regional values and can therefore 
differ between countries/regions. The EQ VAS records the participant's self-rated health on a 
vertical VAS (0-100), where the endpoints are labeled "the best health you can imagine" 
(100 score) and "the worst health you can imagine" (0 score). 

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8.3.9.2. 
Work Productivity and Activity Index 
The WPAI is a 6-item questionnaire that measures the effect of the participant's health problems 
on their ability to work and perform regular activities (Reilly et al 1993) and will be completed at 
the visits noted in the SoA (see Table 3 and Table 4). The WPAI outcomes are expressed as 
impairment percentages, with higher numbers indicating greater impairment and less 
productivity (ie, worse outcomes). 
8.4. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA in Table 3 and Table 4. 
See Section 6.5 for guidelines regarding the management of relevant laboratory or other safety 
assessment abnormalities. 
8.4.1. 
Adverse Events 
Adverse events will be monitored from the time the participant signs the ICF until at least 
30 days after the last application of study cream. Adverse events for enrolled participants that 
begin or worsen after informed consent should be recorded on the Adverse Events Form in the 
eCRF regardless of the assumption of a causal relationship with the study cream. Conditions that 
were already present at the time of informed consent should be recorded on the Medical History 
Form in the eCRF. Adverse events (including laboratory abnormalities that constitute AEs) 
should be described using a diagnosis whenever possible rather than by individual underlying 
signs and symptoms. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant'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 on AEs that are serious, 
that are considered related to the study cream/procedures, or that caused the participant to 
discontinue the study cream. Care will be taken not to introduce bias when detecting AEs and/or 
SAEs. Open-ended and nonleading verbal questioning of the participant, such as "How are you 
feeling?," is the preferred method to inquire about AE occurrences. Adverse events may also be 
detected when they are volunteered by the participant during the screening process or between 
visits or through physical examinations, laboratory tests, or other assessments. The definition, 
reporting, and recording requirements for AEs are described in Section 9. 
All SAEs will be reported to the sponsor or designee by the investigator immediately without 
undue delay and not later than 24 hours (or immediately as mandated per local country 
regulations) of obtaining knowledge of the events. The investigator will also submit any updated 
SAE data to the sponsor immediately without undue delay and not later than 24 hours of 
obtaining knowledge of the update. 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 

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8.4.2. 
Physical Examinations 
Physical examinations must be performed by a medically qualified individual, such as a licensed 
physician, a physician assistant, or an advanced practice registered nurse, as local law permits. 
Abnormalities identified after the first dose of study treatment constitute an AE if they are 
considered clinically meaningful, induce clinical signs or symptoms, require concomitant 
therapy, or require changes in study cream. Investigators should pay special attention to clinical 
signs related to previous serious illnesses. 
At the screening visit, a comprehensive physical examination should be conducted. The 
comprehensive physical examination will include height and body weight and assessment(s) of 
the following organ or body systems: skin; head, eyes, ears, nose, and throat; thyroid; lungs; 
cardiovascular system; abdomen (liver, spleen); extremities; and lymph nodes; as well as a brief 
neurological examination. 
During the study, participants will have targeted physical examinations. Participants will be 
assessed by the investigator or medically qualified designee per institutional standard of care. 
These assessments should be an evaluation as indicated by participant symptoms, AEs, or other 
findings and documented on the Adverse Events Form in the eCRF. 
8.4.3. 
Vital Signs 
Vital sign measurements (to be taken before blood collection for laboratory tests) will be 
performed at each study visit and include blood pressure, pulse, respiratory rate, and body 
temperature. Blood pressure and pulse will be taken with the participant in the recumbent, 
semirecumbent, or sitting position after 5 minutes of rest. 
If vital signs cannot be taken before blood collection for laboratory tests, there must be a 
minimum of 30 minutes from the completion of the blood collection procedures to the beginning 
of the vital signs collection. Abnormal vital sign results identified after the first application of 
study cream constitute an AE if they are considered clinically meaningful, induce clinical signs 
or symptoms, require concomitant therapy, or require changes in study cream. 
8.4.4. 
Electrocardiograms 
A single 12-lead ECG will be obtained at the screening visit as outlined in the SoA (see Table 3 
and Table 4) using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTc intervals. The 12-lead ECG will be performed with the participant in a 
recumbent or semirecumbent position after 5 minutes of rest. An ECG is acceptable if performed 
within 2 months of the baseline visit. 
The decision to include or exclude a participant or discontinue study treatment based on an ECG 
flagged as "Abnormal, Clinically Significant" is the responsibility of the investigator, in 
consultation with the sponsor's medical monitor, as appropriate. Any safety assessments, 
including ECGs that are considered clinically significant in the judgment of the investigator, are 
to be reported as AEs. 
8.4.5. 
Laboratory Assessments 
See Table 10 for the list of clinical laboratory tests to be performed, and Table 3 and Table 4 for 
the timing and frequency. A central laboratory will perform all clinical laboratory assessments 

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for safety (ie, blood chemistries, hematology assessments). The sponsor or designee will perform 
all PK and translational sample analyses. Additional testing may be required by the sponsor 
based on emerging safety data. All Protocol-required laboratory assessments must be conducted 
in accordance with the Laboratory Manual. Information regarding collection, processing, and 
shipping of samples for laboratory assessment is provided in the Laboratory Manual. 
Clinically significant abnormal laboratory findings are those that are not associated with the 
underlying disease unless judged by the investigator to be more severe than expected for the 
participant's condition. All laboratory tests with values considered clinically significantly 
abnormal during participation in the study or within 30 days after the last application of study 
cream should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor. 
Screening laboratory assessments must be performed within 28 days before Day 1. If performed 
more than 28 days before Day 1, then the test must be repeated and eligibility confirmed before 
study cream application on Day 1. 

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Table 10: 
Required Laboratory Analytes 
Chemistry 
Hematology 
Serology 
Pregnancy Testing 
Albumin 
Alkaline phosphatase 
ALT 
AST 
Blood urea nitrogen or urea 
Creatinine 
Creatine kinase 
Glucose 
Total bilirubin 
Direct bilirubin (if total bilirubin is 
elevated above ULN) 
Complete blood count, including: 
• Hemoglobin 
• Hematocrit 
• Platelet count 
• Red blood cell count 
• Reticulocyte count 
• White blood cell count 
 
Differential count (absolute and %), 
including: 
• Basophils 
• Eosinophils 
• Lymphocytes 
• Monocytes 
• Neutrophils 
• HIV 
• HBsAg  
• HBsAba 
• HBcAba 
• HCVAbb 
• HBV DNA (reflex)a 
• HCV RNA (reflex)b 
• Human chorionic gonadotropin 
(WOCBP only) 
• FSH (women of nonchildbearing 
potential only) 
• WOCBP require a serum test at 
screening and a urine pregnancy 
test at all other visits. A positive 
urine test will be confirmed by a 
serum test. 
• Pregnancy tests (serum or urine) 
should be repeated if required by 
local regulations. 
Thyroid Function Markers 
• Thyroid-stimulating hormone 
• Free thyroxine 
Note: Additional tests may be required, as agreed upon by the investigator and sponsor, based on emerging safety data or to rule out a diagnosis. 
a If either HBsAb or HBcAb is positive, a reflexive HBV DNA must be obtained (see Section 8.4.5.3.1). 
b If HCVAb is positive, a reflexive HCV RNA must be obtained (see Section 8.4.5.3.2). 

