Clinical trial NCT05593445
Conditions: Lichen Sclerosus
Keywords: Lichen Sclerosus Skin Diseases 18424 Ruxolitinib topical cream vulvar disease
Sponsor: Incyte Corporation
Start date: 2022-11-18; Completion date: 2023-12-21
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of Ruxolitinib cream in participants With Lichen Sclerosus. This is randomized, double-blind, vehicle-controlled (DBVC) study with a DBVC period of 12 weeks followed by an open label period (OLE) period of 12 weeks.

Detailed description:

Arms: arm 1: Ruxolitinib 1.5% cream BID for 12 weeks followed by ruxolitinb 1.5% cream BID (or QD) for 12-weeks in an open-label extension. arm 2: Vehicle cream BID for 12 weeks followed by ruxolitinb 1.5% cream BID (or QD) for 12-weeks in an open-label extension.
Interventions: intervention 1: Ruxolitinib cream intervention 2: Vehicle cream
Intervention descriptions: intervention 1: Ruxolitinib cream is a topical formulation applied as a thin film to affected areas. intervention 2: Vehicle cream is matching in appearance to ruxolitinib cream and is to be applied in the same manner as ruxolitinib cream.

Protocol documents:
Prot_000.pdf: 
Official Title:    A Phase 2, Randomized, Double-Blind, Vehicle-Controlled, Study 
of the Efficacy and Safety of Ruxolitinib Cream in Participants With 
Lichen Sclerosus
NCT Number: 
 NCT05593445 
Document Date: 
Clinical Study Protocol: 18-December-2023


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Clinical Study Protocol 
TITLE PAGE 
INCB 18424-220 
A Phase 2, Randomized, Double-Blind, Vehicle-Controlled, Study of the 
Efficacy and Safety of Ruxolitinib Cream in Participants With Lichen 
Sclerosus 
Product: 
Ruxolitinib Cream 
IND Number: 
77101 
Phase of Study: 
2 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 USA 
Original Protocol: 
29 APR 2022 
Protocol Amendment 1: 
17 AUG 2022 
Protocol Amendment 2: 
07 MAR 2023 
Protocol Amendment 3: 
18 DEC 2023 
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 18424-220 Protocol Amendment 3 (dated 18 DEC 2023) 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 ......................................................................................................22 
2.1. 
Background .................................................................................................................22 
2.1.1. 
Scientific Rationale for Study Design ........................................................................24 
2.1.2. 
Justification for Dose ..................................................................................................25 
2.2. 
Benefit/Risk Assessment ............................................................................................25 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................27 
4. 
STUDY DESIGN .......................................................................................................28 
4.1. 
Overall Design ............................................................................................................28 
4.2. 
Overall Study Duration ...............................................................................................29 
4.3. 
Study Termination ......................................................................................................29 
5. 
STUDY POPULATION .............................................................................................29 
5.1. 
Inclusion Criteria ........................................................................................................29 
5.2. 
Exclusion Criteria .......................................................................................................30 
5.3. 
Lifestyle Considerations .............................................................................................32 
5.4. 
Screen Failures ............................................................................................................32 
5.5. 
Replacement of Participants .......................................................................................33 
6. 
STUDY TREATMENT ..............................................................................................33 
6.1. 
Study Treatments Administered .................................................................................33 
6.2. 
Preparation, Handling, and Accountability ................................................................35 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................36 
6.4. 
Study Treatment Compliance .....................................................................................36 
6.5. 
Dose Modifications .....................................................................................................36 
6.5.1. 
Criteria and Procedures for Dose Interruptions and Adjustments of Study 
Drugs ...........................................................................................................................37 
6.5.2. 
Criteria for Permanent Discontinuation of Study Drug Due to an Adverse 
Event ...........................................................................................................................38 
6.6. 
Concomitant Medications and Procedures .................................................................38 


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6.6.1. 
Permitted Medications and Procedures ......................................................................39 
6.6.2. 
Restricted Use Medications and Procedures ...............................................................39 
6.6.3. 
Prohibited Medications and Procedures .....................................................................40 
6.7. 
Treatment After the End of the Study .........................................................................40 
7. 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
WITHDRAWAL ........................................................................................................41 
7.1. 
Discontinuation of Study Treatment ...........................................................................41 
7.1.1. 
Reasons for Discontinuation .......................................................................................41 
7.1.2. 
Discontinuation Procedures ........................................................................................42 
7.2. 
Participant Withdrawal from the Study ......................................................................42 
7.3. 
Lost to Follow-Up.......................................................................................................43 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................44 
8.1. 
Administrative and General Procedures .....................................................................44 
8.1.1. 
Informed Consent Process ..........................................................................................44 
8.1.2. 
Screening Procedures ..................................................................................................45 
8.1.3. 
Interactive Response Technology Procedure ..............................................................45 
8.1.4. 
Distribution of Reminder Cards and/or Diaries ..........................................................45 
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 ..........................................................46 
 
46 
8.2. 
Efficacy Assessments .................................................................................................47 
8.2.1. 
Medical Resource Utilization and Health Economics ................................................47 
 
47 
8.2.3. 
Clinical Lichen Sclerosus Score .................................................................................47 
 
47 
8.2.5. 
Body Surface Area ......................................................................................................48 
8.2.6. 
Photography ................................................................................................................48 
8.2.7. 
Patient-Reported Outcomes ........................................................................................48 
8.2.7.1. 
Diary Assessments: Itch NRS and Skin Pain NRS .....................................................48 
 
49 
 
49 
 
49 


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50 
 
50 
8.3. 
Safety Assessments .....................................................................................................50 
8.3.1. 
Adverse Events ...........................................................................................................50 
8.3.2. 
Physical Examinations ................................................................................................51 
8.3.3. 
Vital Signs ..................................................................................................................51 
8.3.4. 
Laboratory Assessments .............................................................................................52 
8.3.4.1. 
Pregnancy Testing ......................................................................................................53 
8.3.4.2. 
Serology ......................................................................................................................53 
8.3.4.3. 
Lichen Sclerosus Assessment Under Magnification ..................................................53 
 
53 
 
53 
 
53 
 
54 
8.5.3. 
Biopsy .........................................................................................................................54 
8.6. 
Unscheduled Visits .....................................................................................................54 
8.7. 
End of Treatment and Early Termination ...................................................................54 
8.8. 
Follow-Up ...................................................................................................................55 
8.8.1. 
Safety Follow-Up ........................................................................................................55 
9. 
ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ......................56 
9.1. 
Definition of Adverse Event .......................................................................................56 
9.2. 
Definition of Serious Adverse Event ..........................................................................57 
9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse Events .........58 
9.4. 
Reporting of Serious Adverse Events .........................................................................60 
9.5. 
Potential Drug-Induce Liver Injury ............................................................................61 
9.6. 
Events of Clinical Interest ..........................................................................................61 
9.7. 
Emergency Unblinding of Treatment Assignment .....................................................62 
9.8. 
Pregnancy ...................................................................................................................62 
9.9. 
Warnings and Precautions ..........................................................................................63 
9.10. 
Product Complaints ....................................................................................................63 
9.11. 
Treatment of Overdose ...............................................................................................63 
10. 
STATISTICS ..............................................................................................................64 


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10.1. 
Sample Size Determination ........................................................................................64 
10.2. 
Populations for Analysis .............................................................................................64 
10.3. 
Level of Significance ..................................................................................................64 
10.4. 
Statistical Analyses .....................................................................................................64 
10.4.1. 
Primary Analysis ........................................................................................................64 
10.4.2. 
Secondary 
 Analyses .........................................................................65 
10.4.3. 
Safety Analyses ..........................................................................................................66 
10.5. 
Interim Analysis ..........................................................................................................66 
11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................67 
11.1. 
Investigator Responsibilities .......................................................................................67 
11.1.1. 
Identification of the Coordinating Principal Investigator ...........................................68 
11.2. 
Data Management .......................................................................................................68 
11.3. 
Data Quality Assurance ..............................................................................................70 
11.4. 
Data Privacy and Confidentiality of Study Records ...................................................70 
11.5. 
Financial Disclosure ...................................................................................................71 
11.6. 
Publication Policy .......................................................................................................71 
11.7. 
Study and Site Closure................................................................................................72 
12. 
REFERENCES ...........................................................................................................73 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS AND DEFINITIONS ............................................76 
APPENDIX B. COVID-19 PANDEMIC MITIGATION STRATEGIES AND 
INSTRUCTIONS .......................................................................................................77 
APPENDIX C. PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................80 
 


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LIST OF TABLES 
Table 1: 
Primary and Secondary Objectives and Endpoints .....................................................11 
Table 2: 
Key Study Design Elements .......................................................................................12 
Table 3: 
Schedule of Activities .................................................................................................14 
Table 4: 
Objectives and Endpoints ...........................................................................................27 
Table 5: 
Dose Administration Guidance for OLE Period .........................................................33 
Table 6: 
Study Treatment Information .....................................................................................34 
Table 7: 
Guidelines for Interruption of Study Drug for Treatment-Related Adverse 
Events and Restarting of Study Drug .........................................................................37 
Table 8: 
Schedule of Laboratory Assessments .........................................................................52 
Table 9: 
Populations for Analysis .............................................................................................64 
Table 10: Summary of Primary Analysis....................................................................................65 
 
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 
BV 
bacterial vaginosis 
CCR 
C-C motif chemokine receptor 
CI 
confidence interval 
CLISSCO 
Clinical Lichen Sclerosus Score 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CLISSCO 
Clinical Lichen Sclerosus Score 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
coronavirus disease 2019 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CXCR 
C-X-C chemokine receptor 
CYP 
Cytochrome P450 
DBVC 
double-blind, vehicle-controlled 
 
 
DNA 
deoxyribonucleic acid 
EDC 
Electronic Data Capture 
EOT 
end of treatment 
ET 
early termination 
FDA 
Food and Drug Administration (US) 
 
 
 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GFR 
glomerular filtration rate 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 


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Abbreviations and 
Special Terms 
Definition 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
IB 
Investigator's Brochure 
IC50 
concentration that results in 50% inhibition 
ICF 
informed consent form 
ICH 
International Council on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ID 
identification 
IEC 
independent ethics committee 
IGA 
Investigator's Global Assessment 
 
 
 
IL 
interleukin 
INF 
interferon 
IRB 
institutional review board 
IRT 
interactive response technology 
ITCH4 
≥ 4-point improvement in WI-NRS score 
ITT 
intent-to-treat 
JAK 
Janus kinase 
LS 
lichen sclerosus 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
numeric rating scale 
OLE 
open-label extension 
 
 
 
 
QD 
once daily 
 
 
RCT 
randomized controlled trial 
RNA 
ribonucleic acid 
RSI 
Reference Safety Information 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SCC 
squamous cell carcinoma 
SoA 
schedule of activities 
SOP 
standard operating procedure 


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Abbreviations and 
Special Terms 
Definition 
STAT 
signal transducer and activator of transcription 
STD 
sexually transmitted disease 
TEAE 
treatment-emergent adverse event 
Th1 
T-helper 1 
TNF 
tumor necrosis factor 
ULN 
upper limit of normal 
VC 
vehicle control 
 
 
WOCBP 
woman of childbearing potential 


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1. 
PROTOCOL SUMMARY 
Protocol Title: A Phase 2, Randomized, Double-Blind, Vehicle-Controlled, Study of the 
Efficacy and Safety of Ruxolitinib Cream in Participants with Lichen Sclerosus 
Protocol Number: INCB 18424-220 
Objectives and Endpoints: 
Table 1 presents the primary and major/key secondary objectives and endpoints. 
Table 1: 
Primary and Secondary Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To establish the efficacy of ruxolitinib 1.5% 
cream BID in participants with LS. 
ITCH4 response (defined as a ≥ 4-point improvement in Itch 
NRS score from baseline) at Week 12. 
[Proportion of participants with ITCH4 at Week 12] 
Secondary 
To further evaluate efficacy of ruxolitinib 1.5% 
cream BID in participants with LS. 
• Change from baseline in CLISSCO score at Week 12. 
• Change from baseline in the Skin Pain NRS score at 
Week 12. 
• Time to achieve ITCH4. 
To evaluate the safety and tolerability of 
ruxolitinib 1.5% cream BID. 
The type, frequency, and severity of AEs, including the 
changes in vital signs and clinical laboratory blood samples. 
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 2 
Clinical Indication 
Treatment of patients with LS. 
Population 
Female participants ≥18 years of age who have LS diagnosed (confirmed 
by biopsy) with IGA of ≥ 2 and have a baseline Itch NRS score ≥ 4. 
Number of Participants 
Approximately 60 participants will be randomized 1:1 to 1 of 2 treatment 
groups (ruxolitinib 1.5% cream BID or vehicle cream BID).  
Study Design 
This is a 12-week, randomized, DBVC study with a 12-week OLE period 
with crossover to active treatment for participants who complete 12 weeks 
of DBVC period followed by a 30-day post-treatment, safety follow-up 
visit. 
Estimated Duration of 
Study Participation 
Estimated total duration of participants is up to approximately 32 weeks, 
including up to 4 weeks for screening, up to 24 weeks for treatment, and 
30 days for safety follow-up. 
Data Safety Monitoring 
Board/Data Monitoring 
Committee 
No 
Treatment Groups and Duration: 
This is a Phase 2, randomized, DBVC study with DBVC period of 12 weeks followed by an 
OLE period of 12 weeks. 
Approximately 60 female participants will be randomized 1:1 to either ruxolitinib 1.5% cream or 
vehicle cream (see Figure 1). Participants will apply either ruxolitinib 1.5% cream or vehicle 
cream (both BID) through Week 12 to all the affected areas identified at baseline. Treatment 
assignment during the DBVC period will remain blinded to investigators and participants until 
after all participants have completed treatment or discontinued and completed the safety 
follow-up period. 
At Week 12, participants who meet the criteria (compliant with the Protocol and without safety 
concerns) will enter the 12-week OLE period. Participants randomized initially to vehicle in the 
DBVC period will be crossed over to ruxolitinib 1.5% cream and participants randomized to 
ruxolitinib 1.5% cream at baseline will continue to apply ruxolitinib 1.5% cream through 
Week 24 in an open-label fashion. At the Week 12 visit, the LS treatment area will be evaluated 
by the investigator to assess for symptoms and signs of active disease. Those participants who in 
the opinion of the investigator, have symptoms and signs of active disease, will continue 
ruxolitinib 1.5% cream BID until their symptoms and signs have resolved. Those participants, 
who in the opinion of the investigator have resolution of symptoms and signs, can continue 
ruxolitinib 1.5% cream once a day. Participants can cycle between ruxolitinib 1.5% cream QD 
and BID dose administration based on investigator's clinical judgment. During the OLE period, 
all participants will apply ruxolitinib 1.5% cream through Week 24 at least once per day. 
Participants who develop symptoms or signs of active disease during OLE period on ruxolitinib 
1.5% cream QD treatment regimen will have dose increased to ruxolitinib 1.5% cream BID until 
symptoms and signs have resolved. Continuous treatment is recommended to suppress 


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inflammation and to reduce long-term risk of cancerous transformation associated with LS 
lesions (see Section 6.1). 
Table 3 presents the SoA. Adherence to the study design requirements, including those specified 
in the SoA, is essential and required for study conduct. 
The COVID-19 global pandemic may present challenges to the normal conduct of this study 
(including AE and laboratory assessments), requiring the implementation of potential mitigation 
strategies described in Appendix B. 
Figure 1: 
Study Design Schema 
 
 


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Table 3: 
Schedule of Activities 
Visit Day (Range) 
Screening 
Baseline 
(Day 1) 
DBVC Period 
OLE Perioda 
Unscheduled 
Visit 
Safety 
Follow-up 
Notes 
Days 
−28 to −1 
Wk 2 
(± 3 d) 
Wk 4 
(± 3 d) 
Wk 8 
(± 3 d) 
Wk 12a 
(EOT1)b 
(± 3 d) 
Wk 16 
(± 3 d) 
Wk 20 
(± 3 d) 
Wk 24 
(EOT2)/ETb 
(± 3 d) 
30 Days 
(+ 7 Days After 
Last Application) 
Administrative procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographic, medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Contact IRT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomization to 
treatment 
 
X 
 
 
 
 
 
 
 
 
 
 
Apply study drug in 
clinic 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Distribute diary 
X 
 
 
 
 
 
 
 
 
 
 
 
Distribute reminder 
cards 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Diary verification 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Weigh/dispense study 
drug  
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Collect/weigh study 
drug and review study 
drug diary 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Assess study drug 
compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


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Table 3: 
Schedule of Activities (Continued) 
Visit Day (Range) 
Screening 
Baseline 
(Day 1) 
DBVC Period 
OLE Perioda 
Unscheduled 
Visit 
Safety 
Follow-up 
Notes 
Days 
−28 to −1 
Wk 2 
(± 3 d) 
Wk 4 
(± 3 d) 
Wk 8 
(± 3 d) 
Wk 12a 
(EOT1)b 
(± 3 d) 
Wk 16 
(± 3 d) 
Wk 20 
(± 3 d) 
Wk 24 
(EOT2)/ETb 
(± 3 d) 
30 Days 
(+ 7 Days After 
Last Application) 
Safety assessments 
Comprehensive 
physical examination* 
X 
 
 
 
 
 
 
X 
 
 
*Targeted physical 
examination can be 
performed for 
assessment of AE 
during other visits 
including unscheduled 
visits as per discretion 
of the investigator. A 
targeted physical 
examination should be 
guided by symptoms 
reported by the 
participant, AEs, or 
other findings. 
Height and body 
weight 
X 
 
 
 
 
 
 
 
 
 
 
 
LS assessment under 
magnification* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
*See Section 8.3.4.3.  
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Efficacy assessments 
 
CLISSCO 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
%BSA* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
*The total %BSA 
affected should be 
≤ 10% to be eligible for 
study entry and 
continued participation. 
Photography (selected 
sites only) 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 


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Table 3: 
Schedule of Activities (Continued) 
Visit Day (Range) 
Screening 
Baseline 
(Day 1) 
DBVC Period 
OLE Perioda 
Unscheduled 
Visit 
Safety 
Follow-up 
Notes 
Days 
−28 to −1 
Wk 2 
(± 3 d) 
Wk 4 
(± 3 d) 
Wk 8 
(± 3 d) 
Wk 12a 
(EOT1)b 
(± 3 d) 
Wk 16 
(± 3 d) 
Wk 20 
(± 3 d) 
Wk 24 
(EOT2)/ETb 
(± 3 d) 
30 Days 
(+ 7 Days After 
Last Application) 
Patient-reported outcomes 
Itch NRS 
Completed each evening through the last application of study drug. 
 
 
 
Skin Pain NRS 
Completed each evening through the last application of study drug. 
 
 
 
Laboratory assessments 
 
Chemistry assessments 
X 
X* 
 
 
 
X 
 
 
X 
X† 
X 
*Not necessary if 
screening assessment is 
performed within 
14 days of Day 1. 
†Laboratory assessment 
are optional during 
unscheduled visits based 
on investigator's 
discretion and clinical 
judgment. 
Hematology 
assessments 
X 
X* 
 
 
 
X 
 
 
X 
X† 
X 
*Not necessary if 
screening assessment is 
performed within 
14 days of Day 1. 
†Laboratory assessment 
are optional during 
unscheduled visits based 
on investigator's 
discretion and clinical 
judgment. 


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Table 3: 
Schedule of Activities (Continued) 
Visit Day (Range) 
Screening 
Baseline 
(Day 1) 
DBVC Period 
OLE Perioda 
Unscheduled 
Visit 
Safety 
Follow-up 
Notes 
Days 
−28 to −1 
Wk 2 
(± 3 d) 
Wk 4 
(± 3 d) 
Wk 8 
(± 3 d) 
Wk 12a 
(EOT1)b 
(± 3 d) 
Wk 16 
(± 3 d) 
Wk 20 
(± 3 d) 
Wk 24 
(EOT2)/ETb 
(± 3 d) 
30 Days 
(+ 7 Days After 
Last Application) 
FSH* 
X 
 
 
 
 
 
 
 
 
 
 
*Women of 
nonchildbearing 
potential only. 
Follicle-stimulating 
hormone is not needed 
in women with a 
documented 
hysterectomy, bilateral 
salpingectomy, or 
bilateral oophorectomy. 
Serum pregnancy test* 
X 
 
 
 
 
 
 
 
 
 
 
*Female participants of 
childbearing potential 
will have a serum test at 
screening and a urine 
test at other visits noted. 
A positive urine test 
must be confirmed by a 
serum test. 
Urine pregnancy test* 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*Female participants of 
childbearing potential 
will have a serum test at 
screening, a urine 
pregnancy test before 
Day 1 study cream 
administration, and a 
urine test at other visits 
noted. A positive urine 
test must be confirmed 
by a serum test. 
HIV/Hepatitis 
serology 
X 
 
 
 
 
 
 
 
 
 
 
 


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Table 3: 
Schedule of Activities (Continued) 
Visit Day (Range) 
Screening 
Baseline 
(Day 1) 
DBVC Period 
OLE Perioda 
Unscheduled 
Visit 
Safety 
Follow-up 
Notes 
Days 
−28 to −1 
Wk 2 
(± 3 d) 
Wk 4 
(± 3 d) 
Wk 8 
(± 3 d) 
Wk 12a 
(EOT1)b 
(± 3 d) 
Wk 16 
(± 3 d) 
Wk 20 
(± 3 d) 
Wk 24 
(EOT2)/ETb 
(± 3 d) 
30 Days 
(+ 7 Days After 
Last Application) 
STD/BV* 
X 
 
 
 
 
 
 
 
 
 
 
*Prior test for STD/BV 
can be accepted if 
participants is 
asymptomatic, has no 
signs of active STD, 
and test done within 
6 weeks of screening 
visit. Participants who 
test positive for 
STD/BV during 
screening, can be 
treated and if repeat 
testing is negative, they 
can enroll and the 
screening window can 
be extended to 6 weeks 
to accommodate the 
treatment and washout 
requirements.  
STD/BV test can be 
performed at the 
discretion of the 
investigator during any 
visit or during 
unscheduled visit if a 
reasonable suspicion of 
STD/BV exists. STD 
testing should at least 
include testing for 
chlamydia and 
gonorrhea. 


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Table 3: 
Schedule of Activities (Continued) 
Visit Day (Range) 
Screening 
Baseline 
(Day 1) 
DBVC Period 
OLE Perioda 
Unscheduled 
Visit 
Safety 
Follow-up 
Notes 
Days 
−28 to −1 
Wk 2 
(± 3 d) 
Wk 4 
(± 3 d) 
Wk 8 
(± 3 d) 
Wk 12a 
(EOT1)b 
(± 3 d) 
Wk 16 
(± 3 d) 
Wk 20 
(± 3 d) 
Wk 24 
(EOT2)/ETb 
(± 3 d) 
30 Days 
(+ 7 Days After 
Last Application) 


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Table 3: 
Schedule of Activities (Continued) 
Visit Day (Range) 
Screening 
Baseline 
(Day 1) 
DBVC Period 
OLE Perioda 
Unscheduled 
Visit 
Safety 
Follow-up 
Notes 
Days 
−28 to −1 
Wk 2 
(± 3 d) 
Wk 4 
(± 3 d) 
Wk 8 
(± 3 d) 
Wk 12a 
(EOT1)b 
(± 3 d) 
Wk 16 
(± 3 d) 
Wk 20 
(± 3 d) 
Wk 24 
(EOT2)/ETb 
(± 3 d) 
30 Days 
(+ 7 Days After 
Last Application) 
Biopsy 
(select sites only) 
X* 
*Screening biopsy from 
anogenital area to 
confirm diagnosis (to be 
performed locally) if no 
prior biopsy was done. 
If a biopsy is done to 
confirm the diagnosis of 
LS during screening 
period, screening period 
can be extended to 6 
weeks to allow for 
histological 
examination. 
 


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Table 3: 
Schedule of Activities (Continued) 
Visit Day (Range) 
Screening 
Baseline 
(Day 1) 
DBVC Period 
OLE Perioda 
Unscheduled 
Visit 
Safety 
Follow-up 
Notes 
Days 
−28 to −1 
Wk 2 
(± 3 d) 
Wk 4 
(± 3 d) 
Wk 8 
(± 3 d) 
Wk 12a 
(EOT1)b 
(± 3 d) 
Wk 16 
(± 3 d) 
Wk 20 
(± 3 d) 
Wk 24 
(EOT2)/ETb 
(± 3 d) 
30 Days 
(+ 7 Days After 
Last 
Application) 
a All Week 12 assessments must be completed before the participant can continue in the OLE. 
b Assessment for ET will be the same as Week 24 visit. Early termination will be called ET1 during DBVC and ET2 during OLE.


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2. 
INTRODUCTION 
2.1. 
Background 
Lichen sclerosus is a chronic relapsing inflammatory dermatosis with an unknown pathogenesis 
marked by white scaly plaques involving anogenital areas in about 85 to 98% of cases (Powell 
and Wojnarowska 1999, Thomas et al 1996). Both anogenital and extragenital LS primarily 
affect females. Extragenital lesions usually affect back, shoulders, neck, and thighs (Neill et al 
2010). Vulvar LS is the most common presentation in females. Lichen sclerosus is considered to 
have bimodal peaks at onset where disease often starts in either prepubertal or perimenopausal 
period. 
Lichen sclerosus lesions are usually seen as white plaques, which may be atrophic or thickened, 
often present on labia minora and majora but may involve perineum and perianal areas. In 
advanced stages, LS lesions may become hyperkeratotic or ulcerated leading to bleeding and 
ultimately scarring, and anatomical changes such as fusion of labium, stricture or narrowing of 
vaginal opening, and fissures (Fistarol and Itin 2013). The hallmark of LS is intolerable pruritus, 
scarring, and drastic changes to genital anatomy, often culminating in sexual and urinary 
dysfunction with an increased risk for SCC, if left untreated (Smith and Haefner 2004, Tran et al 
2019). In patients with typical clinical presentation, diagnosis can be made on clinical ground; 
however, biopsy is advised to confirm diagnosis and to rule other diagnoses. 
The true prevalence of LS is unknown, due to the lack of extensive epidemiologic (screening) 
studies in this area and because a significant percentage of cases can be asymptomatic 
(15%-40%) (Vieira-Baptista et al 2015). Lichen sclerosus has been found to affect 1 in 
70 women presenting to a general gynecology practice with practitioners experienced in 
diagnosing this condition (Goldstein et al 2005), and when confined to older populations, it can 
even be as high as 1 in 30 women (Leibovitz et al 2000). Data from the Netherlands have shown 
that the incidence of vulvar LS between 1991 and 2011 nearly doubled (7.4 to 14.6 per 
100,000 woman-years, when only considering biopsy-proven cases; Bleeker et al 2016). 
Although the etiology of LS remains unknown, there are several lines of evidence that suggest 
LS is an autoimmunogenic disease against a genetic background (Tran et al 2019). Lichen 
sclerosus is often associated with other autoimmune disease such as alopecia areata, vitiligo, and 
thyroid disorders. In one series of 350 biopsy-proven LS patients, 21% had at least 1 first-degree 
relative affected with an autoimmune disorder and 42% had positive autoantibodies (Meyrick 
et al 1988). 
Immunological dysreactivity and autoimmune response appear relevant pathophysiological 
mechanisms of LS. Abnormal activation of a Th1 autoimmune response has been found in 
affected tissue. A large panel of cytokine-mediated signaling cascades have been identified as 
part of the pathophysiology of LS, including (IL-1, IL-7, IL-15, INF-γ, TNF-α; Szabo et al 2003, 
Terlou et al 2012). This supports the likelihood that a Th1 reactivity may promote the 
development of vulvar LS. An increased tissue expression of CXCR3 and CCR5, chemokine 
receptors known to characterize a Th1 response, is in line with this hypothesis (Farrell et al 
2006). 


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Patients with LS currently have limited treatment options, which include irritant avoidance and 
first-line treatment with topical corticosteroids. Topical calcineurin inhibitors are the second line 
of choice when topical corticosteroids are not effective or not tolerated. 
Ruxolitinib is a small molecule inhibitor of the JAKs with specificity for JAK1 and JAK2, which 
play an important role in signal transduction following cytokine and growth factor binding to 
their receptors. Increased production of cytokines and growth factors has been associated with a 
number of chronic inflammatory conditions, including AD, vitiligo, and other autoimmune 
diseases of the skin. In cell‑based assays relevant to the pathogenesis of inflammatory skin 
diseases, such as IL‑2–stimulated phosphorylation of STATs and IL‑2–induced proliferation of 
T cells, ruxolitinib demonstrates excellent potency (IC50 values of 10 to 40 nM). Ruxolitinib also 
potently inhibited the phosphorylation of STAT proteins and the production of proinflammatory 
factors induced by cytokines such as IL‑23 and IFN‑γ. Therefore, JAK inhibition may be 
expected to be efficacious in these diseases (refer to the IB for more information). 
Ruxolitinib cream has shown efficacy in AD and vitiligo. Ruxolitinib cream has shown 
statistically significant and clinically meaningful efficacy in 2 pivotal Phase 3 studies 
(INCB 18424-303 and -304) in adults and adolescents with mild to moderate AD and 3% to 20% 
affected BSA (excluding the scalp). In both AD Phase 3 studies, over 50% (53.8 and 51.3%) of 
participants (≥ 12 years of age) who applied ruxolitinib 1.5% cream BID for 8 weeks achieved 
an IGA-TS (ie, IGA score of 0 or 1 with ≥ 2-point improvement from baseline) compared with 
15.1% and 7.9% of participants who applied vehicle cream, respectively. Participants who 
applied ruxolitinib cream also saw a substantial improvement in itch (4-point reduction in 
Itch NRS) compared with participants who applied vehicle in both studies (50.7% and 52.2% for 
ruxolitinib cream vs 16.3% and 15.4% for vehicle, respectively). In addition, ruxolitinib 
1.5% cream administered BID was safe and well tolerated in adolescent and adult participants 
with AD. 
Ruxolitinib cream 1.5% has demonstrated efficacy in vitiligo. Studies INCB 18424-306 and -307 
were identically designed randomized, VC, Phase 3 studies in adolescent and adult participants 
(≥ 12 years old, ≈10% of whom were adolescents) with vitiligo. Participants received blinded 
study treatment for 24 weeks and were then offered the opportunity to receive an additional 
28 weeks of treatment with ruxolitinib 1.5% cream BID. Both studies met the primary endpoint 
(p < 0.0001), demonstrating that significantly more participants treated with ruxolitinib 1.5% 
cream BID achieved a ≥ 75% improvement from baseline in the Facial Vitiligo Area Scoring 
Index at Week 24 compared to participants treated with a vehicle control. 
Ruxolitinib 1.5% cream is approved in the US as Opzelura™ for 1) 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; and 2) the topical treatment of nonsegmental 
vitiligo in adult and pediatric patients 12 years of age and older. Refer to the Opzelura™ package 
insert (Opzelura 2022) for full details. 
This study is designed to evaluate the efficacy and safety of ruxolitinib 1.5% cream in 
participants with LS. 