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8.4.5.1. 
Pregnancy Testing 
A serum pregnancy test will be required for all WOCBP during screening. Urine pregnancy tests 
will be performed locally as outlined in Table 3 and Table 4, as medically indicated (eg, in case 
of loss of menstrual cycle, when pregnancy is suspected), or per country-specific requirement 
(note that country-required urine pregnancy testing will be outlined and communicated to 
investigational sites under separate cover). If a urine pregnancy test is positive, the result should 
be confirmed with a serum pregnancy test. 
If the serum pregnancy test result is negative after a urine test result was positive, the 
investigator will assess the potential benefit/risk to the participant and determine whether it is in 
the participant's best interest to resume study cream and continue participation in the study. 
If a pregnancy is confirmed by a serum pregnancy test result, see Section 9.8 for reporting 
requirements. 
8.4.5.2. 
HIV Testing 
HIV screening assessments will be performed at the screening visit to rule out HIV infection 
(see Table 10). Generally, HIV tests should be performed early in the screening process due to 
the length of time needed to obtain the results. Additional tests may be performed if clinically 
indicated. 
8.4.5.3. 
Hepatitis Testing 
All participants will be tested for the presence of HBV and HCV at screening. Participants 
enrolled prior to Protocol Amendment 1 should have hepatitis testing performed at the next 
scheduled or unscheduled visit.  
8.4.5.3.1. Hepatitis B Virus 
Participants must undergo HBV testing at screening. This includes testing for HBsAg, HBcAb, 
and HBsAb with reflex HBV DNA testing.  
A diagram is shown in Table 11 with further explanation below. 
Table 11: 
Interpretation and Management of HBV Serologic Test Results 
Scenario 
HBsAg 
HBcAb 
HBsAb 
Status 
A 
Positive or indeterminate 
Negative or positive 
Negative or positive 
Not eligible 
B 
Negative 
Negative 
Negative 
Eligible 
C 
Negative 
Negative 
Positive 
HBV DNA PCR required 
Positive results: not eligible 
Negative results: eligible 
D 
Negative 
Positive 
Positive 
E 
Negative 
Positive 
Negative 

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For participants in Scenarios C, D, and E:  
• If the HBV DNA PCR test is negative, the participant is eligible and may be 
randomized.  
• If the HBV DNA PCR test is positive, the participant is not eligible and will be 
screen failed.  
• In the event the HBV DNA PCR test cannot be performed, the participant is not 
eligible and will be screen failed. 
8.4.5.3.2. Hepatitis C Virus 
Blood samples for HCV testing will be obtained at the screening visit. Participants with negative 
HCVAb are eligible. A positive HCVAb will trigger an HCV RNA test (reflex test). A 
participant will not be eligible and will be screen failed if test results indicate active hepatitis C 
(HCV RNA detectable in any participant with positive HCVAb). Participants who test positive 
for HCV but are successfully treated for HCV infection and have their screening visit at least 
12 weeks after the last dose of HCV therapy may be eligible if HCV RNA is undetectable. 
8.5. 
Pharmacokinetic Assessments 
Trough PK blood samples will be collected at the study visits indicated in the SoA (see Table 3 
and Table 4). During the DBVC period, samples will be collected from all participants and may 
be collected at any time during the study visit prior to study cream application. 
During the OLE period, samples will only be collected from participants who have applied study 
cream BID at least 1 day prior to the day of the study visit. Note that participants who are 
off-treatment but are then instructed to restart applying study cream (IGA-CPG-S score ≥ 1 
and/or the presence of PN-related itching) during the study visit, will still be considered 
off-treatment and a trough PK sample will not be collected for that visit. If a PK sample is to be 
collected, it may be drawn at any time during the study visit prior to any application of study 
cream at the site. 
Pharmacokinetic blood samples must either be drawn from an area that has not been treated with 
study cream, or the participant must not apply the previous application of study cream on the 
immediate body area where blood is to be drawn (ie, for site visits in the morning, this means the 
application on the evening before [second dose of that day]; for site visits in the afternoon this 
means the application on the morning of the same day [first dose of that day]). 
The exact date and time of the PK blood draws, and the date and time of the last application of 
study cream preceding the blood draw (if applicable), will be recorded in the eCRF. 
It is preferred that the venous blood PK sample is drawn from an unaffected (ie, untreated) skin 
area, if available. 
Instructions for sample preparation and shipping will be provided in the Laboratory Manual. 
Participants will receive reminder cards in advance of the study visit providing instruction to 
hold the application of study cream on the day of the visit. The time of the prior application of 
study cream will be recorded in the eDiary and EDC. 

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8.7. 
Unscheduled Visits 
Unscheduled visits may occur at any time medically warranted, including when participants 
develop new pruriginous lesions. Any assessments performed at those visits should be recorded 
in the eCRF. 

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8.8. 
End of Treatment and/or Early Termination 
The EOT1 coincides with the Week 12 visit and EOT2 with the Week 52 visit. A participant who 
completes the study through the Week 52/EOT2 visit will have reached the EOT with study 
cream. 
If a decision is made that the participant will permanently discontinue study cream prior to the 
Week 12/EOT1 visit, then the ET1 visit should be conducted. If a participant completed the 
Week 12/EOT1 visit and permanently discontinues study cream prior to the Week 52/EOT2 
visit, then the ET2 visit should be conducted. If the ET1 or ET2 visit coincides with a regular 
study visit, then the ET evaluations will supersede those of that scheduled visit, and the data 
should be entered in the ET1 or ET2 page in the eCRF. If this decision does not coincide with a 
regular visit, reasonable efforts should be made to have the participant return to the site to 
complete the ET procedures. 
8.9. 
Follow-Up 
8.9.1. 
Safety Follow-Up 
The safety follow-up period is the interval between the Week 52/EOT2 visit or ET visit and the 
scheduled follow-up visit, which should occur 30 (+ 7) days after the Week 52/EOT2 visit or 
ET visit, with the following 2 exceptions: 
• If the Week 52/EOT2 visit or ET visit was not performed, the follow-up visit should 
occur 30 days after the last application of study cream. 
• If the participant is in the OLE period and has been in an observation/no-treatment cycle 
with an IGA-CPG-S score of 0 and a WI-NRS score of 0 for at least 30 days prior to the 
Week 52/EOT2 visit, then the Week 52/EOT2 visit will also count as the safety 
follow-up visit.  
During this period, new AEs and SAEs must be reported up to 30 days after the last application 
of study cream. All AEs and SAEs must be followed until resolution, return to baseline, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up, whichever 
is longest. Reasonable efforts (eg, at least 2 documented attempts) should be made to have the 
participant return for the follow-up visit. 

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9. 
ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING 
9.1. 
Definition of Adverse Event 
Adverse Event Definition 
• An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or 
not it is considered drug-related. 
• An AE can therefore be any unfavorable or unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study 
cream. 
Additional Guidance for Events Meeting the Adverse Event Definition 
• Any safety assessments (eg, ECG, 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) are to be reported as an AE. 
• Abnormal laboratory test results are to be reported as an AE if they are considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes in 
study cream. Whenever possible, a diagnosis (eg, anemia, thrombocytopenia) should be recorded in 
the eCRF rather than the abnormal laboratory test result (eg, low hemoglobin, platelet count 
decreased). 
• Exacerbation of a chronic or intermittent pre-existing condition/disease, including either an increase 
in the frequency and/or intensity of the condition, is to be reported as an AE. 
• New conditions detected or diagnosed after the start of study cream application are to be reported as 
an AE. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction are to be reported as 
an AE. 
• Signs and/or symptoms from dose application errors of a study cream (eg, overdose) or a 
concomitant medication are to be reported as an AE. 
• "Lack of efficacy," "disease progression," or "failure of expected pharmacological action" will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
• A condition that leads to a medical or surgical procedure (eg, endoscopy, appendectomy) will be 
reported as an AE if it occurs after obtaining informed consent. If the condition is present before 
entering the study, then it should be captured as medical history. 
• Pre-existing diseases or conditions with expected fluctuations in signs or symptoms should be 
reported as an AE only if the investigator judges the fluctuation to have worsened more than 
expected during study participation. 

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9.2. 
Definition of Serious Adverse Event 
If an event is not an AE per the definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death due 
to progression of disease). 
A serious adverse event is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term "life-threatening" in the definition of "serious" refers to an adverse drug experience that 
places the participant, in the opinion of the initial reporter, at immediate risk of death from the adverse 
experience as it occurs. This does not include an adverse drug experience that, had it occurred in a 
more severe form, might have caused death. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (involving at least an 
overnight stay) at the hospital or emergency department 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 or planned surgery (eg, stent replacement, hip surgery) is not 
considered an SAE. 
Hospitalization for medical interventions in which no unfavorable medical occurrence occurred 
(ie, elective procedures or routine medical visits) is not considered an SAE. 
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. 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), that may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Is an important medical event 
An important medical event is an event that may not result in death, be immediately life-threatening, or 
require hospitalization but may be considered serious when, based on appropriate medical judgment, 
the event may jeopardize the participant and may require medical or surgical intervention to prevent 
one of the outcomes listed in the above definition. Examples of such events include new invasive or 
malignant cancers; intensive treatment in an emergency department or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization; development of 
drug dependency or drug abuse; or suspected transmission of an infectious agent via a medicinal 
product.  