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2.1.1. 
Scientific Rationale for Study Design 
Similar to AD and vitiligo, LS is considered to be an inflammatory dermatosis. Although 
etiology of LS is unknown, it is considered to be an autoimmune disease with dysregulation of 
Th1 response. Several cytokines including IL-1, IL-7, IL-15, INF-γ, TNF-α have been implicated 
in the pathogenesis of LS (Szabo et al 2003, Terlou et al 2012). Additionally, Th1 associated 
chemokines such as CXCR3 and CCR5, are overexpressed in LS. Similar to AD and vitiligo, 
JAK1 and JAK2-associated cytokines are involved in the pathogenesis of LS. Ruxolitinib is a 
selective inhibitor of JAK1 and JAK2 and, based on its demonstrated efficacy in both AD and 
vitiligo in well-designed pivotal Phase 3 trials, ruxolitinib 1.5% cream is expected to have 
potential activity in LS. 
There is currently no FDA approved treatment of LS. High-potency steroids are the mainstay of 
treatment; however, their continued use is associated with skin atrophy and other side effects, 
which limits their use. There are no published studies on topical JAK inhibitors in LS. Prior 
studies comparing high-potency topical steroids with either topical pimecrolimus (Goldstein et al 
2011) or topical tacrolimus (Funaro et al 2014) demonstrate the superiority of high-potency 
topical steroids. Symptoms (eg, itching or pain) can be partially improved by application of 
vehicle with up to 75% participants reporting improvement in some studies (Sideri et al 1994). 
Because of substantial response to vehicle or petroleum ointments, it is crucial to compare 
ruxolitinib 1.5% cream to vehicle to assess the independent effect of ruxolitinib on LS. For this 
reason, a random 1:1 allocation design was chosen for this study. Additionally, symptoms of LS 
may wax and wane and may be exacerbated by sexual or physical activity. Therefore, a 12-week 
double-blind vehicle-controlled study has been designed, which will allow sufficient length of 
time to compare ruxolitinib against vehicle and is ethically acceptable. This is in line with prior 
RCTs in LS, which used a 12-week duration of treatment (Goldstein et al 2011). The proposed 
study would also assess safety of ruxolitinib 1.5% cream in participants with LS. 
Because LS carries a serious long-term risk of cancerous transformation with a cumulative 
incidence of vulvar SCC of 6.7% (Bleeker et al 2016), usually treatment for LS is lifelong with 
close follow-up to detect early signs of vulvar carcinoma. Once the symptoms are 
well-controlled after an initial intensive treatment with high-potency steroids, participants are 
recommended to use maintenance therapy in which they apply topical steroids from 2 times a 
week to once a day. For this reason, this trial will include an OLE period for maintenance 
treatment. Participants will be asked to continue treatment without stopping unless there are AEs 
that necessitate treatment discontinuation. The use of ruxolitinib cream during the OLE period 
will demonstrate continued safety and efficacy of ruxolitinib 1.5% cream in LS. 
This study will evaluate the efficacy and safety of ruxolitinib 1.5% cream BID versus vehicle in 
LS. The VC period is 12 weeks. Participants who are randomly assigned to ruxolitinib 1.5% 
cream will continue to treat (ruxolitinib 1.5% cream QD) active LS areas during the OLE for 
additional 12 weeks. Participants assigned to vehicle will then be crossed over to receive active 
maintenance treatment for an additional 12 weeks. During the OLE period, all participants will 
apply ruxolitinib 1.5% cream through Week 24 at least once per day. Participants who develop 
symptoms or signs of active disease during OLE period on ruxolitinib 1.5% cream QD treatment 
regimen will have dose increased to ruxolitinib 1.5% cream BID until symptoms and signs have 
resolved. At the Week 12 visit, the LS treatment area will be evaluated by the investigator to 
assess for symptoms and signs of active disease. Those participants who in the opinion of the 


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investigator, have symptoms and signs of active disease, will continue ruxolitinib 1.5% cream 
BID until their symptoms and signs have resolved. Those participants, who in the opinion of the 
investigator have resolution of symptoms and signs, can continue ruxolitinib 1.5% cream once a 
day. Improvement in itch is chosen as a clinically relevant outcome because it is the most 
common symptoms in patients with LS. While the mechanism underlying the genesis of itch in 
LS is not known, improvement in itch can improve the quality of life in patients with LS and 
provide initial evidence of efficacy of ruxolitinib 1.5% cream in LS. In addition, relevant clinical 
and histological measures have been included as secondary 
 outcomes. There is 
currently no universally accepted clinical scale to assess the disease severity of LS. A 
customized 
 will be used to assess disease severity. In addition, we plan to utilize CLISSCO, 
which is a validated tool to assess disease severity in vulvar LS (Erni et al 2021). This design 
will provide a well-controlled assessment of the efficacy of ruxolitinib 1.5% cream in LS 
compared to vehicle. 
2.1.2. 
Justification for Dose 
The ruxolitinib cream strength and application frequency for this study (ruxolitinib 1.5% cream 
BID) was selected primarily based on data from the Phase 3 pivotal studies (INCB 18424-303 
and -304) in participants ≥ 12 years of age with AD, which evaluated the safety and efficacy of 
ruxolitinib 1.5% cream BID and ruxolitinib 0.75% cream BID. Overall, ruxolitinib 1.5% cream 
was found to be more efficacious than ruxolitinib 0.75% cream, while the safety and tolerability 
profiles of both treatment arms were comparable and nondifferentiating. Phase 3 AD studies also 
demonstrated rapid (as early as 12 hours) and substantial decrease in itch following application 
of ruxolitinib 1.5% cream with better efficacy against itch when compared to ruxolitinib 0.75% 
cream. Similarly, Phase 3 pivotal studies in vitiligo (INCB 18424-306 and -307) provide further 
support for the superior efficacy of ruxolitinib cream 1.5% versus vehicle cream. 
Given the overall data for AD and vitiligo, and the pathogenic and clinical manifestations of LS, 
ruxolitinib 1.5% cream BID was selected as the treatment regimen for this study. 
2.2. 
Benefit/Risk Assessment 
Ruxolitinib 1.5% cream showed statistically significant and clinically meaningful improvement 
in the signs and symptoms of AD in participants with mild to moderate AD, including itch 
(Papp et al 2021). Given that itch is most bothersome and prevailing symptom of LS, it is 
anticipated that participants with LS will benefit from application of ruxolitinib cream. 
Safety data from the Phase 3 AD studies (INCB 18424-303 and -304) demonstrated that 
ruxolitinib 1.5% cream BID applied 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. 
Safety and tolerability in the Phase 2 and Phase 3 studies in vitiligo (INCB 18424-211, -306, 
and -307) showed that the rate of Grade 3 TEAEs, SAEs, and TEAEs leading to discontinuation 
was low. There were no significant TEAEs or application site events and no clinically relevant 
hematological changes suggestive of systemic toxicity. The majority of participants with vitiligo 
had good local tolerability with ruxolitinib cream use and reported application site reactions were 
all Grades 1 or 2 in severity. The most commonly reported application site reactions were 


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application site pruritus in 15 participants (2.0%) and application site acne in 7 participants 
(1.0%). All other application site reactions in participants with vitiligo were reported in < 1% of 
participants overall. 
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 where 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 (< 1%) compared with the vehicle cream treatment group (3-5%) during the 
8-week, VC period, which may be attributable to worsening of the underlying disease in the 
absence of active drug treatment. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of ruxolitinib cream may be found in the IB. 
Based on cumulative efficacy and safety data from AD and vitiligo studies, pathogenesis of LS, 
and role of Th1 cytokines in LS, it is expected that benefit-risk ratio of ruxolitinib cream in LS 
will be positive. 


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3. 
OBJECTIVES AND ENDPOINTS 
Table 4 presents the objectives and endpoints. 
Table 4: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To establish the efficacy of ruxolitinib 1.5% 
cream BID in participants with LS. 
ITCH4 response (defined as a ≥ 4-point improvement in Itch 
NRS score from baseline) at Week 12. 
[Proportion of participants with ITCH4 at Week 12] 
Secondary 
To further evaluate efficacy of ruxolitinib 1.5% 
cream BID in participants with LS. 
• Change from baseline in CLISSCO score at Week 12. 
• Change from baseline in the Skin Pain NRS score at 
Week 12. 
• Time to achieve ITCH4. 
To evaluate the safety and tolerability of 
ruxolitinib 1.5% cream BID. 
The type, frequency, and severity of AEs, including the 
changes in vital signs and clinical laboratory blood samples. 


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Table 4: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 2, randomized, DBVC study in participants ≥ 18 years of age with a 
biopsy-confirmed diagnosis of LS. The study will consist of a 12-week DBVC period followed 
by a 12-week OLE period. 
Approximately 60 female participants will be randomized 1:1 to either ruxolitinib 1.5% cream or 
vehicle cream (see Figure 1). Participants will apply either ruxolitinib 1.5% cream or vehicle 
cream (both BID) through Week 12 to all the affected areas identified at baseline. Treatment 
assignment during the DBVC period will remain blinded to investigators and participants until 
after all participants have completed treatment or discontinued and completed the safety 
follow-up period. 
At Week 12, participants who meet the criteria (compliant with the Protocol and without safety 
concerns) will enter the 12-week OLE period. Participants randomized initially to vehicle in the 
DBVC period will be crossed over to ruxolitinib 1.5% cream and participants randomized to 
ruxolitinib 1.5% cream at baseline will continue to apply ruxolitinib 1.5% cream through 
Week 24 in an open-label fashion. During the OLE period, participants who have no symptoms 
or signs of active LS (based on investigator's assessment) will apply ruxolitinib 1.5% cream QD 
through Week 24. Ruxolitinib dose can be increased to BID for those participants who have 
symptoms or signs of active disease (based on investigator's assessment) until symptoms and 
signs of active LS have resolved in the opinion of the investigator. Continuous treatment is 
recommended to suppress ongoing inflammation and because LS lesions are at risk of cancerous 
transformation (see Section 6.1). Table 3 presents the SoA. 
The COVID-19 global pandemic may present challenges to the normal conduct of this study 
(including AE and laboratory assessments), requiring the implementation of potential mitigation 
strategies described in Appendix B. 


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4.2. 
Overall Study Duration 
The study begins when the first participant signs the study ICF. It is estimated that an individual 
will participate for approximately 32 weeks, including up to 28 days for screening, 12 weeks for 
treatment during the DBVC period, 12 weeks for treatment during the OLE period, and up to 
30 days for follow-up after the last application of study treatment. If a biopsy is done to confirm 
the diagnosis of LS during screening period, screening period can be extended to 6 weeks to 
allow for histological examination.  
The end of the study is defined as the date of the last visit of the last participant in the study. 
A participant is considered to have completed the study if they have completed all study visits 
including the safety follow-up visit. 
4.3. 
Study Termination 
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study 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. 
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. Females only, aged 18 years or older at screening. 
3. Biopsy-proven LS in the anogenital area. Total BSA including anogenital and 
nonanogenital area should not exceed 10% BSA.  
Note: Participants who have newly diagnosed LS, or have LS refractory to prior 
treatments, or have progressive LS (such as fusion of the labia minora, phimosis of the 
clitoral hood, and fissures) will be allowed to participate in the study. 
4. Baseline IGA score ≥ 2 for LS. 
5. Baseline Itch NRS score ≥ 4 in anogenital area. Baseline Itch NRS score is defined as 
7-day average of Itch NRS score before Day 1 (data from a minimum 4 out of 7 days 
directly prior to Day 1 is needed). 


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6. Participants who agree to discontinue all agents used by the participant to treat LS from 
the screening visit (according to washout timeline enumerated under exclusion 
criterion 4; see Section 5.2) through the final safety follow-up visit. 
7. Willingness to avoid pregnancy based on the criteria below. 
a. Female participants who are WOCBP must have a negative serum pregnancy test at 
screening and a negative urine pregnancy test before the first application 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 treatment 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. 
b. A female participant not considered to be of childbearing potential as defined in 
Appendix A is eligible. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Participants who do not have LS involving anogenital area. 
2. Concurrent conditions and history of other diseases: 
a. Are suspected clinically (or confirmed diagnostically) of having alternative causes of 
vaginal symptoms including: candidiasis, chlamydia trachomatis, trichomonas 
vaginalis, neisseria gonorrhoeae, bacterial vaginosis, or herpes simplex. Participants 
who test positive during screening, can be treated and if repeat testing is negative, can 
be enrolled. If treatment is needed for vaginal infections (eg, for bacterial vaginosis), 
the screening window can be extended to 6 weeks to accommodate the treatment and 
washout requirements.  
b. Have active genital/vulvar lesions at screening and Day 1, not related to LS, including 
active herpes simplex lesions or other vaginal or vulvar conditions, which could 
confound the interpretation of the clinical response, as determined by the investigator. 
c. Chronic or acute infection requiring treatment with systemic antibiotics, antivirals, 
antiparasitics, antiprotozoals, or antifungals within 2 weeks before baseline. 
3. Participants with the following conditions: 
a. Clinically significant or uncontrolled cardiovascular disease, including unstable 
angina, acute myocardial infarction, or stroke within 6 months from Day 1 of study 
drug application, New York Heart Association Class III or IV congestive heart 
failure, and arrhythmia requiring therapy. Participants with persistent uncontrolled 
hypertension (blood pressure > 150/90 mm Hg) unless they are on stable regimen and 
blood pressure is controlled as per assessment of the investigator. 
b. Current or previous malignancy within 5 years of study entry, except for adequately 
treated, nonmetastatic nonmelanoma skin cancer. 
c. Active acute bacterial, fungal, or viral skin infection (eg, herpes simplex, herpes 
zoster, chicken pox, clinically infected AD, or impetigo) within 1 week before 
baseline. 


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d. Unstable asthma or COPD requiring systemic treatment (such as intravenous steroids) 
or hospital admission or emergency room treatment within 3 months from baseline or 
stable asthma or COPD requiring 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. 
e. Immunocompromised (eg, lymphoma, acquired immunodeficiency syndrome, or 
Wiskott-Aldrich syndrome). 
f. Current and/or history of arterial or venous thrombosis, including deep venous 
thrombosis and pulmonary embolism. 
g. Current and/or history of active tuberculosis; or current and/or history of latent 
tuberculosis unless adequately treated. 
h. History of severe anemia, severe thrombocytopenia, or severe neutropenia requiring 
transfusion or ongoing treatment. 
i. 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 
administration of study drug and attending required study visits; pose a significant 
risk to the participant; or interfere with interpretation of study data. Investigator 
should consult with the medical monitor to clarify eligibility when in doubt. 
4. Any of the following clinical laboratory test results at screening: 
a. Cytopenias at screening, 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 GFR < 30 mL/min/1.73 m2 (using the Chronic Kidney Disease 
Epidemiology Collaboration creatinine 2021 equation). 
d. Positive serology test results at screening for HIV antibody. 
e. History of acute or chronic active hepatitis B or C virus infection. Participants who 
have recovered or have been successfully treated with no evidence of active hepatitis, 
and those who are immune due to hepatitis B vaccination can enroll. Participants who 
are positive for the hepatitis B surface antigen will be eligible if they are negative for 
HBV-DNA; participants who are positive for the anti-HCV antibody will be eligible 
if they are negative for HCV RNA. 
f. Any other clinically significant laboratory result that, in the opinion of the 
investigator, poses a significant risk to the participant. 
5. Use of any of the following treatments within the indicated washout period before the 
baseline visit: 
a. 5 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. 


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b. 4 weeks – systemic corticosteroids or adrenocorticotropic hormone analogs, 
cyclosporin A, methotrexate, azathioprine, or other systemic immunosuppressive or 
immunomodulating agents (eg, mycophenolate or tacrolimus). 
c. 2 weeks or 5 half-lives, whichever is longer - strong systemic CYP3A4 inhibitors. 
d. 2 weeks – systemic antibiotics and immunizations with live-attenuated vaccines, 
sedating antihistamines unless on a long-term stable regimen (nonsedating 
antihistamines are permitted). 
Note: Live-attenuated vaccines are prohibited during the DBVC period. COVID-19 
vaccination (not live-attenuated) is permitted. 
e. 2 weeks – treatment with topical therapy (eg, topical corticosteroids, pimecrolimus, 
and tacrolimus) in the affected area. 
6. Current treatment or treatment within 30 days or 5 half-lives (whichever is longer) before 
the baseline visit with another investigational medication or current enrollment in another 
investigational drug protocol. 
7. Pregnant or lactating participants or those considering pregnancy during the period of 
their study participation. 
8. 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 administration schedule and study assessments. 
9. Previous treatment with systemic or topical JAK inhibitors (eg, ruxolitinib, tofacitinib, 
baricitinib, filgotinib, lestaurtinib, pacritinib). 
10. Known allergy or reaction to any of the components of the study cream including history 
of allergy to propylene glycol. 
11. In the opinion of the investigator, are unable or unlikely to comply with the 
administration schedule and study evaluations. 
12. Committed to a mental health institution by virtue of an order issued either by the judicial 
or the administrative authorities. 
13. Employees of the sponsor or investigator or otherwise dependents of them. 
5.3. 
Lifestyle Considerations 
Participants should be cautioned to avoid excessive 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. Sexual partners of participants should be advised to use barrier protection such as 
male condom. 
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 


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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 ID 
number. 
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). 
6. 
STUDY TREATMENT 
6.1. 
Study Treatments Administered 
During the DBVC period, ruxolitinib cream or matching vehicle will be applied as a thin film 
BID, with applications approximately 8-12 hours apart in the morning and in the evening at least 
1 hour before bedtime. 
At the baseline visit, an estimate of the %BSA to be treated will be used by the IRT system to 
calculate the number of tubes of study cream to be dispensed. During clinic visits, the participant 
should apply a thin film of study cream in front of site staff until all the affected areas to be 
treated are covered. This supervised application will be limited to one application of the study 
drug during the clinic visit. 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. 
During the OLE period, starting at the Week 12 visit, the LS treatment area will be evaluated by 
the investigator to assess the frequency of treatment during OLE period. Frequency of study drug 
application during OLE period can be adjusted and this should be recorded in the eCRF. 
Participant will apply ruxolitinib 1.5% cream during OLE period per following guidance in 
Table 5 below: 
Table 5: 
Dose Administration Guidance for OLE Period 
Clinical Assessment 
OLE Dose Administration Guidance  
Completely symptoms free and no sign of active LS 
disease (IGA score 0) 
Apply study drug QD 
Symptoms associated with LS such as itching/pain and 
signs of active disease (IGA score 1 or higher) 
Apply study drug BID 
Participants will be allowed to apply study cream to treat nonanogenital LS lesions as long as the 
total BSA does not exceed 10% (total BSA including anogenital [≈1%] and nonanogenital area 
should not exceed 10%). New lesions of LS can be treated if permitted by the investigator as 
long as total BSA does not exceed 10%. At any time during the DBVC and OLE period, if a 
participant's new areas to be treated in addition to the areas identified at the previous visit exceed 


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10% BSA, then the participant should be discontinued from study treatment and the EOT 
assessment should be completed. 
If there are new areas to be treated, including expansion of existing areas or development of new 
areas, after consultation with the investigator, study cream should be applied to these areas in 
addition to the areas treated at baseline (total affected areas ≤ 10% BSA), and the percentage of 
BSA to be treated will be recalculated and increased. 
The amount of study cream used per application will be determined by weighing a tube before 
and after the participant applies study drug to the affected areas. 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. Detailed instruction on study drug application will be provided in 
pharmacy manual. 
Participants will be recommended to take a warm bath/shower/wash at least once a day and 
preferably twice a day before applying study cream. Given the thickened lesions of LS, 
participants will be recommended to rub the study cream in for about 30 to 90 seconds. 
Table 6 presents the study treatment information. 
Table 6: 
Study Treatment Information 
 
Study Treatment 1 
Study Treatment 2 
Study treatment name: 
Ruxolitinib 
Vehicle 
Mechanism of action: 
JAK 1/2 inhibitor 
Not applicable 
Dosage formulation: 
Cream 
Cream 
Treatment strength: 
1.5% 
Not applicable 
Administration instructions: 
DBVC period: Apply a thin film and rubbing the study cream to 
affected areas identified at baseline in the morning and at least 
1 hour before bedtime with applications at least 8-12 hours apart 
for 12 weeks. A warm bath/shower/wash is recommended before 
study drug application. Study cream should be rubbed for about 
30-90 seconds. 
OLE period: Frequency of application (either QD or BID) will 
vary based on LS signs and symptoms and investigator's clinical 
judgment. Apply a thin film to affected areas. A warm 
bath/shower/wash is recommended before study drug application. 
Study cream should be rubbed for about 30-90 seconds. Nightly 
dose, if applicable, should be applied at least 1 hour before 
bedtime. If participant is applying study drug BID, an interval of 
8-12 hours between the 2 doses is recommended. 
Packaging and labeling: 
Ruxolitinib or vehicle cream will be provided in 60-g tubes. 
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 


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6.2. 
Preparation, Handling, and Accountability 
The investigator or designee must confirm appropriate temperature conditions (both ruxolitinib 
cream and vehicle cream are to be stored between 15°C and 30°C [59°F-86°F]) 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 study treatment. Refer to the Study Pharmacy Manual for participant 
instructions for handling of study cream. 
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. Participants should store study treatment at ambient 
temperature conditions. 
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 drug(s) to the study site. 
• Inventory of study drug(s) at the site. 
• Participant use of the study drug(s), including tube counts from each supply 
dispensed. 
• Return of study drug(s) 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 drug. 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 drug 
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 
drug according to institutional SOPs. If, however, local procedures do not allow on-site 
destruction, shipment of the study drug 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 the sites. 


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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 a study number to participants and randomize participants to study treatments 
in a 1:1 ratio. The IRT system will be used to track participant visits, maintain the blinding, and 
manage study cream inventory. Full details will be provided in the IRT Manual. 
Participants, investigators, and the sponsor will be blinded to each participant's treatment 
assignment during the DBVC period. During the OLE period, participants and investigators 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 emergency unblinding procedures in Section 9.7 and refer to the IRT Manual). 
6.4. 
Study Treatment Compliance 
Compliance with all study-related treatments should be emphasized to the participant by site 
staff, 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' diaries. 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 treatment will be evaluated 
by the participant's adherence to the BID application regimen during DBVC period and BID or 
QD 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 diary entries for compliance. Participants will be 
considered compliant with the treatment regimen if they apply at least 80% but no more than 
120% of the prescribed number of applications during participation in the DBVC and OLE 
period of the study. Participants who are noncompliant during the DBVC period and OLE period 
will be reinstructed by the investigator (or designee), and the sponsor should be consulted by the 
investigator for instruction on the proper handling of the participant. 
Drug accountability will be assessed by documenting the quantities of drug used between study 
visits (tube counts and weighing). At the first clinic visit and subsequent study visits, 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/modifications allowed (decrease or increase in study drug 
frequency of application) during the DBVC period except for drug interruption or permanent 
discontinuation, if needed (eg, for management of an AE). 
Temporary interruption could be due to an AE in the DBVC or OLE period. 


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6.5.1. 
Criteria and Procedures for Dose Interruptions and Adjustments of Study Drugs 
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 drug (see Table 7). In 
the event that an AE is present at a specific site of study drug application, treatment may be 
temporarily 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 drug applications. Additionally, the 
investigator must obtain approval from the medical monitor before restarting study drug. 
Participants who experience a recurrence of the initial AEs upon restarting the study drug may 
need to permanently discontinue treatment with the study drug. 
Participants should be closely monitored for the development of signs and symptoms of infection 
during treatment with the study drug and up to the safety follow-up visit. Study drug should be 
interrupted if a participant develops a serious infection, an opportunistic infection, or sepsis. 
Study drug application should not be resumed until the infection is controlled. 
Table 7: 
Guidelines for Interruption of Study Drug for Treatment-Related Adverse 
Events and Restarting of Study Drug 
Adverse Event Related 
to Study Drug 
Action Taken 
Any Grade 3 laboratory 
abnormality 
Laboratory abnormalities should be confirmed with repeat testing within 
48-72 hours whenever possible and immediate delivery of the laboratory 
results should be requested. 
Interrupt study drug, based on clinical judgment in consultation with the 
medical monitor (whenever possible), taking into account the relatedness 
of the AE to the study drug 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 drug 
must be interrupted unless the medical monitor approves continuation. 
At the discretion of the investigator, after consultation with the sponsor, 
study drug application may be restarted once the laboratory abnormality 
has resolved. 
Any Grade 4 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 drug, based on clinical judgment in consultation with the 
medical monitor (whenever possible), taking into account the relatedness 
of the AE to the study drug and the participant's underlying condition. 
Discontinue study drug permanently if laboratory abnormalities are 
confirmed and deemed related to study drug. 
Note: Severity of AEs will be based on the National Cancer Institute CTCAE v5.0 using Grades 1 through 5. 


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6.5.2. 
Criteria for Permanent Discontinuation of Study Drug Due to an Adverse Event 
The occurrence of unacceptable severity of an AE, such that it would interfere with study drug 
treatment or study procedures, and may require that the study drug be permanently discontinued. 
Unacceptable severity is defined as follows: 
• Occurrence of an AE that is related to treatment with the study drug that, in the 
judgment of the investigator or the sponsor's medical monitor, compromised the 
participant's ability to continue study-specific procedures, or continuing in the study 
is considered to not be in the participant's best interest. 
• Worsening of LS that requires treatment with a prohibited concomitant medication. 
• Adverse event requiring an interruption of study drug for more than 2 weeks. 
• Confirmed Grade 4 laboratory abnormalities deemed related to study drug. 
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. 
Non-LS medications received up to 28 days before the first application of study treatment will be 
recorded in the eCRF. Any prior LS treatments received at least 1 year before the first 
application of study drug will be collected, including the response to treatment and reason for 
stopping the treatment. All medications received from the first application through the follow-up 
period 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 drug 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. 
Any addition, deletion, or change in the dose/regimen of these medications will also be recorded. 
Concomitant medications administered 30 days after the last application of study treatment 
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 if, in the judgment of the investigator, the intake of 
these medications and procedures will not impact the safety of the participant or efficacy of the 
treatment: 
• Participants may use/continue to use bland emollients. Participants may not change or 
introduce a new emollient within 4 weeks of baseline visit. 
Note: Emollients should not be used within 4 hours before and 1 hour after 
application of study drug. 
• Participants may use nonsedating, over-the-counter antihistamines. 
• Established and stable treatment with sedating antihistamines (≥ 28 days prior to 
baseline) may be continued as long as no changes are made in the course of the 
study). 
• Use of inhaled corticosteroids for bronchial asthma or COPD are allowed with the 
dose equivalent of budesonide (not to exceed 720 µg/day or 2 puff 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. 
• Use of any over-the-counter, nonprescription vitamins, minerals, and 
phytotherapeutic, herbal, or plant-derived preparations. 
6.6.2. 
Restricted Use Medications and Procedures 
The use of following medications and procedures is restricted to specified conditions and if 
deemed acceptable by the investigator from 14 days before the baseline visit through follow-up 
visit: 
• Use of any prescription medication to treatment chronic medical conditions (such as 
hypertension) if on stable regimen in the judgment of the investigator. 
• Short course of topical anti-infectives, including antibacterial, antifungal, and 
antiviral medications (≤ 5 days) applied to active LS lesions to treat skin infection. 
Anti-infective treatment should not be used for at least 4 hours before and 1 hour after 
application of study cream. 
• Short duration treatment of vaginal/cervical infection is allowed as long as treatment 
is ≤ 7 days. 
• Treatment is not considered strong inhibitor of CYP3A4, and treatment, in the 
opinion of the investigator, is not expected to influence the course of LS. 


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6.6.3. 
Prohibited Medications and Procedures 
No rescue treatment or therapy is allowed during the study. In addition, the following are not 
permitted during the study: 
• Any investigational medication other than the study drug. 
• Treatment known to affect the course of LS. 
• Topical corticosteroids or topical calcineurin inhibitors. 
• Systemic corticosteroids, methotrexate, cyclosporine A, azathioprine and biological 
therapies, or other immunosuppressant agents or any other topical or systemic 
treatment for LS. 
• Phototherapy or tanning beds. 
• Live-attenuated vaccination during the DBVC period. Note: COVID-19 vaccination 
(not live-attenuated) 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: 
• Disease worsens during either the DBVC period or the OLE period, to the point 
where the extent of affected area to be treated exceeds 10% BSA. 
• Worsening LS and treatment with a prohibited medication as noted in Section 6.6.3. 
• 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 
public domain, may be collected on or solicited from the participant. Participants may 
choose to discontinue study treatment and remain in the study to be followed for 
safety/efficacy assessments. 
• Further participation would be injurious to the participant's health or well-being, in 
the investigator's medical judgment. 
• Unacceptable toxicity occurs (see Table 7). 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
A participant may be discontinued from study treatment for the following reasons: 
• If, after 2 consecutive study visits and reinforcement of study drug application by site 
staff, a participant's drug 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, during the course of the study, a participant is found not to have met eligibility 
criteria, the medical monitor, in collaboration with the investigator, will determine 
whether the participant should be withdrawn from study treatment. 
• If a participant is noncompliant with study procedures or study drug 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 12 (or Week 24) visit, the ET1 (or ET2) visit should be conducted. Reasonable efforts 
should be made to have the participant return for a follow-up visit. 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 the date recorded. 
• The status of the participant should be updated to ET in the IRT system. 
• Participants must be followed for safety until the time of the follow-up visit or until 
study drug-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. 
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 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, he/she 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. 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 country(ies) in 
which the study is being conducted as well as the IRB/IEC or study center. 
• The participant must be informed that their personal study-related data will be used 
by the sponsor 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 and must be assigned 
a new participant ID number. 


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8.1.2. 
Screening Procedures 
Screening is the interval between signing the ICF and the day the participant is enrolled 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. 
Procedures conducted as part of the participant's routine clinical management (eg, blood counts 
or physical examinations) and obtained before signing of the ICF may be used for screening or 
baseline purposes provided that the procedure meets the Protocol-defined criteria and has been 
performed in the timeframe of the study (ie, within 28 days or less prior to Day 1). For 
participants who are enrolled in the study, information associated with eligibility requirements 
must be entered into the appropriate eCRF pages. 
Results from the screening visit evaluations will be reviewed to confirm eligibility before 
randomization and the administration of study drug. 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 a country's abbreviation, the site ID, and the participant ID number. Site staff 
should contact the IRT to obtain the participant ID number during screening. Upon determining 
that the participant is eligible for study entry, the IRT will be contacted to obtain the treatment 
assignment. Additionally, the IRT will be contacted at each regular study visit during both the 
DBVC period and the OLE period including unscheduled visits and safety follow-up visits (see 
Table 3) to update the study drug supply. Additional details are provided in the IRT Manual. 
8.1.4. 
Distribution of Reminder Cards and/or Diaries 
Participants will be provided with a reminder card at each 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 
morning application of study drug on Week 2 and Week 4 visit, as they will apply it after blood 
draws 
 for 
 safety evaluation have been completed. 
Participants will be instructed on the use of the drug application diary during the screening visit. 
Daily study drug administration will be recorded in the diary and verified by the study 
investigator/designee at study visits as shown in Table 3. 


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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, medical and surgical 
history, and current illnesses. Medical history will include relevant medical or surgical 
treatments within the last 2 years that are considered to be clinically significant by the 
investigator. 
8.1.5.2. 
Disease Characteristics and Treatment History 
Relevant medical and treatment history for the past year will be collected at screening by the 
investigator or qualified designee. Details regarding the participant's history of LS, including 
date of diagnosis, relevant disease characteristics, and prior treatments with outcome (eg, 
inadequate response) and reason for stopping treatment will be recorded. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 


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8.2. 
Efficacy Assessments 
8.2.1. 
Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics parameters are not evaluated in this study. 
 
 
 
 
 
 
 
 
 
 
8.2.3. 
Clinical Lichen Sclerosus Score 
The CLISSCO is a validated tool to assess disease severity in vulvar lichen sclerosus. Clinical 
Lichen Sclerosus Score consists of 12 items divided into 3 sections: (a) symptoms (3 items; 
likely reversible [ie, itch, pain, dysuria]), (b) signs (3 items; possibly reversible [ie, whitening, 
petechiae/ecchymosis, fissures]), and (c) architectural changes (6 items; irreversible [ie, skin 
fusion, perianal involvement, etc]). All symptoms, signs, and architectural changes will be rated 
on a 4-point Likert scale (0 = absent; 1 = mild; 2 = moderate; 3 = severe; Erni et al 2021). 
Investigator will be asked to document score of each of the 12 items based on schedule stipulated 
in SoA (see Table 3). 
 
  
 
 
 
 


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8.2.5. 
Body Surface Area 
Total % BSA affected will be estimated at each visit as outlined in the SoA (see Table 3). Body 
surface area assessment will be approximated to the nearest 0.1% using the Palmar Method as a 
guide, which is the palm plus 5 digits, with fingers tucked together and thumb tucked to the side 
(handprint), as 1% BSA and the thumb as 0.1% BSA. 
8.2.6. 
Photography 
At select sites, photographs of the LS lesions will be taken at visits indicated in Table 3. Detailed 
methods for capturing photographs will be provided in the Study Manual. 
8.2.7. 
Patient-Reported Outcomes 
Patient-reported outcomes will be collected and assessed as outlined in the SoA (see Table 3). 
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. 
8.2.7.1. 
Diary Assessments: Itch NRS and Skin Pain NRS 
The participant will rate the following: 
• Itch NRS: The Itch NRS is a daily participant-reported measure (24-hour recall) of 
the worst level of itch intensity (Kimball et al 2016, Silverberg et al 2021). The 
participant will be instructed to complete and record the Itch NRS via a diary, daily, 
in the evening beginning on the day of screening through Week 24 or treatment 
discontinuation. The participant will rate itch severity of their LS by selecting a 
number from 0 (no itch) to 10 (worst imaginable itch) that best describes the worst 
level of itching in the past 24 hours. 
• Skin Pain NRS: Pain (includes all types of pain such as feeling of burning, tearing, 
pulling, stabbing, etc) severity of the LS by selecting a number from 0 (no pain) to 10 
(worst imaginable pain) that best describes their worst level of pain in the past 
24 hours. The participant will be instructed to complete and record the Pain NRS via 
a diary, daily, in the evening beginning on the day of screening through Week 24 or 
treatment discontinuation based on 24-hour recall. 
The average of the 7-day Itch NRS score prior to the baseline visit (minimum 4 out of 7 days' 
data required) will be used to determine if a participant meets inclusion criteria. 
In addition, the diary may be used for optional reporting of sexual activity or other activities, 
which may exacerbate pain or itching. Detailed directions for the administration of a diary will 
be provided in the Study Manual. 


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8.3. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA in Table 3. 
See Section 6.5 for guidelines regarding the management of relevant laboratory or other safety 
assessment abnormalities. 
8.3.1. 
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 drug. 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 drug. 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) 


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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 drug/procedures, or that caused the participant to 
discontinue the study drug. 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, 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 within 24 hours (see Section 9.4). The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
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). 
8.3.2. 
Physical Examinations 
At the screening visit and the Week 24 (EOT2) or ET visit, a comprehensive physical 
examination should be conducted. The comprehensive physical examination will include 
assessment(s) of the following organ or body systems: skin; head, eyes, ears, nose, and throat; 
thyroid; lungs; cardiovascular system; abdomen (liver, spleen); extremities; genitalia, and lymph 
nodes; as well as a brief neurological examination. Fitzpatrick skin classification will be included 
as part of the physical examination at screening. 
During the study, a targeted physical examination may be conducted by the investigator or 
medically qualified designee (per institutional policies and local standard of care) to assess AEs, 
symptoms/signs, laboratory abnormalities, or other findings. Findings from the targeted physical 
exam should be reported on the AE eCRF. 
Height and body weight will be assessed at screening. 
8.3.3. 
Vital Signs 
Vital sign measurements (to be taken at each study visit and before blood collection for 
laboratory tests), include blood pressure, pulse, respiratory rate, and body temperature. Blood 
pressure and pulse will be taken with the participant in the sitting position after 5 minutes of rest. 
Abnormal vital sign results identified after the first dose of study treatment, 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. 