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9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse 
Events 
Adverse Event and Serious Adverse Event Recording 
• An AE/SAE that begins or worsens after informed consent is signed should be recorded on the 
Adverse Events Form in the eCRF. All AEs/SAEs should be reported for enrolled participants, but 
only SAEs need to be reported for screen failure participants. For enrolled participants, conditions 
that were present at the time informed consent was given should be recorded on the Medical History 
Form in the eCRF. For detailed information, refer to the eCRF guidelines. 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(eg, hospital progress notes, laboratory reports, and diagnostic reports) related to the event. 
• The investigator (or designee) will then record all relevant AE/SAE information in the eCRF. 
• It is not acceptable for the investigator to send photocopies of the participant's medical records 
in lieu of completing the Adverse Events Form in the eCRF. 
• There may be rare instances when copies of medical records for certain cases are requested. In this 
case, all participant identifiers, with the exception of the participant number, will be redacted by the 
site staff on the copies of the medical records before submission. These records can be submitted to 
Incyte Pharmacovigilance by email/fax per the contact information listed in the Study Reference 
Manual or as per SAE completing guidelines. 
• 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. When a clear diagnosis cannot be identified, each sign or symptom 
should be reported as a separate AE/SAE. 
To the extent possible, each AE/SAE should be evaluated to determine the following: 
• The severity grade (CTCAE v5.0 Grade 1 to 5). See below for further instructions on the assessment 
of intensity. 
• Whether there is at least a reasonable possibility that the AE is related to the study cream: suspected 
(yes) or not suspected (no). See below for further instructions on the assessment of causality. 
• The start and end dates, unless unresolved at the final safety follow-up visit. 
• The action taken with regard to study cream as a result of the AE/SAE(s). 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown). 
• The seriousness, as per the SAE definition provided in Section 9.2. 
• The action taken with regard to the event. Note: If an AE is treated with a concomitant medication or 
nondrug therapy, this action should be recorded on the Adverse Events Form and the treatment 
should be specified on the appropriate eCRF (eg, Prior/Concomitant Medications, Procedures and 
Nondrug Therapy). 

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Assessment of Intensity 
The severity of AEs will be assessed using CTCAE v5.0 Grades 1 through 5. If an event is not 
classified by CTCAE, the severity of the AE will be graded according to the scale below to estimate 
the grade of severity. 
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: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment 
not indicated. 
• Grade 2: Moderate; minimal, local, or noninvasive treatment indicated; limiting age-appropriate 
activities of daily living. 
• Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. 
• Grade 4: Life-threatening consequences; urgent treatment indicated. 
• Grade 5: Fatal. 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study cream and each occurrence of 
each AE/SAE.  
• A "reasonable possibility" of a relationship conveys that there are medical 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 possibility of a relationship. 
• The investigator will also consult the RSI in the IB in making their assessment. 
• Alternative causes, such as underlying or concurrent disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study cream application, will be 
considered and investigated. 
• For each AE/SAE, the investigator must document in the medical notes that they have reviewed the 
AE/SAE and have provided an assessment of causality. 
• With regard to assessing causality of SAEs: 
− There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report. However, the causality assessment is one of the criteria 
used when determining regulatory reporting requirements. Therefore, it is very important that 
the investigator always make an assessment of causality based on the available information 
for every event before the initial transmission of the SAE. 
− The investigator may change their opinion of causality in light of follow-up information and 
submit the updated causality assessment. 

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Follow-Up of Adverse Events and Serious Adverse Events 
• 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 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. 
• Once an AE is detected, it should be followed in the Adverse Events Form in the eCRF until it has 
resolved or until it is judged to be permanent; assessment should be made at each visit (or more 
frequently if necessary) of any changes in severity, the suspected relationship to the study cream, the 
interventions required to treat the event, and the outcome. 
• When the severity of an AE changes over time for a reporting period (eg, between visits), each 
change in severity will be reported as a separate AE. 
• If a participant dies during participation in the study or during a recognized follow-up period, the 
investigator will provide the sponsor with a copy of any postmortem findings, including 
histopathology.  
• Updated SAE information will be recorded in the originally completed eCRF and reported to Incyte 
Pharmacovigilance (SAE via the EDC system [primary method] or by completing the Serious 
Adverse Event Report Form in English [only if the EDC system is not available]) until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up. 
• Any updated SAE data (including SAEs being downgraded to nonserious) will be submitted to the 
sponsor (or designee) within 24 hours of receipt of the information (or immediately as mandated per 
local country regulations). 
9.4. 
Reporting of Serious Adverse Events 
Regardless of suspected causality (eg, relationship to study cream or study procedure[s]), all 
SAEs occurring after the participant has signed the ICF through the last safety visit or at least 
30 days after the last application of study cream must be reported to the sponsor (or designee) 
immediately, without undue delay but not later than within 24 hours* of obtaining knowledge of 
its occurrence unless otherwise specified by the Protocol. The investigator will submit any 
updated SAE data to the sponsor (or designee) immediately, without undue delay but not later 
than within 24 hours of it being available. *Note: Immediate reporting of SAEs is required in 
certain countries as per local country regulations. 
Investigators are not obligated to actively seek SAE information after the safety follow-up visit 
or more than 30 days after the last application of study cream. If the investigator learns of any 
SAE, including death, at any time and they consider the event to be reasonably related to the 
study cream or study participation, then the investigator must notify the sponsor (or designee) 
within 24 hours* of becoming aware of the event. *Note: Immediate reporting of SAEs is 
required in certain countries as per local country regulations. 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Prompt notification by the investigator to the sponsor regarding an SAE is essential so that legal 
obligations and ethical responsibilities for the safety of participants and the safety of a study drug 
under clinical investigation are met. 

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If the SAE is not documented in the RSI of the IB for the study cream (new occurrence) and is 
thought to be related to the study cream, the sponsor or its designee may urgently require further 
information from the investigator for expedited reporting to health authorities. The sponsor or its 
designee may need to issue an Investigator Notification to inform all investigators involved in 
any study with the same cream that this SAE has been reported. Suspected unexpected serious 
adverse reactions will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC or as per national regulatory requirements 
in participating countries. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study drug under clinical investigation. The sponsor 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and sponsor policy and forwarded to investigators as 
necessary. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate, according to local requirements. 
Serious Adverse Event Reporting 
• Information about all SAEs is collected and recorded on the Adverse Events Form in the eCRF. 
• The investigator must report within 24 hours* of learning of its occurrence any SAE via the EDC 
system (primary method) or by completing the Serious Adverse Event Report Form in English (only 
if the EDC system is not available). The contact information for Incyte Pharmacovigilance by 
email/fax is listed in the Study Reference Manual or the Incyte Reference Guide for Completing the 
Serious Adverse Event Report Form. *Note: Immediate reporting of SAEs is required in select 
countries per local country regulations. 
• In circumstances where the EDC system is not accessible for reporting SAE information (initial 
and/or follow-up SAE information) to the sponsor within 24 hours, refer to the Incyte Reference 
Guide for Completing the Serious Adverse Event Report Form. Once the EDC system is functional, 
the SAE report should be retrospectively added to the EDC system and follow-up should be 
completed through the EDC. The original copy of the Serious Adverse Event Report Form and the 
email or facsimile confirmation sheet must be kept at the study site (refer to the Incyte Reference 
Guide for Completing the Serious Adverse Event Report Form or Study Reference Manual for 
details and for the email address or fax number). 
• Follow-up information is also recorded in the eCRF and transmitted to Incyte Pharmacovigilance via 
the EDC system. The follow-up report should include information that was not provided previously, 
such as the outcome of the event, treatment provided, action taken with study cream because of the 
SAE (eg, dose reduced, interrupted, or discontinued), or participant disposition (eg, continued or 
withdrew from study participation). Each recurrence, complication, or progression of the original 
event should be reported as follow-up to that event, regardless of when it occurs. 