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8.3.4. 
Laboratory Assessments 
See Table 8 for the list of clinical laboratory tests to be performed and Table 3 for the timing and 
frequency. A central laboratory will perform clinical laboratory assessments for safety (eg, blood 
chemistries or hematology assessments), 
 
 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. Procedures conducted as part of the participant's routine 
clinical management (eg, blood counts or physical exams) and obtained before signing of the 
ICF may be used for screening or baseline purposes provided that the procedure meets the 
Protocol-defined criteria and has been performed in the timeframe of the study (ie, within 
28 days or less prior to Day 1). 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 the study 
drug should be repeated until the values return to normal or baseline or are no longer considered 
clinically significantly abnormal by the investigator or medical monitor. 
See Section 9.1 for information regarding laboratory abnormalities that should be recorded as an 
AE in the eCRF. 
Table 8: 
Schedule of Laboratory Assessments 
Chemistry 
Hematology 
Serology 
Pregnancy Testing 
Alkaline phosphatase 
ALT 
AST 
Blood urea nitrogen or 
urea 
Creatinine (and estimated 
GFR based on CKD-EPI 
equation) 
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 
Hepatitis B surface 
antigen 
HCV antibody 
HIV antibody 
HBV-DNAa 
HCV-RNAb 
Human chorionic 
gonadotropin 
(WOCBP only) 
FSH (women of 
nonchildbearing potential 
only) 
Female participants of 
childbearing potential 
only require a serum test 
at screeningc 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. 
Other: 
STD 
Bacterial vaginosis 
Note: Additional tests may be required, as agreed by investigator and sponsor, based on emerging safety data or to rule out a 
diagnosis. 
a Reflex testing if hepatitis B surface antigen is positive. 
b Reflex testing if HCV antibody is positive. 
c A negative urine pregnancy test at baseline is required prior to initiating Day 1 study cream application. 


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8.3.4.1. 
Pregnancy Testing 
A serum pregnancy test will be required for all WOCBP during screening. Urine pregnancy tests 
will be performed locally, as outlined in the SoA (see Table 3), and as medically indicated (eg, in 
case of loss of menstrual cycle or when pregnancy is suspected). 
If a urine pregnancy test is positive, the results must be confirmed with a serum pregnancy test. 
If the serum pregnancy test is negative after a urine test 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 drug and continue participation in the study. 
If a pregnancy is confirmed by a serum pregnancy test, see Section 9.8 for reporting 
requirements. 
8.3.4.2. 
Serology 
HIV and hepatitis screening assessment will be performed at the screening visit to rule out 
infection (see Table 8). Generally, virology and serology 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. 
8.3.4.3. 
Lichen Sclerosus Assessment Under Magnification 
Anogenital area affected by LS should be assessed under magnification (eg, using colposcope, 
dermatoscope, magnifying glass) for precancerous or cancerous lesion(s) per SoA; see Table 3. 
Participants, who have suspicious lesions during screening requiring immediate medical 
assessment and treatment, should not be enrolled. If a suspicious lesion is identified during the 
study, a biopsy should be performed under examination with magnification. Participants 
requiring immediate medical assessment and treatment should be discontinued from the study 
and treated appropriately. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8.5.3. 
Biopsy 
 
 
 
 
 
 
A biopsy can be performed at screening to confirm LS diagnosis if no previous biopsy was done 
to confirm the diagnosis and to rule out other diagnoses. If a biopsy is done to confirm the 
diagnosis of LS, the screening period can be extended to 6 weeks to allow for histological 
examination. (The diagnostic biopsy is evaluated locally.) 
8.6. 
Unscheduled Visits 
Unscheduled visits may occur at any time medically warranted, including when participants 
develop new areas of LS. Any assessments performed at those visits should be recorded in the 
eCRF. 
8.7. 
End of Treatment and Early Termination 
The EOT1 coincides with the Week 12 visit and the EOT2 coincides with the Week 24 visit. A 
participant that completes the Week 24/EOT2 visit will have reached the EOT with study drug. 
If a decision is made that the participant will permanently discontinue study drug prior to the 
Week 12/EOT1 or Week 24/EOT2 visit, then the ET visit will be conducted. The assessment for 
ET will be the same as Week 24 EOT2 visit. Early termination will be called ET1 and ET2 
during the DBVC and OLE periods, respectively. If the ET visit coincides with a regular study 


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visit, then the ET evaluations will supersede those of that scheduled visit, and the data should be 
entered in the ET 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. 
8.8. 
Follow-Up 
8.8.1. 
Safety Follow-Up 
The safety follow-up period is the interval between the Week 24 (EOT2) or ET visit and the 
scheduled follow-up visit, which should occur 30 days (+7 days' visit window) after the Week 24 
(EOT2) or ET visit (or 30 days after the last application of study drug if the Week 24 (EOT2) or 
ET visit was not performed). 
Adverse events and SAEs must be reported up until 1) at least 30 days after the last application 
of study drug or 2) until toxicities resolve, return to baseline, or are deemed irreversible, 
whichever is longer. Reasonable efforts should be made to have the participant return for the 
follow-up visit and report any AEs that may occur during this period. 


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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 drug. 
Additional Guidance for Events Meeting the Adverse Event Definition 
• Any safety assessments (eg, ECG or 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 drug. Whenever possible, a diagnosis (eg, anemia or thrombocytopenia) should be recorded in 
the eCRF rather than the abnormal laboratory test result (eg, low hemoglobin or 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 drug administration 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 administration errors of a study drug (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. However, the 
signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as an AE or 
SAE if they fulfill the definition of an AE or SAE. 
• A condition that leads to a medical or surgical procedure (eg, endoscopy or 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, 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, or diagnostic reports) related to the event. 
• The investigator (or delegate) 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 ID 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 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 Grades 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 drug: 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 drug 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, or unknown). 
• The seriousness, 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, or 
Non-Drug 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 drug 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 drug administration, 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 drug, 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 (either via email/fax if paper SAE form is used or in the SAE EDC CRF) 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. 
9.4. 
Reporting of Serious Adverse Events 
Regardless of suspected causality (eg, relationship to study drug or study procedure[s]), all SAEs 
occurring after the participant has signed the ICF through the last study visit or at least 30 days 
after the last application of study drug 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. 
Investigators are not obligated to actively seek SAE information after the safety follow-up visit 
or 30 days after the last dose of study drug. If the investigator learns of any SAE, including 
death, at any time during this period, and they considers the event to be reasonably related to the 
study drug or study participation, then the investigator must notify the sponsor (or designee) 
within 24 hours of becoming aware of the event. 
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 toward the safety of participants and the safety of a study 
drug under clinical investigation are met. 
If the SAE is not documented in the RSI of the IB (new occurrence) and is thought to be related 
to the study drug, 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 


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issue an Investigator Notification to inform all investigators involved in any study with the same 
drug 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 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 Event 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). 
• 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 drug 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. 
9.5. 
Potential Drug-Induce Liver Injury 
Not applicable. 
9.6. 
Events of Clinical Interest 
Not applicable. 


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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 IRT system has an 
option to select for "Emergency Code Break" action for a given participant. After entering the 
study drug 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 staff performing assessments, or a participant is unblinded, then the 
participant must discontinue study drug 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 drug 
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 
drug, the following procedures should be followed in order to ensure safety: 
• The study drug must be discontinued immediately. 
• 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 evaluation. 
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 drug 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. 
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 
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9.9. 
Warnings and Precautions 
Special warnings or precautions for the study drug, derived from safety information collected by 
the sponsor or its designee, are presented in the ruxolitinib cream 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. 
There are no study-specific warnings or precautions in this study. 
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 60 participants will be randomized 1:1 to ruxolitinib 1.5% cream BID or vehicle 
cream BID. Due to the lack of data with ruxolitinib cream in LS, the sample size was not 
calculated based on statistical power calculations, but for demonstration of preliminary findings 
of clinical response. It is anticipated that a sample size of approximately 60 participants will 
provide sufficient data to determine whether ruxolitinib 1.5% cream warrants further 
investigation in LS. Also, the sample size is considered sufficient to provide enough data for the 
evaluation of the ruxolitinib 1.5% cream safety profile in LS. 
10.2. 
Populations for Analysis 
The populations for analysis are provided in Table 9. 
Table 9: 
Populations for Analysis 
Population 
Description 
ITT 
The ITT population includes all randomized participants. 
Safety 
The safety population includes all participants who applied study drug at least 
once. Treatment groups for this population will be determined according to 
the actual treatment the participant received on Day 1. 
OLE evaluable 
All analyses for the OLE period will be conducted with the OLE evaluable 
population, which includes all participants who applied ruxolitinib 1.5% 
cream at least once during the OLE period. 
 
 
 
 
 
10.3. 
Level of Significance 
The significance level for primary efficacy analysis will be 0.05 for a two-sided test. 
10.4. 
Statistical Analyses 
The SAP will be developed and finalized before database lock and will describe the participant 
populations to be included in the analyses and procedures for accounting for missing, unused, 
and spurious data. This section is a summary of the planned statistical analyses of the primary 
and secondary endpoints. 
10.4.1. 
Primary Analysis 
The primary analysis will be based on the ITT population. The summary of primary endpoint 
analysis is provided in Table 10. 


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Table 10: 
Summary of Primary Analysis 
Parameter 
Definition 
Treatment 
Ruxolitinib 1.5% cream compared with vehicle cream 
Population  
ITT Population 
Variable 
ITCH4 response at Week 12: ≥ 4-point improvement in Itch NRS score from 
baseline to at Week 12 
Population-level 
summary 
ITCH4 response rate difference with 95% CI 
Note: Participants with missing Week 12 data, as well as all participants who discontinue study treatment at any 
time before the timepoint of interest, or discontinue from the study for any reason, will be defined as 
nonresponders. No rescue therapy or treatment switch is allowed in this study. 
The primary alternative hypothesis (superiority of ruxolitinib 1.5% cream BID compared with 
vehicle) against null hypothesis will be tested at a 2 sided α = 0.05 level using a Chi-squared test. 
The p-value and ITCH4 response rate difference with 95% CI will be provided. A Fisher's exact 
test will be performed for the comparison if either of the treatment groups has an expected cell 
count less than 5. Summary of ITCH4 rates will be reported for each treatment group. Subgroup 
analysis by baseline characteristic (eg, IGA, age) will be performed. Details will be provided in 
the SAP. 
The Itch NRS score at each visit will be determined by averaging the 7 daily Itch NRS scores 
before the corresponding visit day. If 4 or more daily scores are missing (out of the 7), the Itch 
NRS score at the visit will be set to missing. 
10.4.2. 
Secondary 
 Analyses 
All secondary 
 efficacy variables will be summarized using descriptive statistics. 
For categorical measurements, summary statistics will include sample size, frequency, and 
percentages. For continuous measurements, summary statistics will include sample size, mean, 
median, standard deviation, standard error of the mean, minimum, and maximum. Summary 
statistics for continuous measures will be provided for baseline, the actual measurements at each 
visit, and the change and percentage change from baseline at each visit, if applicable. For the 
time to achieve ITCH4, a log-rank test will be used for between -treatment group comparisons. 
The hazard ratio and its 95% CI will be estimated based on the 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). 
The Skin Pain NRS score at each visit will be determined by averaging the 7 daily Skin Pain 
NRS scores before the corresponding visit day. If 4 or more daily scores are missing (out of the 
7), the Skin Pain NRS score at the visit will be set to missing. 


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10.4.3. 
Safety Analyses 
Safety analysis in the OLE period will be conducted based on the OLE evaluable population. All 
other safety analysis will be conducted based on the safety population, unless otherwise 
specified. 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after 
first application of study drug. Analysis of AEs will be limited to TEAEs, but data listings will 
include all AEs regardless of their timing to study drug administration. 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 causal relationship to study drug will 
be considered treatment-related AEs. If the investigator does not specify the relationship of the 
AE to study drug, then the AE will be considered treatment-related. The incidence of AEs and 
treatment-related AEs will be tabulated. 
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 
There is no planned interim analysis for the study. There are 2 formal planned analyses: 
• The primary analysis will occur after the primary database lock, when all participants 
have completed the DBVC period. The sponsor will be unblinded after the primary 
database lock; however, investigators and participants will remain blinded to the 
individual study treatment assignment during DBVC period. 
• The final analysis will occur when all participants have completed or withdrawn from 
the study. 


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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. 
• Adhering to the Protocol as described in this document and agreeing 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, diary 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 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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• 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/or the Monitoring Plan. 
Quality tolerance limits will be predefined in the Quality Risk Management Plan or Integrated 
Project 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 QTLs and remedial actions taken, including reporting to IRBs/IECs and 
health authorities if applicable, will be summarized in the CSR. 
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, 


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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. 
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, 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. 


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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. 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. 
REFERENCES 
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and risk of vulvar squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 
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Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29-41. 
 
 
Clinical Trials Facilitation and Coordination Group. Recommendations related to contraception 
and pregnancy testing in clinical trials. 2020. 
Erni B, Navarini AA, Huang D, Schoetzau A, Kind A, Mueller SM. Proposition of a severity 
scale for lichen sclerosus: The "Clinical Lichen Sclerosus Score." Dermatol Ther 
2021;34:e14773. 
Farrell AM, Dean D, Millard PR, Charnock FM, Wojnarowska F. Cytokine alterations in lichen 
sclerosus: an immunohistochemical study. Br J Dermatol 2006;155:931-940. 
 
 
 
Fistarol SK, Itin PH. Diagnosis and treatment of lichen sclerosus: an update. Am J Clin Dermatol 
2013;14:27-47. 
Funaro D, Lovett A, Leroux N, Powell J. A double-blind, randomized prospective study 
evaluating topical clobetasol propionate 0.05% versus topical tacrolimus 0.1% in patients with 
vulvar lichen sclerosus. J Am Acad Dermatol 2014;71:84-91. 
Goldstein AT, Marinoff SC, Christopher K, Srodon M. Prevalence of vulvar lichen sclerosus in a 
general gynecology practice. J Reprod Med 2005;50:477-480. 
Goldstein AT, Creasey A, Pfau R, Phillips D, Burrows LJ. A double-blind, randomized 
controlled trial of clobetasol versus pimecrolimus in patients with vulvar lichen sclerosus. J Am 
Acad Dermatol 2011;64:e99-104. 
 
 
 
 
 
 


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Kimball AB, Naegeli AN, Edson-Heredia E, et al. Psychometric properties of the Itch Numeric 
Rating Scale in patients with moderate-to-severe plaque psoriasis. Br J Dermatol 
2016;175:157-162. 
Leibovitz A, Kaplun VV, Saposhnicov N, Habot B. Vulvovaginal examinations in elderly 
nursing home women residents. Arch Gerontol Geriatr 2000;31:1-4. 
Meyrick Thomas RH, Ridley CM, McGibbon DH, Black MM. Lichen sclerosus et atrophicus 
and autoimmunity--a study of 350 women. Br J Dermatol 1988;118:41-46. 
Neill SM, Lewis FM, Tatnall FM, Cox NH; British Association of Dermatologists. British 
Association of Dermatologists' guidelines for the management of lichen sclerosus 2010. Br J 
Dermatol 2010;163:672-682. 
Opzelura (ruxolitinib) [prescribing information]. Incyte Corporation; July 2022. 
Papp K, Szepietowski JC, Kircik L, et al. Efficacy and safety of ruxolitinib cream for the 
treatment of atopic dermatitis: pooled analysis of 2 Phase 3, randomized, double-blind studies. 
J Am Acad Dermatol 2021;85:863-872. 
Powell JJ, Wojnarowska F. Lichen sclerosus. Lancet 1999;353:1777-1783. 
Ruxolitinib Cream Investigator's Brochure. Wilmington, DE: Incyte Corporation. 
 
 
 
Sideri M, Origoni M, Spinaci L, Ferrari A. Topical testosterone in the treatment of vulvar lichen 
sclerosus. Int J Gynecol Obstet 1994;46:53-56. 
Silverberg JI, DeLozier A, Sun L, et al. Psychometric properties of the itch numeric rating scale, 
skin pain numeric rating scale, and atopic dermatitis sleep scale in adult patients with 
moderate-to-severe atopic dermatitis. Health Qual Life Outcomes 2021;19:247. 
 
 
Smith YR and Haefner HK, Vulvar lichen sclerosus: pathophysiology and treatment 
2004;5:105-125. 
Szabo SJ, Sullivan BM, Peng SL, Glimcher LH. Molecular mechanisms regulating Th1 immune 
responses. Annu Rev of Immunol 2003;21:713-758. 
Terlou A, Santegoets LAM, van der Meijden WI, et al. An autoimmune phenotype in vulvar 
lichen sclerosus and lichen planus: a Th1 response and high levels of microRNA-155. J Invest 
Dermatol 2012;132: 658-666. 
Thomas RH, Ridley CM, McGibbon DH, Black MM. Anogenital lichen sclerosus in women. J R 
Soc Med 1996;89:694-698. 