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9.5. 
Potential Drug-Induced Liver Injury 
Not applicable. 
9.6. 
Events of Clinical Interest 
Not applicable. 
9.7. 
Emergency Unblinding of Treatment Assignment 
In case of a medical emergency, for a participant's safety management, the procedure for 
emergency unblinding is provided to the investigator in the IRT Manual. The investigator may 
unblind a participant in the event of a medical emergency. The IRT system has an option to 
select for "Emergency Code Break" action for a given participant. After entering the study cream 
tube number and verification of the unmasking information, the investigator/subinvestigator will 
proceed to either final confirmation or cancellation of the code break procedure. If a participant's 
treatment assignment is unblinded, the sponsor or its designee should be notified immediately by 
telephone for awareness. 
If an investigator, the site personnel performing assessments, or a participant is unblinded, then 
the participant must discontinue study cream unless there are ethical reasons to have the 
participant remain on the study treatment. In these cases, the investigator must obtain specific 
approval from the sponsor's (or its designee's) medical monitor for the participant to continue in 
the study. 
9.8. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that the study 
cream may have interfered with the effectiveness of a contraceptive medication or method. When 
a pregnancy has been confirmed in a participant during maternal or paternal exposure to study 
cream, the following procedures should be followed in order to ensure safety: 
• The study cream must be discontinued immediately (female participants only; see 
Section 6.5.1 for the maximum permitted duration of study cream interruption). 
• The investigator must complete and submit the Incyte Clinical Trial Pregnancy Form 
to the sponsor or its designee within 24 hours of learning of the pregnancy. 
Data on fetal outcome are collected for regulatory reporting and drug safety evaluations. 
Follow-up should be conducted for each pregnancy to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications by following until the first 
well-baby visit. Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported 
by the investigator to the sponsor or its designee. Pregnancy follow-up information should be 
recorded on the same form and should include an assessment of the possible causal relationship 
to the sponsor's study cream to any pregnancy outcome, as well as follow-up to the first 
well-baby visit or the duration specified in local regulations, whichever is later. Refer to the 
Incyte Reference Guide for Completing the Clinical Trial Pregnancy Form or Study Reference 
Manual for further details. 

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Any SAE occurring during the pregnancy of a study participant must be recorded and 
reported as described in Section 9.4. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, or ectopic pregnancy) are considered SAEs (if occurring in the study participant) and 
must be reported as described in Section 9.4. If an abnormal pregnancy outcome is reported in a 
study participant's partner, the event should be reported to the sponsor on the Clinical Trial 
Pregnancy Form. 
9.9. 
Warnings and Precautions 
Special warnings or precautions for the study cream, derived from safety information collected 
by the sponsor or its designee, are presented in the IB. Additional safety information collected 
between IB updates will be communicated in the form of Investigator Notifications. Any 
important new safety information should be discussed with the participant during the study as 
necessary. If new significant risks are identified, they will be added to the ICF. 
9.10. 
Product Complaints 
The sponsor collects product complaints on study drugs and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and facilitate 
process and product improvements. 
All product complaints associated with material packaged, labeled, and released by the sponsor 
or its designee will be reported to the sponsor. All product complaints associated with other 
study material will be reported directly to the respective manufacturer. 
The investigator or their designee is responsible for reporting a complete description of the 
product complaint via email or other written communication to the sponsor contact or respective 
manufacturer as noted in the packaging information. Any AE associated with a product 
complaint should be recorded as described in Section 9.3. 
If the investigator is asked to return the product for investigation, they will return a copy of the 
product complaint communication with the product. 
9.11. 
Treatment of Overdose 
There has been no clinical experience with overdose resulting from excessive use of ruxolitinib 
cream. Treatment of overdose should consist of general supportive measures. 

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10. 
STATISTICS 
10.1. 
Sample Size Determination 
Approximately 180 participants will be randomized 1:1 to ruxolitinib 1.5% cream BID or vehicle 
cream BID. The sample size calculation is based on the Fisher exact test for the primary efficacy 
endpoint, which is the proportion of participants with WI-NRS4 response at Week 12. The 
mechanism of stopping the itch-scratch cycle and reducing the pruritus are similar between PN 
and AD. Additionally, based on the results from a Phase 2 study in AD of nemolizumab 
(Silverberg et al 2020), and a Phase 2 study in PN (Galderma 2021) and a Phase 3 study in PN 
(Galderma 2022) of nemolizumab, the improvement in WI-NRS are not substantially different 
between AD and PN; therefore, the results from the 2 Phase 3 studies of ruxolitinib cream 
(INCB 18424-303 and -304) in the treatment of AD are used to build the assumptions of the 
proportion of participants with WI-NRS4 response, which are 50% for ruxolitinib 1.5% cream 
BID and 25% for vehicle cream BID. Using a 2-sided alpha of 0.05, the sample size based on the 
current assumption will have > 90% power to detect a difference between ruxolitinib cream and 
vehicle cream. In addition, the assumptions and powers for key secondary endpoints are 
provided in Table 12. 
Table 12: 
Powering for Key Secondary Endpoints 
Variables 
Response Rates in 
Ruxolitinib 1.5% 
BID 
Response Rates 
in Vehicle 
BID 
Power: 
1.5% BID vs Vehicle 
BID 
WI-NRS4 response at Week 4 
40% 
15% 
>90% 
Overall-TS (WI-NRS4 response 
and IGA-CPG-S-TS) at Week 12 
30% 
10% 
>90% 
IGA-CPG-S-TS at Week 12 
40% 
20% 
80% 
WI-NRS4 response on Day 7 
30% 
10% 
>90% 
Note: Based on Fisher's exact test, 2-sided α= 0.05. 
In addition to providing adequate power for efficacy variables, the sample size is determined to 
provide an adequate database for safety evaluations. 
10.2. 
Populations for Analysis 
The populations for analysis are provided in Table 13. 

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Table 13: 
Populations for Analysis 
Population 
Description 
ITT  
The ITT population incudes all randomized participants. 
PP 
The PP population includes randomized participants who are considered to be 
sufficiently compliant with the Protocol. 
Safety 
The safety population includes all participants who applied at least 1 dose of study 
cream. Treatment groups for this population will be determined according to the 
actual treatment the participant received on Day 1. 
10.3. 
Level of Significance 
The gatekeeping testing strategy for the primary and key secondary analyses will be 
implemented to control the overall Type I error rate, 2-sided α = 0.05. These endpoints will be 
tested in a fixed sequence at a 2-sided α = 0.05 level in the following order: 
• WI-NRS4 response at Week 12 
• WI-NRS4 response at Week 4 
• Overall-TS at Week 12, defined as achieving both WI-NRS4 response and 
IGA-CPG-S-TS 
• IGA-CPG-S-TS at Week 12 
• WI-NRS4 response on Day 7 
10.4. 
Statistical Analyses 
10.4.1. 
Primary Analysis 
The primary analysis will be based on the ITT population. The baseline WI-NRS score will be 
determined by averaging the 7 daily NRS scores before Day 1 (Day −7 to Day −1). The by-visit 
WI-NRS score for postbaseline visits will be determined by averaging the 7 daily NRS scores 
before the visit day. If 4 or more daily scores are missing (out of the 7), the WI-NRS score at the 
visit will be set to missing. The proportion of participants with a WI-NRS4 response, defined as 
achieving a ≥ 4-point improvement in WI-NRS score from baseline to Week 12, will be 

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summarized by treatment groups. Table 14 presents the summary of the primary endpoint 
analysis. 
Table 14: 
Summary of Primary Analysis 
Parameter 
Definition 
Treatment 
Ruxolitinib 1.5% cream compared with vehicle cream 
Population  
ITT population 
Variable 
WI-NRS4 response at Week 12 
Population-level summary 
WI-NRS4 response rate difference with 95% CI 
The primary alternative hypothesis (superiority of active ruxolitinib group 1.5% BID compared 
with vehicle) will be tested at a 2-sided α = 0.05 level using a CMH test stratified by 
stratification factors IGA-CPG-S score (2 or ≥ 3) and geographic region (North America or 
outside of North America). The p-value and stratum-adjusted WI-NRS4 response rate difference 
with 95% CI will be provided. Overall odds ratio will also be provided with 95% CI. Participants 
with missing Week 12 data for any reason, and participants who develop AD lesions, will be 
defined as nonresponders. No rescue therapy is allowed in this study. 
Subgroup analysis by baseline characteristics such as geographic region and any underlying 
condition known to be associated with the clinical presentation of PN will be performed. In 
addition, the following sensitivity analyses may be performed, and details will be provided in the 
SAP. 
• Longitudinal logistic regression with repeated measures: 
To adjust for the dependence underlying the hierarchical multilevel data structure 
(visit, participant, and site), a longitudinal logistic regression with repeated measures 
will be applied. In the model, visits are nested within participants, which are further 
nested within sites. 
The primary endpoint binary response of the participant at each of the postbaseline 
scheduled visits up to Week 12 will be included as the dependent variable. Treatment 
(ruxolitinib 1.5% cream BID and vehicle cream BID), randomization stratification 
factors, visit, and treatment by visit interaction will be included as fixed effects. 
Site-level intercept and participant nested in site-level intercept will be included as 
random effects. The within-participant and within-site errors will be modeled by an 
unstructured variance-covariance matrix. The Kenward-Roger approximation will be 
used to estimate denominator degrees of freedom for this model. 
• Last observation carried forward: 
For the participants who are missing postbaseline values, the last observed 
nonmissing postbaseline value will be used to fill in missing values at Week 12. Then 
a CMH test stratified by the randomization stratification factors will be performed 
using the imputed dataset. 

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• Multiple imputation: 
A fully conditional specification method (van Buuren 2007) that assumes the 
existence of a joint distribution for all variables will be used to impute missing 7-day 
average WI-NRS scores at each visit. A regression model, including treatment group, 
stratification factors, baseline WI-NRS score, and WI-NRS scores for each scheduled 
postbaseline visit, up to Week 12, will be specified for the fully conditional 
specification method. The imputation will be repeated a number of times to generate 
corresponding complete data sets, in order to reflect the uncertainty around the true 
values. After the missing values are imputed, the binary variables will be derived 
based on the definition. The CMH test similar to that for the primary analysis will be 
applied to each imputed dataset, and then the results will then be combined for the 
inference using Rubin's rule. 
• Tipping point analysis: 
A tipping point analysis will be conducted to examine the potential effects of missing 
data. The missing binary response on the primary endpoint in each treatment group 
will be replaced by a range of values from the most conservative case to the most 
aggressive case. The most conservative case is that all the missing participants in the 
ruxolitinib cream group are nonresponders and all the missing participants in the 
vehicle cream group are responders, while the most aggressive case is the other way 
around. For each scenario, between-treatment comparisons will be performed using 
Fisher exact test. 
10.4.2. 
Key Secondary Analysis 
Key secondary efficacy analyses will be conducted on the ITT population. If the primary 
objective is achieved, the statistical comparisons for the key secondary endpoints will be tested 
in the order specified in Section 10.3. 
The key secondary endpoints will be analyzed using the similar method as specified in the 
primary analysis. Participants with missing WI-NRS scores at Week 4 will be defined as 
nonresponders for the WI-NRS4 response for that week. Participants missing Week 12 data will 
be defined as nonresponders for the following endpoints: Overall-TS (both WI-NRS4 response 
and IGA-CPG-S-TS) at Week 12 and IGA-CPG-S-TS at Week 12. 
For WI-NRS4 response on Day 7, missing daily WI-NRS scores from Day 1 to Day 7 will be 
imputed and analyzed using the similar multiple imputation method as specified in the sensitivity 
analysis for the primary endpoint. 
The summary of key secondary endpoint analyses is provided in Table 15. 

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Table 15: 
Summary of Key Secondary Analyses 
Parameter 
Definition 
Treatment 
Ruxolitinib 1.5% cream compared with vehicle cream 
Population  
ITT population 
Variable 
WI-NRS4 response at Week 4 
Overall-TS (WI-NRS4 response and IGA-CPG-S-TS at Week 12) 
IGA-CPG-S-TS at Week 12 
WI-NRS4 response on Day 7 
Population-level summary 
Overall odds ration with 95% CI 
10.4.3. 
Secondary Analyses 
Secondary efficacy analyses will be conducted on the ITT population. For the time to achieve 
≥ 2-point or ≥ 4-point improvement from baseline in WI-NRS, a log rank test stratified by 
randomization stratification factors will be used for between-treatment group comparisons. The 
hazard ratio and its 95% CI will be estimated based on the stratified Cox regression model using 
Efron's method accounting for ties. Kaplan-Meier curves will be presented by treatment groups. 
The number of participants, number of events, and number of censoring will be summarized by 
treatment groups. The Kaplan-Meier estimate of median time will be presented with its 95% CI. 
The 95% CI will be calculated using the method by Brookmeyer and Crowley (1982). 
All other secondary and exploratory efficacy variables will be summarized using descriptive 
statistics. For categorical measurements, summary statistics will include sample size, frequency, 
and percentages. Similar stratified CMH test as specified in the primary and key secondary 
analysis will be used if applicable. For continuous measurements, summary statistics will include 
sample size, mean, median, standard deviation, standard error of the mean, minimum, and 
maximum. Continuous efficacy endpoints, including the actual measurement, change from 
baseline, and percentage change from baseline, may also be analyzed by the mixed model for 
repeated measures. 
10.4.4. 
Safety Analyses 
Safety analyses will be conducted for the safety population. A TEAE is any AE either reported 
for the first time or worsening of a pre-existing event after first application of study cream. 
Analysis of AEs will be limited to TEAEs, but data listings will include all AEs regardless of 
their timing to study cream application. Adverse events will be tabulated by the MedDRA 
preferred term and system organ class. Severity of AEs will be based on the National Cancer 
Institute CTCAE v5.0 using Grades 1 through 5. 
The subset of AEs considered by the investigator to have a relationship to study cream will be 
considered treatment-related AEs. If the investigator does not specify the relationship of the AE 
to study cream, then the AE will be considered treatment-related. The incidence of AEs and 
treatment-related AEs will be tabulated. 

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The clinical laboratory data will be analyzed using summary statistics; no formal treatment group 
comparisons are planned. Laboratory test values outside the normal range will be assessed for 
severity based on the normal ranges for the clinical reference laboratory. The incidence of 
abnormal laboratory values and shift tables relative to baseline will be tabulated. 
Descriptive statistics and mean change from baseline will be determined for vital signs (blood 
pressure, pulse, respiratory rate, and body temperature) at each assessment time. 
10.5 
Interim Analysis 
No formal interim analysis is planned in this study. The primary analysis will occur after the 
primary database lock when all participants have completed the DBVC treatment period. The 
sponsor will be unblinded, but the investigators and participants will remain blinded to the study 
treatment after the primary database lock. The final analysis will occur when all participants 
have completed or withdrawn from the study. 
If the p-value for the primary endpoint is deemed insignificant in the primary analysis outlined in 
Section 10.4.1, the study will be terminated due to a lack of demonstrable efficacy benefits for 
the participants. 