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Tran DA, Tan X, Macri CJ, Goldstein AT, Fu SW. Lichen sclerosus: an autoimmunopathogenic 
and genomic enigma with emerging genetic and immune targets. Int J Biol Sci 
2019;15:1429-1439. 
Vieira-Baptista P, Lima-Silva J, Cavaco-Gomes J, Beires J, Martinezde-Oliveira J. What 
differentiates symptomatic from asymptomatic women with lichen sclerosus? Gynecol Obstet 
Invest 2015;79:263-268. 
Wilkins T, Sams R, Carpenter M. Hepatitis B: screening, prevention, diagnosis, and treatment. 
Am Fam Physician 2019;99:314-323. 


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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 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 
ovulationb 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulationb 
− oral 
− injectable 
− implantablec 
• Intrauterine devicec 
• Intrauterine hormone-releasing systemc 
• Bilateral tubal occlusionc 
• Vasectomized partnerc,d 
• Sexual abstinencee 
a Documentation can come from the site personnel's review of the participant's medical records, medical examination, or medical 
history interview. 
b 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. 
c Contraception methods that in the context of this guidance are considered to have low user dependency. 
d 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. 
e 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.  
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 drug 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, 
see Table 3) may be allowed in 1 of 2 ways: 
− Use of home nursing services. 
− Instruct 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 12 visit 
During the OLE period, the following visits must be performed in person: 
• Week 24 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 drug via shipment 
to participants. 
If the participant cannot attend a visit at the study site, adequate supplies of study drug 
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, 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 site monitor will continue to employ off-site monitoring practices such as routine 
communication methods (eg, phone calls, e-mails, 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 drug 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 drug 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, couriers, etc). 
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], the 
costs of local [nearby] laboratory tests). 


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APPENDIX C. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment 1 
17 AUG 2022 
Amendment 2 
07 MAR 2023 
Amendment 3 
18 DEC 2023 
Amendment 3 (18 DEC 2023) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to add clarification regarding planned analysis on 
biopsy samples from select sites. 
1. Section 8.5.3, Biopsy 
Description of change: Added planned analysis on biopsy samples from select sites. 
Rationale for change: Clarification. 
 


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Amendment 2 (07 MAR 2023) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is 
 
to address FDA comments on the protocol. Additional changes are summarized below. 
1. Section 1, Protocol Summary (Figure 1: Study Design Schema) 
Description of change: Updated the safety follow-up period from 4 weeks to 30 days. 
Rationale for change: To be consistent with the SoA. 
2. Section 1, Protocol Summary (Table 3: Schedule of Activities); Section 5.2, 
Exclusion Criteria (Criterion 2a) 
Description of change: Clarified that if treatment is needed for vaginal infections (such 
as bacterial vaginosis), the screening window can be extended to 6 weeks. 
Rationale for change: To accommodate the treatment and washout requirements. 
3. 
 
 
 
 
 
 
 
 
4. Section 1, Protocol Summary (Table 3: Schedule of Activities); Section 8.3.4.3, 
Lichen Sclerosus Assessment Under Magnification 
Description of change: Changed the section heading and assessment from vulvoscopy 
(optional) at screening, Week 12, and Week 24 to LS assessment under magnification at 
every visit from screening to Week 24. 
Rationale for change: To address FDA comments. 
5. Section 5.1, Inclusion Criteria (Criterion 3) 
Description of change: Added a note regarding the types of LS that can be included in 
the study. 
Rationale for change: To address FDA comments. 
6. Section 5.1, Inclusion Criteria (Criterion 7a) 
Description of change: Updated to include that WOCBP must have a negative serum 
pregnancy test at screening and a negative urine pregnancy test before the first 
application on Day 1. 
Rationale for change: To be consistent with the pregnancy test requirements in the SoA.  


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7. Section 5.2, Exclusion Criteria (Criteria 3, 3i) 
Description of change: Updated exclusion criterion 3 to relocate the investigator's 
opinion of conditions into new criterion 3i as one of the listed conditions. 
Rationale for change: To allow the investigator's opinion to determine additional 
exclusions. 
8. Section 5.2, Exclusion Criteria (Criterion 3b) 
Description of change: Updated to cover current or previous malignancy within 5 years 
of study entry, except for adequately treated nonmetastatic nonmelanoma skin cancer. 
Rationale for change: To be consistent with other ruxolitinib cream study protocols. 
9. Section 10.4.2, Secondary 
 Analyses 
Description of change: Updated to include Skin Pain NRS analysis from daily diary 
data. 
Rationale for change: Not specified in Protocol Amendment 1. 
10. Appendix A, Information Regarding Effectiveness of Contraceptive Methods and 
Definitions 
Description of change: Removed the contraception requirements for male participants. 
Rationale for change: No male participant is included in the study. 
11. Incorporation of administrative changes. Other regulatory guidance and administrative 
changes have been incorporated in the Protocol and are noted in the redline version of the 
amendment. 


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Amendment 1 (17 AUG 2022) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to add BSA assessment. Additional changes are 
summarized below. 
1. Section 1, Protocol Summary (Table 3: Schedule of Assessment); Section 8.2.5, Body 
Surface Area 
Description of change: BSA was added as a new line item under Efficacy Assessments, 
along with a description of the assessment criteria. 
Rationale for change: BSA assessment is required for assessment of eligibility, trial 
continuation, and drug dispense. 
2. Section 1, Protocol Summary (Table 3: Schedule of Assessment); Section 5.1, 
Inclusion Criteria (Criteria 3 and 4); Section 5.2, Exclusion Criteria (Criterion 1); 
Section 6.1, Study Treatments Administered; Section 8.5.3, Biopsy 
Description of change: Added specification that biopsy will be taken from the 
anogenital area. Additionally, specified the exclusion of participants who do not have LS 
involving the anogenital area, and clarified text to specify the application of cream to 
nonanogenital versus anogenital BSA. 
Rationale for change: Original Protocol was not clear on location of biopsy samples; 
exclusion of participants; and specification of cream application. 
3. Section 1, Protocol Summary (Table 3: Schedule of Assessment); Section 7.1.2, 
Discontinuation Procedures; Section 8.3.2, Physical Examinations; Section 8.7, End 
of Treatment and Early Termination 
Description of change: Clarified the procedure for ET assessment, which will be the 
same as the Week 24 visit; clearly identified early termination periods for DBVC as ET1 
and OLE as ET2. 
Rationale for change: Original Protocol was not clear on ET1 and ET2. 
4. Section 6.3, Measures to Minimize Bias: Randomization and Blinding; Section 
10.4.2, Secondary 
 Analyses 
Description of change: Stratification by baseline 
 score was removed. 
Rationale for change: Stratification is not included in the study due to the limited 
sample size. 
5. 
 
 
 
 


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6. Incorporation of administrative changes. Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 


Signature Page for VV-CLIN-019820 v6.0
Signature Page for VV-CLIN-019820 v6.0
Approval Task
Approval Task
Approval Task
Approval Task
Approval Task
Approver

SAP_001.pdf: 
Official Title:    A Phase 2, Randomized, Double-Blind, Vehicle-Controlled, Study 
of the Efficacy and Safety of Ruxolitinib Cream in Participants With 
Lichen Sclerosus
NCT Number: NCT05593445 
Document Date: Statistical Analysis Plan (Original Version): 24-August-2023


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Statistical Analysis Plan 
TITLE PAGE 
INCB 18424-220 
A Phase 2, Randomized, Double-Blind, Vehicle-Controlled, Study of the 
Efficacy and Safety of Ruxolitinib Cream in Participants With Lichen 
Sclerosus 
IND Number: 
77,101 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
United States 
Protocol Version: 
Protocol Amendment 2 dated 07 MAR 2023 
CRF Approval Date: 
02 JUN 2023 
SAP Version: 
Original 
SAP Author: 
, PhD 
 
Date of Plan: 
24 AUG 2023 
This study is being conducted in compliance with Good Clinical Practice, 
including the archiving of essential documents. 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1. 
INTRODUCTION ........................................................................................................6 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS.................................7 
2.1. 
Protocol and Case Report Form Version ......................................................................7 
2.2. 
Study Objectives and Endpoints ...................................................................................7 
3. 
STUDY DESIGN .........................................................................................................9 
3.1. 
Randomization ..............................................................................................................9 
3.2. 
Control of Type I Error .................................................................................................9 
3.3. 
Sample Size Considerations .......................................................................................10 
3.4. 
Schedule of Assessments ............................................................................................10 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS ..................................11 
4.1. 
Scheduled Study Evaluations and Study Periods .......................................................11 
4.1.1. 
Day 1 ...........................................................................................................................11 
4.1.2. 
Study Day ...................................................................................................................11 
4.1.3. 
Baseline Value ............................................................................................................11 
4.1.4. 
Handling of Missing and Incomplete Dates ...............................................................12 
4.2. 
Variable Definitions ....................................................................................................12 
4.2.1. 
Body Mass Index ........................................................................................................12 
4.2.2. 
Prior and Concomitant Medication .............................................................................12 
5. 
STATISTICAL METHODOLOGY ...........................................................................13 
5.1. 
General Methodology .................................................................................................13 
5.2. 
Treatment Groups .......................................................................................................13 
5.3. 
Analysis Populations ..................................................................................................13 
5.3.1. 
Intent-to-Treat Population ..........................................................................................13 
5.3.2. 
Safety Population ........................................................................................................13 
5.3.3. 
Open-Label Extension Evaluable Population .............................................................13 
 
14 
6. 
BASELINE, EXPOSURE, AND DISPOSITION ......................................................14 
6.1. 
Demographics, Baseline Characteristics, and Disease History ..................................14 


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6.1.1. 
Demographics and Baseline Characteristics ...............................................................14 
6.1.2. 
Baseline Disease Characteristics ................................................................................14 
6.1.3. 
Disease History ...........................................................................................................15 
6.1.4. 
Medical History ..........................................................................................................15 
6.2. 
Disposition of Participant ...........................................................................................15 
6.3. 
Protocol Deviations ....................................................................................................15 
6.4. 
Exposure .....................................................................................................................15 
6.5. 
Study Drug Compliance .............................................................................................16 
6.6. 
Prior and Concomitant Medication .............................................................................16 
7. 
EFFICACY .................................................................................................................17 
7.1. 
Efficacy Hypotheses ...................................................................................................17 
7.2. 
Efficacy Measures ......................................................................................................17 
 
17 
7.2.2. 
Clinical Lichen Sclerosus Score .................................................................................17 
 
17 
7.2.4. 
Body Surface Area ......................................................................................................18 
7.2.5. 
Patient-Reported Outcomes ........................................................................................18 
7.2.5.1. 
Itch Numerical Rating Scale .......................................................................................18 
7.2.5.2. 
Skin Pain Numerical Rating Scale ..............................................................................19 
 
19 
 
20 
 
20 
 
20 
 
21 
7.3. 
Analysis of the Primary Efficacy Parameter ..............................................................21 
7.3.1. 
Primary Efficacy Analysis ..........................................................................................21 
7.3.2. 
Subgroup Analyses for Primary Endpoint ..................................................................21 
7.4. 
Analysis of the Secondary Efficacy Parameters .........................................................22 
7.4.1. 
Continuous Efficacy Endpoints ..................................................................................22 
7.4.2. 
Time-To-Event Efficacy Endpoint .............................................................................22 
 
22 
 
24 
 
24 


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24 
9. 
SAFETY AND TOLERABILITY ..............................................................................25 
9.1. 
General Considerations ...............................................................................................25 
9.2. 
Adverse Events ...........................................................................................................25 
9.2.1. 
Adverse Event Definitions ..........................................................................................25 
9.2.2. 
Adverse Event Summaries ..........................................................................................26 
9.3. 
Clinical Laboratory Tests ...........................................................................................27 
9.3.1. 
Laboratory Value Definitions .....................................................................................27 
9.3.2. 
Laboratory Value Summaries .....................................................................................27 
9.4. 
Vital Signs ..................................................................................................................28 
10. 
PLANNED ANALYSES ............................................................................................29 
11. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN ........................29 
11.1. 
Changes to Protocol-Defined Analyses ......................................................................29 
11.2. 
Changes to the Statistical Analysis Plan .....................................................................29 
12. 
REFERENCES ...........................................................................................................30 
APPENDIX A. PLANNED TABLES, FIGURES, AND LISTINGS ........................................32 
 
LIST OF TABLES 
Table 1: 
Objectives and Endpoints .............................................................................................7 
Table 2: 
Criteria for Clinically Notable Vital Sign Abnormalities ...........................................28 
Table 3: 
Statistical Analysis Plan Versions ..............................................................................29 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema ...................................................................................................9 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
BID 
twice daily/2 times a day 
BMI 
body mass index 
BSA 
body surface area 
CI 
confidence interval 
CLISSCO 
Clinical Lichen Sclerosus Score 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBVC 
double-blind, vehicle-controlled 
 
 
eCRF 
electronic case report form 
 
 
 
 
 
 
 
 
 
ITCH4 
≥ 4-point improvement in WI-NRS score 
ITT 
intent-to-treat 
LS 
lichen sclerosus 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures 
NCI 
National Cancer Institute 
NRS 
numeric rating scale 
OLE 
open-label extension 
 
 
 
 
PT 
preferred term 
SAP 
Statistical Analysis Plan 
SI 
International System of Units 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
 
 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
INCB 18424-220 is a Phase 2, randomized, DBVC study to evaluate the efficacy and safety of 
ruxolitinib 1.5% cream in participants with LS over a 12-week treatment period followed by a 
12-week OLE period during which all participants receive active treatment. A 30-day 
post-treatment safety follow-up visit will be conducted after the OLE period. 
The purpose of this SAP is to provide details of the statistical analyses that have been outlined in 
the INCB 18424-220 Protocol. 


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2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS 
2.1. 
Protocol and Case Report Form Version 
This SAP is based on INCB 18424-220 Protocol Amendment 2 dated 07 MAR 2023 and CRFs 
approved 02 JUN 2023. Unless superseded by an amendment, this SAP will be effective for all 
subsequent Protocol amendments and eCRF versions. 
2.2. 
Study Objectives and Endpoints 
Table 1 presents the objectives and endpoints. 
Table 1: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To establish the efficacy of ruxolitinib 1.5% cream 
BID in participants with LS. 
• ITCH4 response (defined as a ≥ 4-point 
improvement in Itch NRS score from baseline) at 
Week 12. 
(Proportion of participants with ITCH4 at Week 12.) 
Secondary 
To further evaluate efficacy of ruxolitinib 1.5% cream 
BID in participants with LS. 
• Change from baseline in CLISSCO score at 
Week 12. 
• Change from baseline in the Skin Pain NRS score at 
Week 12. 
• Time to achieve ITCH4. 
To evaluate the safety and tolerability of 
ruxolitinib 1.5% cream BID. 
• The type, frequency, and severity of AEs, including 
the changes in vital signs and clinical laboratory 
blood samples. 


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Table 1: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 


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3. 
STUDY DESIGN 
This is a Phase 2, randomized, DBVC study in participants aged ≥ 18 years with a 
biopsy-confirmed diagnosis of LS. The study will consist of a 12-week DBVC period followed 
by a 12-week OLE period. 
Approximately 60 female participants will be randomized 1:1 to either 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 the affected areas identified at baseline. 
At Week 12, participants who meet the criteria (compliant with the Protocol and without safety 
concerns) will enter the 12-week OLE period. Participants randomized initially to vehicle in the 
DBVC period will be crossed over to ruxolitinib 1.5% cream and participants randomized to 
ruxolitinib 1.5% cream at baseline will continue to apply ruxolitinib 1.5% cream through 
Week 24 in an open-label fashion. During the OLE period, participants who have no symptoms 
or signs of active LS (based on investigator's assessment) will apply ruxolitinib 1.5% cream once 
daily through Week 24. Ruxolitinib dose can be increased to BID for those participants who have 
symptoms or signs of active disease (based on investigator's assessment) until symptoms and 
signs of active LS have resolved in the opinion of the investigator.  
The study schema is shown below in Figure 1. 
Figure 1: 
Study Design Schema 
 
The primary analysis will occur after the primary database lock, when all participants have 
completed the DBVC period. The final analysis will occur when all participants have completed 
or withdrawn from the study. 
3.1. 
Randomization 
Approximately 60 participants will be randomized 1:1 to either ruxolitinib 1.5% cream or vehicle 
cream BID. 
3.2. 
Control of Type I Error 
The significance level for primary efficacy analysis will be 0.05 for a 2-sided test.  


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3.3. 
Sample Size Considerations 
Approximately 60 participants will be randomized 1:1 to ruxolitinib 1.5% cream BID or vehicle 
cream BID. Due to the lack of data with ruxolitinib cream in LS, the sample size was not 
calculated based on statistical power calculations, but for demonstration of preliminary findings 
of clinical response. It is anticipated that a sample size of approximately 60 participants will 
provide sufficient data to determine whether ruxolitinib 1.5% cream warrants further 
investigation in LS. Also, the sample size is considered sufficient to provide enough data for the 
evaluation of the ruxolitinib 1.5% cream safety profile in LS. 
3.4. 
Schedule of Assessments 
Refer to Protocol Amendment 2 dated 07 MAR 2023for a full description of all study procedures 
and assessment schedules for this study. 


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4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS 
4.1. 
Scheduled Study Evaluations and Study Periods 
4.1.1. 
Day 1 
Day 1 is the date that the first application of ruxolitinib cream or vehicle cream is administered 
to the participants in the specific period. 
For randomized participants not treated with any study drug, Day 1 is defined as the date of 
randomization. 
4.1.2. 
Study Day 
If a visit/reporting date is on or after Day 1, then the study day at the visit/reporting date will be 
calculated as 
Day # = (visit/reporting date – Day 1 date + 1). 
If the visit/reporting date is before Day 1, then the study day at the visit/reporting date will be 
calculated as 
Day # = (visit/reporting date – Day 1 date). 
A study day of –1 indicates 1 day before Day 1. 
4.1.3. 
Baseline Value 
Baseline is the last nonmissing measurement obtained before or on the day of the first 
application of ruxolitinib cream or vehicle cream for the DBVC period.  
For randomized participants not treated with any study treatment, baseline is defined as the last 
nonmissing assessment before or on the date of randomization. 
For participants who continue in the OLE period, baseline is defined as follows: 
• For efficacy evaluation in the OLE period, baseline is the last nonmissing 
measurement obtained before or on the day of first application of study treatment in 
the DBVC period. 
• For safety evaluation in the OLE period, baseline is the last nonmissing measurement 
obtained before or on the day of first application of ruxolitinib 1.5% cream in the 
study. 
When a scheduled assessment and an unscheduled assessment occur on the same day and the 
times of the assessments are not available, use the following convention to determine baseline: 
• If both a scheduled and an unscheduled visit are available on the day of the first 
application and the time is missing, use the scheduled assessment as baseline. 
• If the scheduled assessment is missing on the day of the first application and an 
unscheduled assessment is available, use the unscheduled assessment as baseline. 


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4.1.4. 
Handling of Missing and Incomplete Dates 
In general, values for missing dates will not be handled unless methods for handling missing 
dates are specified in this section or relevant sections. The original reported dates collected on 
the eCRF should be used in all relevant listings. The following rules will be used for handling 
partial dates for analyses requiring dates. 
Partial LS diagnosis date will be handled as follows in the calculation: 
• If only the day is missing, then the fifteenth of the month will be used. 
• If both the month and day are missing, then 01 JUL of the year will be used. 
• If the diagnosis date is completely missing, then the time since diagnosis will not be 
calculated. 
4.2. 
Variable Definitions 
4.2.1. 
Body Mass Index 
Body mass index will be calculated as follows: 
BMI (kg/m2) = [weight (kg)] / [height (m)]2 
4.2.2. 
Prior and Concomitant Medication 
Prior medication is defined as any nonstudy medication started before the first application of 
ruxolitinib 1.5% cream or vehicle cream. 
Concomitant medication is defined as any nonstudy medication that is started accordingly: 
• Before the date of first application of ruxolitinib 1.5% cream or vehicle cream and is 
ongoing throughout the study or ends on/after the date of first study drug application. 
• On/after the date of first application of ruxolitinib 1.5% cream or vehicle cream and is 
ongoing or ends during the course of study. 
A prior medication could also be classified as "both prior and concomitant medication" if the end 
date is on or after first application of ruxolitinib 1.5% cream or vehicle cream. In the listing, it 
will be indicated whether a medication is only prior, only concomitant, or both prior and 
concomitant. 
For the purposes of analysis, all medications will be considered concomitant medications unless 
the medications can unequivocally be defined as not concomitant.  


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5. 
STATISTICAL METHODOLOGY 
5.1. 
General Methodology 
Unless otherwise noted, SAS® software (SAS Institute Inc, Cary, NC; v9.4 or later) will be used 
for the generation of all tables, graphs, and statistical analyses. Descriptive summaries for 
continuous variables will include, but not be limited to the number of observations, mean, 
standard deviation, median, minimum, and maximum. Descriptive summaries for categorical 
variables will include the number and percentage of participants in each category. 
5.2. 
Treatment Groups 
This is a randomized, DBVC study with an open-label extension period. Table summaries, unless 
otherwise indicated, will present data by treatment group. 
For the DBVC period, the treatment groups will be vehicle cream and ruxolitinib 1.5% cream 
BID. 
For the OLE period, the participants will be grouped into the following groups according to the 
treatment group they received during the DBVC period: 
• Vehicle cream to ruxolitinib 1.5% cream 
• Ruxolitinib 1.5% cream 
5.3. 
Analysis Populations 
5.3.1. 
Intent-to-Treat Population 
All participants who are randomized will constitute the ITT population. Treatment groups for 
this population will be defined according to the treatment assignment at the time of 
randomization regardless of the actual study drug the participant might take during their 
participation in the DBVC period. 
The ITT population will be used for the summary of demographics, baseline characteristics, 
participant disposition, and analyses of all efficacy data. 
5.3.2. 
Safety Population 
The safety population will include all participants who applied ruxolitinib 1.5% cream or vehicle 
cream at least once. Treatment groups for this population will be determined according to the 
actual treatment the participant applied on Day 1 regardless of assigned treatment group. 
All safety analyses will be conducted using the safety population. 
5.3.3. 
Open-Label Extension Evaluable Population 
All analyses for the OLE period will be conducted with the OLE evaluable population, which 
includes all participants who applied ruxolitinib 1.5% cream at least once during the OLE period. 


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6. 
BASELINE, EXPOSURE, AND DISPOSITION 
Appendix A provides a list of planned tables, figures, and listings. Sample data displays are 
included in a separate document. 
6.1. 
Demographics, Baseline Characteristics, and Disease History 
6.1.1. 
Demographics and Baseline Characteristics 
The following demographics and baseline characteristics will be summarized by treatment group 
and overall for the ITT population in the DBVC period and for the OLE evaluable population in 
the OLE period: age, sex, race, ethnicity, weight, height, and BMI. 
6.1.2. 
Baseline Disease Characteristics  
For the ITT and OLE population, the baseline disease characteristics will be summarized by 
treatment group and will include, but not limited to the following:  
• Disease duration (years) 
• LS diagnosis confirmed by biopsy (yes/no) 
• Anatomic location (vulva/vagina, other anogenital area, other body areas) 
• Complications with LS (yes/no) 
• Number of flares/episodes of LS in the past year other than current flare 
• Clinical manifestations related to LS (% participants with each of the manifestations) 
• Prior treatment received for LS (yes/no) 
• History of other skin disease (yes/no) 
• Family history of LS (yes/no) 
• History of skin infection related to LS requiring antibiotic treatment (yes/no) 
• Days since onset of current episode of LS flare/activity 
• Skin type (Type I/II/III/IV/V/VI) 
• Total % BSA affected 
• Baseline Itch NRS score 
• Baseline total CLISSCO 
• Baseline CLISSCO subscores (total score for each section) 


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• Baseline Skin Pain NRS 
• Baseline total LSCA score 
• Baseline IGA score 
6.1.3. 
Disease History 
The time since disease duration will be summarized for all participants in the ITT population. 
Time since diagnosis (ie, disease duration [years]) will be calculated as follows:  
Disease duration (years) = (date of randomization – date of initial LS diagnosis +1) / 
365.25 
6.1.4. 
Medical History 
For participants in the ITT population during the DBVC period, medical history will be 
summarized by assigned treatment groups. This summary will include the number and 
percentage of participants with medical history for each body system/organ class as documented 
on the eCRF. 
6.2. 
Disposition of Participant 
The number and percentage of participants who were randomized, treated, and completed the 
DBVC period, as well as the number and percentage of participants who discontinued the 
treatment or withdrew from the study during the DBVC period with a primary reason for 
discontinuation, will be summarized as part of the ITT population. 
The number and percentage of participants who completed the OLE period, in addition to those 
participants who discontinued treatment or withdrew from the study during the OLE period with 
a primary reason for discontinuation, will be summarized as part of the OLE evaluable 
population. 
6.3. 
Protocol Deviations 
Protocol deviations will be summarized and listed by treatment group and overall ITT and 
OLE populations. 
6.4. 
Exposure 
For participants in the safety population in the DBVC period, the OLE evaluable population in 
the OLE period, and those who applied ruxolitinib 1.5% cream BID throughout the study, study 
drug exposure will be summarized by treatment group, descriptively, as follows: 
• Duration of treatment (days): 
Date of last application of ruxolitinib cream or vehicle cream in the specific period –  
date of first application of ruxolitinib cream or vehicle cream in the specific period + 1 


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• Total amount of cream applied (g): 
Total weight of ruxolitinib cream or vehicle cream dispensed in the specific period –  
total weight of ruxolitinib cream or vehicle cream returned in the specific period 
• Average daily application: 
Total amount of cream applied in the specific period (g) / [duration of treatment with 
study cream in the specific period (days) – number of interrupted days with study cream 
in the specific period] 
6.5. 
Study Drug Compliance 
The overall compliance (%) for the application of ruxolitinib 1.5% cream BID or vehicle cream 
BID during the DBVC period will be calculated for all participants in the safety population as 
follows: 
Cream application compliance (%) = 100 × [total number of nonmissing applications] /  
[total number of intended applications], where  
Total number of nonmissing applications = number of applications that the participants 
actually applied during the study, and  
Total number of intended applications = 2 × duration of treatment (days) –  
number of interrupted applications. 
6.6. 
Prior and Concomitant Medication 
Prior medications and concomitant medications will be coded using the WHO Drug Dictionary. 
The number and percentage of participants with prior and concomitant medication will be 
summarized by treatment group, as well as overall for the ITT population during the 
DBVC period, by WHO drug class and WHO drug preferred term. For the OLE period, only 
concomitant medications will be summarized based on OLE evaluable population. 


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7. 
EFFICACY 
Appendix A provides a list of data displays. Sample data displays are included in a separate 
document. 
7.1. 
Efficacy Hypotheses 
The primary hypothesis is the superiority of ruxolitinib 1.5% cream BID compared with vehicle 
cream BID in the proportions of participants achieving ITCH4 at Week 12. 
7.2. 
Efficacy Measures 
 
 
 
 
 
 
 
 
 
 
7.2.2. 
Clinical Lichen Sclerosus Score 
The CLISSCO is a validated tool to assess disease severity in vulvar LS. Clinical Lichen 
Sclerosus Score consists of 12 items divided into 3 sections: symptoms (3 items; likely reversible 
[ie, itch, pain, dysuria]); signs (3 items; possibly reversible [ie, whitening, petechiae/ecchymosis, 
fissures]); and architectural changes (6 items; irreversible [ie, skin fusion, perianal involvement, 
etc]). All symptoms, signs, and architectural changes will be rated on a 4-point Likert scale: 
0 (absent), 1 (mild), 2 (moderate), and 3 (severe) (Erni et al 2021). The investigator will be asked 
to document the score of each of the 12 items; the CLISSCO will be calculated by summing the 
score of each question with a maximum score of 36 and a minimum score of 0. The higher the 
score, the more severe the disease. Additionally, the total score for each of the 3 sections 
(ie, symptoms, signs, and architectural changes) will be summarized by summing the scores of 
the questions in each section. No imputation will be performed for missing values. 
 
  
 
 
 
 
 
 
 
 
 
 


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7.2.4. 
Body Surface Area 
Total % BSA affected will be estimated at each visit. 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) as 
1% BSA and the thumb as 0.1% BSA. 
7.2.5. 
Patient-Reported Outcomes 
Patient-reported outcomes will be collected and assessed. 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. 
7.2.5.1. 
Itch Numerical Rating Scale  
The Itch NRS is a daily participant-reported measure (24-hour recall) of the worst level of itch 
intensity (Kimball et al 2016, Silverberg et al 2021). Participants will be instructed to complete 
and record their Itch NRS in a diary each evening beginning on the day of screening through 
Week 24 or treatment discontinuation. Participants will rate itch severity of their LS by selecting 
a number from 0 (no itch) to 10 (worst imaginable itch) that best describes the worst level of itch 
they experienced in the past 24 hours. 
The participant's baseline Itch NRS score will be determined by averaging the 7 daily 
NRS scores before Day 1 (ie, Days –7 to –1) for all the by-visit summaries. The by-visit 
Itch 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 (out of the 7) are missing, the by-visit Itch 
NRS score will be set to missing. For all daily itch-related analyses, including time to achieve 
Itch NRS score improvement of at least 4 points analysis, baseline will be defined as the last 
available Itch NRS score during the week prior to Day 1 (ie, Days −7 to −1). Nonresponder 
imputation will be used to handle missing postbaseline values in the DBVC period. 
A participant is said to have an ITCH4 response if they achieved a ≥ 4-point improvement in 
Itch NRS score from baseline. For determining ITCH4 response at a visit, the by-visit 
Itch NRS score will be compared with the baseline Itch NRS score. For the endpoint time to 
achieve ITCH4, the daily Itch NRS score will be compared with the baseline Itch NRS score. 


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7.2.5.2. 
Skin Pain Numerical Rating Scale 
Participants will be instructed to complete and record the Skin Pain NRS in a diary each evening 
beginning on the day of screening through Week 24 or treatment discontinuation. Participants 
will rate their pain, which will include all types of pain (eg, burning, tearing, pulling, stabbing, 
etc) severity of the LS by selecting a number from 0 (no pain) to 10 (worst imaginable pain) that 
best describes the worst level of pain they experienced in the past 24 hours. 
The participant's baseline Skin Pain NRS score will be determined by averaging the 7 daily 
NRS scores before Day 1 (ie, Days –7 to –1) for all the by-visit summaries. The by-visit 
Skin Pain 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 (out of the 7) are missing, the 
Skin Pain NRS score at the visit will be set to missing. For all daily skin pain-related analyses, 
baseline will be defined as the last available Skin Pain NRS score during the week prior to Day 1 
(ie, Days −7 to −1). No imputation will be performed for missing values. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.3. 
Analysis of the Primary Efficacy Parameter 
7.3.1. 
Primary Efficacy Analysis 
The primary efficacy analysis will be based on the ITT population. The primary efficacy 
endpoint is the ITCH4 response, defined as a ≥ 4-point improvement in Itch NRS score from 
baseline, at Week 12. The comparison of the proportions of participants with ITCH4 at Week 12 
will be made between the ruxolitinib 1.5% cream BID arm and the vehicle cream BID arm. The 
primary hypothesis (the superiority of ruxolitinib 1.5% cream BID compared with vehicle cream 
in participants with LS) will be tested using a Chi-squared test at a 2-sided 𝛼= 0.05 level; the 
p-value will be provided. The Wald 95% CI will be provided for the ITCH4 response rate. A 
Fisher's exact test will be performed for the comparison if either of the treatment groups has an 
expected cell count less than 5. Summary of ITCH4 rates will be reported for each treatment 
group. 
All nonresponders in the DBVC period, as well as all participants who are missing Week 12 
values, will be defined as nonresponders for the primary analysis. 
7.3.2. 
Subgroup Analyses for Primary Endpoint 
Subgroups will be formed based on the following participant characteristics and baseline 
variables for those participants whose data are available: 
• Baseline Itch NRS score: ≥ 4 and < 7 versus ≥ 7 
• Baseline IGA score: 2, mild; 3, moderate; and 4, severe 
• Baseline categorical age: ≥ 18 and < 65 versus ≥ 65 
• Baseline duration of disease: ≤ 1, > 1 and ≤ 5, >5 
• Childbearing potential: pre versus postmenopausal status 
The primary efficacy endpoint will be summarized using descriptive statistics based on the 
ITT population for the above defined subgroups. 