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11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
11.1. 
Investigator Responsibilities 
• The Protocol, Protocol Amendments, ICF, IB, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC and health authorities before the study is 
initiated. 
• The investigator is responsible for ensuring that the safety reports provided by the 
sponsor are reviewed and processed in accordance with regulatory requirements, the 
policies and procedures established by the IRB/IEC, and institutional requirements. 
• Any amendments to the Protocol will require approval from both health authorities 
and the IRB/IEC before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants. 
• 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 GCP, 
IRB/IEC requirements, institutional requirements, and applicable laws and 
country-specific regulations. 
• The investigator will adhere to the Protocol as described in this document and agree 
that changes to the Protocol procedures, with the exception of medical emergencies, 
must be discussed and approved, first, by the sponsor or its designee and, second, by 
the IRB/IEC. Each investigator is responsible for enrolling participants who have met 
the specified eligibility criteria. 
• Retaining records in accordance with all local, national, and regulatory laws but for a 
minimum period of at least 2 years after the last marketing application approval in an 
ICH region and until there are no pending or contemplated marketing applications in 
an ICH region, or if not approved, 2 years after the termination of the test article for 
investigation to ensure the availability of study documentation should it become 
necessary for the sponsor or a regulatory authority to review. 
− The investigator must not destroy any records associated with the study during the 
retention period without receiving approval from the sponsor. The investigator 
must notify the sponsor or its designee in the event of accidental loss or 
destruction of any study records. If the investigator leaves the institution where 
the study was conducted, the sponsor or its designee must be contacted to arrange 
alternative record storage options. 

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− All eCRF data entered by the site (including audit trail), as well as computer 
hardware and software (for accessing the data), will be maintained or made 
available at the site in compliance with applicable record retention regulations. 
The sponsor will retain the original eCRF data and audit trail. 
11.1.1. 
Identification of the Coordinating Principal Investigator 
A coordinating principal investigator will be appointed by the sponsor before the end of the 
study. As part of their responsibilities, the coordinating principal investigator will review the 
final CSR. Agreement with the final CSR will be documented by the dated signature of the 
coordinating principal investigator. 
11.2. 
Data Management 
Data management will be performed in a validated EDC system. The investigator will be 
provided with access to an EDC system so that an eCRF can be completed for each participant. 
The site will be provided with eCRF completion guidelines for instructions on data entry in the 
eCRF. The study monitor will reference the Monitoring Plan in order to ensure that each issue 
identified is appropriately documented, reported, and resolved in a timely manner in accordance 
with the plan's requirements. Other data outside the EDC system required in the study conduct of 
the Protocol, such as documents or results transmitted to the sponsor via a central laboratory or 
specialized technical vendors and as designated by the sponsor, will have their own data flow 
management plans, study charters, or biomarker plans, as applicable. 
The sponsor (or designee) will be responsible for the following: 
• Managing the integrity of the data and the quality of the conduct of the study, such as 
ensuring that study monitors perform ongoing source data verification to confirm that 
data entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants 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. 
• Managing and reconciling the data generated and/or collected, including documents 
and results such as laboratory or imaging data analyzed centrally by a designated 
vendor of the sponsor. 
The investigator will be responsible for the following: 
• Recording, or ensuring the recording of, all relevant data relating to the study in the 
eCRF. 
• Delivering, or ensuring the delivery of, all other results, documents, data, know-how, 
or formulas relating to the study to the sponsor or designee electronically and/or 
centrally (eg, laboratory data, imaging data, biomarker data, photographs, eDiary 
data) or as otherwise specified in the Protocol. 

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• Maintaining adequate and accurate source documents and trial records that include all 
pertinent observations on each of the site's trial participants. Source data should be 
attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, should not obscure the original entry, and should be 
explained if necessary (eg, via an audit trail). Source data are, in general, all 
information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source 
documents (original records or certified copies). 
• Verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF. 
• Maintaining accurate documentation (source data) that supports the information 
entered in the eCRF, sent to a central vendor designated by the sponsor, or as 
described in other study and data flow manuals. 
− Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed and 
available at the investigator's site. Examples of source documents are original 
documents, data, and records (eg, hospital records; electronic hospital records; 
clinical and office charts; laboratory notes; memoranda; participants' diaries or 
evaluation checklists; pharmacy dispensing records; recorded data from 
automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiches; photographic negatives; microfilm or 
magnetic media; x-rays; participants' files; and e-records/records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in 
the clinical trial). 
− Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, 
depending on the study. Current applicable medical records must be available. 
• Sending participants' data, either as unique samples, copies, or photographs, to be 
evaluated centrally or analyzed centrally, or both, by a qualified vendor designated by 
the sponsor. 
− As required by privacy and data protection regulations and Incyte's privacy 
policies, if any photographs of participants are to be used in the study, even if 
occasionally, or are to be taken, the photographs must be limited to the area of the 
face or the body that is strictly necessary and the photographs should be masked 
(ie, identifying features such as eyes, mouth, scars, tattoos, or unique markings or 
features should be either obscured with a black bar or digitally pixelated so as to 
not permit the reidentification of the participants and preserve their 
confidentiality) by a specially designated photography vendor prior to sending the 
photographs to Incyte or any other third-party vendors for analysis or further 
processing. 

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− In accordance with French regulations, sites in France must perform the masking 
before the photographs are transferred, including to any specially designated 
photography vendor, Incyte, or any other third-party vendors for analysis or 
further processing. In addition, the participant's specific consent for photographs 
shall be collected. 
• Permitting study-related monitoring, sponsor audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and other relevant clinical study 
documents. 
− Monitoring: Qualified representatives of the sponsor or its designee, study 
monitors, will monitor the study according to a predetermined plan. The 
investigator must allow the study monitors to review any study materials and 
participant records at each monitoring visit. 
− Auditing: Qualified representatives of the sponsor or its designee may audit the 
clinical study site and study data to evaluate compliance with the Protocol, 
applicable local clinical study regulations, and overall study conduct. The 
investigator must allow the auditors to review original source records and study 
documentation for all participants. 
− Regulatory inspection: Regulatory authorities may conduct an inspection of the 
study and the site at any time during the development of an investigational 
product. The investigator and staff are expected to cooperate with the inspectors 
and allow access to all source documents supporting the eCRFs and other 
study-related documents. The investigator must immediately notify the sponsor 
when contacted by any regulatory authority for the purposes of conducting an 
inspection. 
11.3. 
Data Quality Assurance 
The sponsor assumes accountability for actions delegated to other individuals (eg, contract 
research organizations). The sponsor or designee is responsible for the data management of this 
study, including quality checking of the data. Further, monitoring details describing strategy, 
including definition of study-critical data items and processes (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, Protocol deviations, and monitoring techniques (eg, central, remote, or 
on-site monitoring) are provided in the Data Management Plan and the monitoring plan. 
Quality tolerance limits will be predefined in the Integrated Quality Risk Management Plan to 
identify systematic issues that can impact participants' safety, efficacy results and analysis, 
and/or reliability of study results. These predefined parameters will be monitored during the 
study and can be adjusted during the study upon data review. Important deviations from the 
quality tolerance limits and remedial actions taken, including reporting to IRBs/IECs and health 
authorities if applicable, will be summarized in the CSR. 

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11.4. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data protection laws 
and regulations. The investigator and the sponsor or its designee are responsible for ensuring that 
personal information is handled in accordance with local data protection laws (including but not 
limited to HIPAA and GDPR) as applicable, and the sponsor operates comprehensive data 
privacy and data security programs that are applicable to this study. Appropriate notice, or notice 
and consent (as may be required by each applicable jurisdiction), for collection, use, disclosure, 
and/or transfer (if applicable) of personal information must be obtained in accordance with local 
data protection laws. Appropriate data protection terms that comply with applicable laws will be 
included in relevant study agreements. 
To ensure confidentiality of records and protect personal data, participant names will not be 
supplied to the sponsor or its designee. Only the participant number will be recorded in the 
eCRF; if the participant's name appears on any other document (eg, laboratory report), it must be 
obliterated on the copy of the document to be supplied to the sponsor or its designee. Study 
findings stored on a computer will be stored in accordance with appropriate technical and 
organizational measures as required by local data protection laws. 
In the event of a data breach involving participant data, the sponsor or its designee will follow 
the sponsor's incident response procedures. The precise definition of a data breach varies in 
accordance with applicable law but may generally be understood as a breach of security leading 
to the accidental or unlawful destruction, loss, alteration, unauthorized disclosure of, or access to, 
personal data. In accordance with its incident response procedures, the sponsor will assess the 
breach to consider its notification and remediation obligations under applicable law. 
11.5. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies subject to FDA 
Regulation Title 21 CFR Part 54 – Financial Disclosure by Clinical Investigators (ie, "covered 
studies") are required to submit a completed Clinical Investigator Financial Disclosure Form that 
sufficiently details any financial interests and arrangements that apply. For the purpose of this 
regulation, "clinical investigator" is defined as any investigator or subinvestigator who is directly 
involved in the treatment or evaluation of research participants, including the spouse and each 
dependent child of the clinical investigator or subinvestigator. These requirements apply to both 
US and foreign clinical investigators conducting covered clinical studies. 
Any new clinical investigators added to the covered clinical study during its conduct must also 
submit a completed Clinical Investigator Financial Disclosure Form. During a covered clinical 
study, any changes to the financial information previously reported by a clinical investigator 
must be reported to the sponsor or its designee. At the conclusion of the covered clinical study, 
the clinical investigators will be reminded of their obligations. In the event that the clinical 
investigator is not reminded, they nevertheless will remain obligated to report to the sponsor or 
its designee any changes to the financial information previously reported, as well as any changes 
in their financial information for a period of 1 year after completion of the covered clinical study. 

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11.6. 
Publication Policy 
By signing the study Protocol, the investigator and their institution agree that the results of the 
study may be used by the sponsor, Incyte Corporation (Incyte), for the purposes of national and 
international registration, publication, and information for medical and pharmaceutical 
professionals. Study results will be published in accordance with applicable local and national 
regulations. If necessary, the authorities will be notified of the investigator's name, address, 
qualifications, and extent of involvement. The terms regarding the publication of study results 
are contained in the agreement signed with the sponsor or its designee. A signed agreement will 
be retained by the sponsor or its designee. 
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 in line with International Committee of Medical Journal Editors 
authorship requirements. 
11.7. 
Study and Site Closure 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor or the IRB/IEC. 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: 
• Failure of the investigator to comply with the Protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines. 
• Inadequate recruitment of participants by the investigator. 
• Discontinuation of further study treatment development. 

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12. 
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Boozalis E, Tang O, Patel S, et al. Ethnic differences and comorbidities of 909 prurigo nodularis 
patients. J Am Acad Dermatol 2018;79:714-719. 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982:38:29-41. 
Buysse DJ, Yu L, Moul DE. Development and validation of patient-reported outcome measures 
for sleep disturbance and sleep-related impairments. Sleep 2010;33:781-792. 
Cella D, Wilson H, Shalhoub H, et al. Content validity and psychometric evaluation of 
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symptom of atopic and non-atopic diseases: aetiological survey in a consecutive cohort of 
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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS AND DEFINITIONS 
Definitions 
WOCBP: A woman who is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
• Premenarchal 
• Premenopausal with 1 of the following:a 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
• Postmenopausal 
− A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. 
o A high FSH level in the postmenopausal range may be used to confirm a postmenopausal state 
in women not using hormonal contraception or HRT. However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range is required. 
− Female participants on HRT and whose menopausal status is in doubt will be required to use 1 of 
the nonhormonal, 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. 
For male participants of reproductive potentialb 
The following methods during the Protocol-defined timeframe in Section 5.1 are highly effective: 
• Use of a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a WOCBP who is not currently pregnant 
• Vasectomy with medical assessment of the surgical success (verified by site personnel's review of 
the participant's medical records) 
• Sexual abstinencec 
− Abstinence from penile-vaginal intercourse 
The following are not acceptable methods of contraception: 
• Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method 
• Male condom with cap, diaphragm, or sponge with spermicide 
• Male and female condom used together 
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal 
intercourse or use a male condom during each episode of penile penetration.  

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For female participants who are WOCBP 
The following methods during the Protocol-defined timeframe in Section 5.1 that can achieve a failure 
rate of less than 1% per year when used consistently and correctly are considered as highly effective 
birth control methods: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationd 
− oral 
− intravaginal 
− transdermal  
• Progestogen-only hormonal contraception associated with inhibition of ovulationd  
− oral 
− injectable 
− implantablee 
• Intrauterine devicee 
• Intrauterine hormone-releasing systeme 
• Bilateral tubal occlusione 
• Vasectomized partnere,f 
• Sexual abstinencec  
a Documentation can come from the site personnel's review of the participant's medical records, medical examination, or medical 
history interview. 
b If the male participant has a partner of childbearing potential, the partner should also use contraceptives. 
c In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the participant. 
d Hormonal contraception may be susceptible to interaction with the investigational medicinal product, which may reduce the 
efficacy of the contraception method. In this case, 2 methods of contraception should be used. 
e Contraception methods that in the context of this guidance are considered to have low user dependency. 
f Vasectomized partner is a highly effective method of avoiding pregnancy provided that partner is the sole sexual partner of the 
WOCBP study participant and that the vasectomized partner has received medical assessment of the surgical success. 
Source: Clinical Trials Facilitation and Coordination Group 2020. 

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APPENDIX B. COVID-19 PANDEMIC MITIGATION STRATEGIES AND 
INSTRUCTIONS 
The COVID-19 global pandemic is an evolving situation and presents numerous challenges to 
the ongoing conduct of clinical trials. The sponsor has issued the following Protocol 
considerations to ensure participant safety is maintained and adequate benefit/risk analyses are 
applied relative to the completion of study procedures and maintaining the investigational 
product supply chain. 
Recognizing the flexibility required to manage the impact of the pandemic on this clinical trial, 
additional details will be added as needed to respective study manuals and project plan 
documents and communicated to the investigative sites as needed. 
Number of Study Participants 
The evolving situation of the pandemic may result in a substantial number of participants' early 
dropout from the study, which could affect the data integrity of the trial. Because of this risk and 
in order to mitigate it, the sponsor may decide to recruit additional participants in the study, 
beyond the expected number. 
Study Visits 
Remote Site Visit Guidelines: 
In addition to the remote visits already specified in the Protocol, the evolving situation of the 
pandemic may require further travel restrictions and isolation requirements, or the investigator's 
benefit/risk assessment may determine it to be unsafe for participants to attend study visits at the 
investigational site. In such cases, the site staff may elect to pursue the following: 
• In order to minimize participant risk, study visits may be conducted via telemedicine 
modalities (phone or video calls). At a minimum, a review of AEs, concomitant 
medications, and study cream compliance must be completed. Periodic on-site visits 
should be conducted whenever feasible, in addition to the mandatory on-site visits 
outlined below. 
• No efficacy assessments can be performed via telemedicine (video call or phone call). 
• Laboratory sampling: In order to support investigator oversight of participant safety 
and disease management, off-site laboratory sampling (in accordance with the SoA) 
may be allowed in 1 of 2 ways: 
− Use of home nursing services (if local acceptable per local regulations). 
− Instruction of the participant to undergo some laboratory tests at a local (nearby) 
hospital laboratory or facility closer to the participant's residence rather than at the 
investigational site. In this case, the study physician will provide the participant 
with the list of parameters to be checked. These tests should be performed at 
certified laboratories and copies of results provided to the site. 

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Mandatory On-Site Visits: 
The visits outlined below must be performed in person in order to capture the investigator's 
efficacy assessments and the patient-reported outcomes, even if the date that the participant 
eventually comes into the clinic deviates from the visit window. 
No efficacy assessments can be performed via telemedicine (video call, phone call, or 
photography). 
The visit window deviation must be documented, and the sponsor's representative must be 
informed of when it is believed that the participant can come into the clinic. Further instructions 
will be provided if needed. 
During the DBVC period, the following visits must be performed in person: 
• Screening 
• Day 1 (baseline) 
• Week 4, 8, and 12 visits 
During the OLE period, the following visits must be performed in person: 
• Week 52 visit 
Investigational Medicinal Product Dispensing and Distribution 
In order to ensure the continuity of providing their participants' clinical supplies within the 
constraints imparted by the pandemic, the site staff can decide to supply study cream via 
shipment to participants. 
If the participant cannot attend a visit at the study site, adequate supplies of study cream 
determined by the investigator can be shipped to the participant by the investigator or 
appropriately delegated staff (eg, the study pharmacy staff) using a third-party service if duly 
authorized by the participant. 
The study site may use their own preferred courier, provided the courier adheres to certain 
standards (eg, use of personal protection equipment or maintenance of temperature-controlled 
transit environment), or one centrally contracted by the sponsor. 
Clinical Trial Monitoring 
Study monitoring visits may be postponed due to documented COVID-19–related reasons; 
however, the study site monitor will continue to employ off-site monitoring practices such as 
routine communication methods (eg, phone calls, e-mails, or video visits) with the sites to get 
information on trial progress, participant status, and information on issue resolution. The study 
monitor may remotely review data entered into the EDC for accuracy and completeness. If 
allowed by local regulations, remote source data verification may be implemented with 
agreement of the principal investigator and institution, as applicable. 
If the study site monitor cannot be on-site to perform the final study cream accountability for 
reconciliation purposes and the operation cannot be postponed, it may be performed by a 
pharmacist from the hospital pharmacy or by the study coordinator/data manager with suitable 

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training. The study cream can be returned to the sponsor by the hospital pharmacy directly or 
destroyed in accordance with local practices, if applicable, and with sponsor approval. 
Other Considerations 
If necessary, direct contracts can be established with third-party local physicians to conduct 
activities related to the clinical management of participants for whom the investigator is 
responsible and maintains oversight. In such situations, the investigator is required to provide the 
local physician with a delegation letter listing all delegated activities. The sponsor, through the 
study investigator or institution, will reimburse the local physician for the tests/procedures 
conducted outside of the standard of care. 
• In case of need, participants may refer to the local health care provider. Participants will 
be requested to obtain certified copies of the source data at the local health facility with 
the outcome of the contact and provide those to the investigator for appropriate oversight. 
The investigator/delegate will be requested to enter any relevant information into the 
EDC. 
• Should COVID-19–related restrictions be localized and have an effect on a limited 
number of sites, the affected sites may utilize direct contracting of third parties to support 
continuous study conduct (eg, home nursing services or couriers). 
Reimbursement of Extraordinary Expenses 
The sponsor will arrange to reimburse participants for any extraordinary expenses, keeping 
appropriate documentation as evidence (eg, travel expenses for the local laboratory visit[s] or the 
costs of local [nearby] laboratory tests). 

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APPENDIX C. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment 1 
21 JUN 2023 
Amendment 2 
21 FEB 2024 
Amendment 2 (21 FEB 2024) 
Overall Rationale for the Amendment 
The primary purpose of this amendment is to address regulatory requests provided after review 
by the EU national health authorities. 
1. Section 10.5, Interim Analysis 
Description of change: Included a provision that the study will be terminated if the 
primary analysis is deemed insignificant. 
Rationale for change: Health authority request. 
2. Incorporation of administrative changes. Other administrative changes have been 
incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 

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Amendment 1 (21 JUN 2023) 
Overall Rationale for the Amendment 
The primary purpose of this amendment is to incorporate feedback from the FDA regarding the 
addition of hepatitis serology and washout periods for prohibited medications. Additional 
changes and clarifications are summarized below. 
1. Section 1, Protocol Summary (Table 4: Schedule of Activities for the Open-Label 
Extension Period); Section 7.1.2, Discontinuation Procedures; Section 8.9.1, Safety 
Follow-Up 
Description of change: Clarified that if a participant has not applied study cream for at 
least 30 days during the OLE period due to a no-treatment cycle, then the Week 52/EOT2 
visit will count as the safety follow-up visit. 
Rationale for change: To be consistent with the defined window for the safety follow-up 
period. 
2. Section 1, Protocol Summary (Table 3: Schedule of Activities for the Double-Blind 
Vehicle-Controlled Period; Table 4: Schedule of Activities for the Open-Label 
Extension Period); Section 3, Objectives and Endpoints (Table 5: Objectives and 
Endpoints); Section 8.3.4, Patient Global Impression of Severity 
Description of change: Added PGIS and related endpoints. 
Rationale for change: To assess meaningful change in participant assessment of 
PN severity. 
3. Section 1, Protocol Summary (Table 3: Schedule of Activities for the Double-Blind 
Vehicle-Controlled Period); Section 5.2, Exclusion Criteria (Exclusion Criterion 6f); 
Section 8.4.5, Laboratory Assessments (Table 10: Required Laboratory Analytes); 
Section 8.4.5.3, Hepatitis Testing; Section 8.4.5.3.1, Hepatitis B Virus; 
Section 8.4.5.3.2, Hepatitis C Virus 
Description of change: Added current hepatitis B or C virus infection and associated 
testing at screening and revised the related exclusion criterion. 
Rationale for change: Health Authority request. 
4. Section 5.1, Inclusion Criteria (Inclusion Criterion 2) 
Description of change: Added the legal adult age in Korea. 
Rationale for change: To reflect the age of an adult in Korea. 
5. Section 5.2, Exclusion Criteria (Exclusion Criterion 4) 
Description of change: Extended the window for exclusion of participants with active 
AD lesions to within 6 months of screening and baseline.  
Rationale for change: To minimize the potential for participants with active AD flares, 
which could confound the assessment of PN-related itch. 

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6. Section 5.2, Exclusion Criteria (Exclusion Criterion 6g) 
Description of change: Added exclusion of participants with an uncontrolled, underlying 
condition associated with PN.  
Rationale for change: Health Authority request. 
7. Section 5.2, Exclusion Criteria (Exclusion Criterion 8c) 
Description of change: Revised the equation used for estimated glomerular filtration rate 
from Cockcroft-Gault to CKD-EPI 2021. 
Rationale for change: The CKD-EPI has a higher efficacy than Cockcroft-Gault. 
8. Section 5.2, Exclusion Criteria (Exclusion Criterion 9); Section 6.6.3, Prohibited 
Medications and Procedures 
Description of change: Added the following prohibited medications with relevant 
washout periods: opioid antagonists, gabapentin, pregabalin, thalidomide, SSRIs, SNRIs, 
tricyclic antidepressants, cannabis, cannabinoids, and nonsedating antihistamines used for 
the treatment of PN. 
Rationale for change: Health Authority request and to minimize the potential for 
confounding efficacy assessments. 
9. Section 6.1, Study Treatments Administered; Section 7.1.1, Reasons for 
Discontinuation; Section 10.4.1, Primary Analysis 
Description of change: Participants who develop AD lesions cannot treat AD with the 
study cream. A participant who develops AD lesions during the study must be 
discontinued from study treatment, will be considered a treatment failure, and will be 
defined as a nonresponder. 
Rationale for change: Health authority request due to AD possibly confounding efficacy 
assessments. 
10. Section 6.6.1, Permitted Medications and Procedures 
Description of change: Clarified that participants may use nonsedating, over-the-counter 
antihistamines except for the treatment of PN. 
Rationale for change: To minimize the potential for confounding efficacy assessments. 
11. Section 6.6.1, Permitted Medications and Procedures 
Description of change: Removed sedating antihistamines from the list of permitted 
medications. 
Rationale for change: Health authority request. 
12. Section 7.1.1, Reasons for Discontinuation 
Description of change: Added worsening PN as a reason participants must be 
discontinued from study treatment if the total BSA treatment area exceeds 20%. 
Rationale for change: To be consistent with other sections of the Protocol. 

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13. Section 8.1.5.1, Demographics and General Medical History 
Description of change: Added history of atopy to the medical history collected. 
Rationale for change: To ensure atopic history is captured. 
14. Section 8.1.5.2, Disease Characteristics and Treatment History 
Description of change: Added the acceptable documentation for prior prescription 
medications for PN. 
Rationale for change: Clarification of acceptable documentation. 
15. Section 8.3.5, Patient Global Impression of Change 
Description of change: Revised the PGIC tool. 
Rationale for change: To be consistent with the PGIS tool. 
16. Section 10.4.1, Primary Analysis 
Description of change: Added underlying conditions associated with PN to the subgroup 
analysis. 
Rationale for change: To minimize the potential for confounding efficacy assessments. 
17. Incorporation of administrative changes. Other administrative changes have been 
incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 

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