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7.4. 
Analysis of the Secondary Efficacy Parameters 
All secondary efficacy analyses will be conducted for the ITT population. 
7.4.1. 
Continuous Efficacy Endpoints 
Summary statistics for the following continuous measurements, including change and percentage 
change from baseline, if applicable, will be presented for each treatment arm: 
• CLISSCO (total and subscores) at Week 12 
• Skin Pain by-visit NRS score at Week 12 
The summary statistics includes sample size, mean, median, standard deviation, minimum, 
maximum, first quartile, third quartile, and 95% CI. An MMRM may be fit for the comparison 
between ruxolitinib 1.5% cream BID and vehicle cream BID at Week 12. The MMRM will 
include the fixed effect of treatment, visit, and treatment by visit interaction. The 
variance-covariance matrix of the within-participant errors in MMRM will be modeled as 
unstructured. 
7.4.2. 
Time-To-Event Efficacy Endpoint 
The time to achieve Itch NRS score improvement of at least 4 points from baseline (ie, ITCH4) 
will use the daily Itch NRS score in comparison to baseline Itch NRS score in the DBVC period. 
A log-rank test will be used for between-treatment group comparisons. The hazard ratio and its 
95% CI will be estimated based on the 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). 
The last available value for time to ITCH4 during the DBVC period is the last nonmissing 
measurement obtained after the first application of study cream and within 30 days after the last 
application of study cream in DBVC period, or before the first application of study cream in the 
OLE period, whichever is earlier. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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9. 
SAFETY AND TOLERABILITY 
Appendix A provides a list of data displays. 
9.1. 
General Considerations 
The analyses in this section will be provided for the safety population in the DBVC period and 
OLE evaluable population in the OLE period, unless otherwise specified. Summary tables may 
be replaced with listings when appropriate. For instance, an AE frequency table may be replaced 
with a listing if it only contains a few unique preferred terms reported on relatively few 
participants. 
9.2. 
Adverse Events 
9.2.1. 
Adverse Event Definitions 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after 
first application of study drug until 30 days of the last application of study drug. For participants 
who cross over treatments, the first application date is period-specific; however, the end date is 
30 days after the last application date in this period, or the first application date in the next 
period, whichever comes first. Analysis of AEs (as discussed below) will be limited to TEAEs, 
but data listings will include all AEs regardless of their timing in relation to study drug 
application. For purposes of analysis, all AEs will be considered TEAEs unless the AE can 
unequivocally be defined as not treatment-emergent. 
Adverse events will be tabulated by MedDRA PT and SOC. Severity of AEs will be graded 
using the NCI CTCAE v5. The CTCAE reporting guidelines and grading details are available on 
the Cancer Therapy Evaluation Program website. 
The subset of AEs considered by the investigator to be related to study drug will be considered to 
be treatment-related AEs. If the investigator does not specify the relationship of the AE to study 
drug, the AE will be considered to be treatment-related. The incidence of AEs and 
treatment-related AEs will be tabulated. In addition, serious TEAEs will also be tabulated. 
Any missing onset date, causality, or severity must be queried for resolution. Unresolved missing 
causality and severity will be handled according to the following rules: 
• An unresolved missing causality will be considered treatment-related. 
• An unresolved missing severity will be identified as an unknown severity. 
Any missing onset date of a TEAE will be handled according the following rules: 
• If completely missing, then Day 1 will be used. 
• If only the day is missing, then the first day of the month or Day 1, whichever is later, 
will be used. 
• If both the month and day are missing, then 01 JAN of the year or Day 1, whichever 
is later, will be used. 
For purposes of analysis, all AEs will be considered TEAEs unless the AE can unequivocally be 
defined as not treatment-emergent. 


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9.2.2. 
Adverse Event Summaries 
An overall summary of AEs by treatment group will include the following: 
• Number (%) of participants reporting any TEAEs 
• Number (%) of participants reporting any serious TEAEs 
• Number (%) of participants reporting any Grade 3 or higher TEAEs 
• Number (%) of participants reporting any treatment-related TEAEs  
• Number (%) of participants who temporarily interrupted study treatment because 
of TEAEs 
• Number (%) of participants who permanently discontinued study treatment because 
of TEAEs 
• Number (%) of participants who had any fatal TEAEs 
The following summaries will be produced by MedDRA term (if 2 or fewer participants appear 
in a table, a listing may be appropriate): 
• Summary of TEAEs by MedDRA SOC and PT 
• Summary of TEAEs by MedDRA PT in decreasing order of frequency 
• Summary of TEAEs by MedDRA SOC, PT, and maximum severity 
• Summary of TEAEs by MedDRA SOC, PT, and CTCAE grade category 
• Summary of Grade 3 or higher TEAEs by MedDRA SOC and PT 
• Summary of Grade 3 or higher TEAEs by MedDRA PT in decreasing order 
of frequency 
• Summary of serious TEAEs by MedDRA SOC and PT 
• Summary of serious TEAEs by MedDRA PT in decreasing order of frequency 
• Summary of treatment-related TEAEs by MedDRA SOC and PT 
• Summary of treatment-related TEAEs by MedDRA PT in decreasing order 
of frequency 
• Summary of Grade 3 or higher treatment-related TEAEs by MedDRA SOC and PT 
• Summary of treatment-related serious TEAEs by MedDRA SOC and PT 
• Summary of TEAEs with a fatal outcome by MedDRA SOC and PT 
• Summary of TEAEs leading to dose interruption by MedDRA SOC and PT 
• Summary of TEAEs leading to discontinuation of study drug by MedDRA SOC 
and PT 
• Summary of Application Site Reactions by MedDRA PT in decreasing order 
of frequency 


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9.3. 
Clinical Laboratory Tests 
9.3.1. 
Laboratory Value Definitions 
All laboratory assessments will be performed using a central laboratory with the exception of 
urine pregnancy tests. Laboratory values and change from baseline values will be summarized 
descriptively by visit; non-numeric test values will be tabulated when necessary. Baseline will be 
determined according to Section 4.1.3, using the last nonmissing value collected before the first 
application, prioritizing scheduled assessments for baseline identification over unscheduled 
visits. The last record before application in the highest priority will be considered the baseline 
record. For baseline laboratory candidates with the same date and time in the same priority 
category, additional rules may be provided after consultation with the medical monitor to 
delineate which value will be defined as baseline. 
9.3.2. 
Laboratory Value Summaries 
Clinical laboratory tests, including hematology and serum chemistry, will be performed at the 
Protocol-specified visits. If specific safety issues arise, additional unscheduled laboratory 
tests/analyses may be performed at the discretion of the investigator. 
All test results and associated normal ranges from central laboratories will be reported in 
SI units. All tests with numeric values will have a unique unit per test. Any laboratory test results 
and associated normal ranges from local laboratories will be converted to SI units. 
When there are multiple laboratory nonmissing values for a participant's particular test at a 
scheduled visit, central laboratory values have higher priority over local laboratory values. If a 
tie still exists, the laboratory value with the smallest laboratory sequence number will be used in 
by-visit summaries. 
For test results that will be summarized with available normal ranges, the number and percentage 
of participants with the laboratory values being low (but never high), normal, high (but never 
low), and both low and high will be calculated for each test. A shift summary will be produced 
for each test. The denominator for the percentage calculation will use the number of participants 
in the baseline category (ie, low, high, normal, or missing) as the denominator for the percentage 
in each of the categories during the study. 
Severity grades will be assigned to laboratory test values based on the numerical component of 
CTCAE v5. Shift tables will also be presented showing change in CTCAE grade from baseline to 
the worst grade postbaseline. Separate summaries for abnormally high and abnormally low 
laboratory values will be provided when the laboratory parameter has both high and low grading 
criteria. The denominator for the percentage calculation will be the number of participants in the 
baseline category. The number of participants who experienced worsening of laboratory 
abnormalities will be summarized by maximum severity. 


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9.4. 
Vital Signs 
Values at each scheduled visit, change, and percentage change from baseline for vital signs, 
including systolic blood pressure, diastolic blood pressure, pulse, temperature, and respiratory 
rate will be summarized descriptively. 
Normal ranges for vital sign values are defined in Table 2. For participants exhibiting vital sign 
abnormalities, the abnormal values will be listed along with their assigned treatment group. Alert 
vital signs are defined as an absolute value outside the defined normal range and percentage 
change greater than 25%. The abnormal values for participants exhibiting alert vital sign 
abnormalities will be listed. 
Table 2: 
Criteria for Clinically Notable Vital Sign Abnormalities  
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 155 mmHg 
< 85 mmHg 
Diastolic blood pressure 
> 100 mmHg 
< 40 mmHg 
Pulse 
> 100 bpm 
< 45 bpm 
Temperature 
> 38ºC 
< 35.5ºC 
Respiratory rate 
> 20 breaths/min 
< 8 breaths/min 


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10. 
PLANNED ANALYSES 
No formal interim analysis is planned in this study. 
There are 2 formal planned analyses: 
• The primary analysis will occur after the primary database lock, when all participants 
have completed the DBVC period. The sponsor will be unblinded after the primary 
database lock; however, investigators and participants will remain blinded to the 
individual study treatment assignment after the primary database lock. 
• The final analysis will occur when all participants have completed or withdrawn from 
the study. 
11. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN 
All versions of the SAP are listed in Table 3. 
Table 3: 
Statistical Analysis Plan Versions 
SAP Version 
Date 
Original 
24 AUG 2023 
11.1. 
Changes to Protocol-Defined Analyses 
Not applicable. 
11.2. 
Changes to the Statistical Analysis Plan 
Not applicable. 


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12. 
REFERENCES 
 
 
 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29-41. 
 
 
Erni B, Navarini AA, Huang D, Schoetzau A, Kind A, Mueller SM. Proposition of a severity 
scale for lichen sclerosus: The "Clinical Lichen Sclerosus Score." Dermatol Ther 
2021;34:e14773. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Kimball AB, Naegeli AN, Edson-Heredia E, et al. Psychometric properties of the Itch Numeric 
Rating Scale in patients with moderate-to-severe plaque psoriasis. Br J Dermatol 
2016;175:157-162. 
Opzelura (ruxolitinib) [prescribing information]. Incyte Corporation; July 2022. 
Powell JJ, Wojnarowska F. Lichen sclerosus. Lancet 1999;353:1777-1783. 
Ruxolitinib Cream Investigator's Brochure. Wilmington, DE: Incyte Corporation. 
 
 
 
Silverberg JI, DeLozier A, Sun L, et al. Psychometric properties of the itch numeric rating scale, 
skin pain numeric rating scale, and atopic dermatitis sleep scale in adult patients with 
moderate-to-severe atopic dermatitis. Health Qual Life Outcomes 2021;19:247. 


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APPENDIX A. PLANNED TABLES, FIGURES, AND LISTINGS 
This appendix provides a list of the planned tables, figures, and listings for the Clinical Study 
Report. Shells are provided in a separate document for tables that are not in the most current 
Standard Safety Tables v1.13. 
The lists of tables, figures, and listings are to be used as guidelines. Modifications of the lists that 
do not otherwise affect the nature of the analysis will not warrant an amendment to the SAP. 
Tables 
Table No. 
Title 
Population 
Standard 
Baseline and Demographics Characteristics 
1.1 Disposition 
1.1.1 
Analysis Populations 
ITT 
X 
1.1.2.1 
Summary of Participant Disposition in the DBVC Period 
ITT 
X 
1.1.2.2 
Summary of Participant Disposition in the OLE Period 
OLE 
X 
1.1.3 
Summary of Number of Participants Enrolled by Country and Site 
ITT 
X 
1.1.4.1 
Summary of Protocol Deviations in the DBVC Period 
ITT 
X 
1.1.4.2 
Summary of Protocol Deviations in the OLE Period 
OLE 
X 
1.2 Demographics and Baseline Characteristics 
1.2.1 
Summary of Demographics and Baseline Characteristics 
ITT 
X 
1.2.2 
Summary of Demographics and Baseline Characteristics 
OLE 
X 
1.3 Baseline Disease Characteristics 
 
1.3.1 
Summary of Baseline Disease Characteristics 
ITT  
X 
1.3.2 
Summary of Baseline Disease Characteristics 
OLE  
X 
1.4 Prior and Concomitant Medication 
1.4.1 
Summary of Prior Medications 
ITT 
X 
1.4.2.1 
Summary of Concomitant Medications in the DBVC Period 
ITT 
X 
1.4.2.2 
Summary of Concomitant Medications in the OLE Period 
OLE 
X 
1.5 Others 
1.5 
Summary of General Medical History in the DBVC Period 
ITT 
X 
Efficacy 
2.1 Itch NRS Score 
2.1.1 
Summary and Analysis of Participants Achieving ITCH4 in Treatment 
Periods 
ITT 
 
2.1.2 
Summary and Analysis of Participants Achieving ITCH4 by Baseline 
ITCH NRS Score in Treatment Periods 
ITT 
 
2.1.3 
Summary and Analysis of Participants Achieving ITCH4 by Baseline 
IGA Score in Treatment Periods 
ITT 
 
2.1.4 
Summary and Analysis of Participants Achieving ITCH4 by Baseline 
Age Group in Treatment Periods 
ITT 
 
2.1.5 
Summary and Analysis of Participants Achieving ITCH4 by Baseline 
Duration of Disease in Treatment Periods 
ITT 
 
2.1.6 
Summary and Analysis of Participants Achieving ITCH4 by 
Childbearing Potential Status in Treatment Periods 
ITT 
 
2.1.7 
Summary and Analysis of By-Visit Itch NRS Score in Treatment Periods 
ITT 
 
2.1.8 
Summary and Analysis of Daily Itch NRS Score from Day 1 to Day 28 
ITT 
 
2.1.9 
Summary and Analysis of Time to ITCH4 in the DBVC Period 
ITT 
 
2.2 CLISSCO 
2.2.1 
Summary and Analysis of CLISSCO Total Score and Subscores in 
Treatment Periods 
ITT 
 


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Table No. 
Title 
Population 
Standard 
2.3 Skin Pain NRS Score 
2.3.1 
Summary and Analysis of By-Visit Skin Pain NRS Score in Treatment 
Periods 
ITT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.11 BSA 
2.11.1 
Summary of By-Visit Total % BSA in Treatment Periods 
ITT 
 
Safety 
3.1 Exposure & Compliance 
3.1.1.1 
Summary of Exposure in the DBVC Period 
Safety 
X 
3.1.1.2 
Summary of Exposure in the OLE Period 
OLE 
X 
3.1.1.3 
Summary of Exposure in Treatment Periods 
Safety 
X 
3.1.2.1 
Summary of Study Drug Compliance in the DBVC Period 
Safety 
 
3.2 Adverse Events 
3.2.1.x 
Overall Summary of Treatment-Emergent Adverse Events  
Safety 
X 
3.2.2.x 
Summary of Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term  
Safety 
X 
3.2.3.x 
Summary of Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency  
Safety 
X 
3.2.4.x 
Summary of Treatment-Emergent Adverse Events by MedDRA System 
Organ Class, Preferred Term, and Maximum Severity 
Safety 
X 
3.2.5.x 
Summary of Treatment-Emergent Adverse Events by MedDRA System 
Organ Class, Preferred Term, and CTCAE Grade Category  
Safety 
 
3.2.6.x 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Safety 
X 
3.2.7.x 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency 
Safety 
X 
3.2.8.x 
Summary of Serious Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term 
Safety 
X 
3.2.9.x 
Summary of Serious Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency  
Safety 
X 
3.2.10.x 
Summary of Treatment-Related Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term  
Safety 
X 
3.2.11.x 
Summary of Treatment-Related Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency 
Safety 
X 
3.2.12.x 
Summary of Grade 3 or Higher Treatment-Related Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and Preferred Term 
Safety 
 


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Table No. 
Title 
Population 
Standard 
3.2.13.x 
Summary of Treatment-Related Serious Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term 
Safety 
X 
3.2.14.x 
Summary of Treatment-Emergent Adverse Events With a Fatal Outcome 
by MedDRA System Organ Class and Preferred Term 
Safety 
X 
3.2.15.x 
Summary of Treatment-Emergent Adverse Events Leading to Dose 
Interruption by MedDRA System Organ Class and Preferred Term  
Safety 
X 
3.2.16.x 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of Study Drug by MedDRA System Organ Class and 
Preferred Term  
Safety 
X 
3.2.17.x 
Summary of Application Site Reactions by MedDRA Preferred Term in 
Decreasing Order of Frequency 
Safety 
X 
3.3 Laboratory 
3.3.1.1.x 
Summary of Laboratory Values – Hematology  
Safety 
X 
3.3.1.2.x 
Summary of Laboratory Values – Chemistry  
Safety 
X 
3.3.2.1.x 
Shift Summary of Hematology Laboratory Values – to the Worst 
Abnormal Value 
Safety 
X 
3.3.2.2.x 
Shift Summary of Chemistry Laboratory Values – to the Worst 
Abnormal Value 
Safety 
X 
3.3.3.1x 
Shift Summary of Hematology Laboratory Values in CTCAE Grade –  
to the Worst Grade Abnormal Value  
Safety 
X 
3.3.3.2.x 
Shift Summary of Chemistry Laboratory Values in CTCAE Grade –  
to the Worst Grade Abnormal Value  
Safety 
X 
3.4 Vital Signs 
3.4.1.x 
Summary of Systolic Blood Pressure  
Safety 
X 
3.4.2.x 
Summary of Diastolic Blood Pressure  
Safety 
X 
3.4.3.x 
Summary of Pulse  
Safety 
X 
3.4.4.x 
Summary of Respiratory Rate  
Safety 
X 
3.4.5.x 
Summary of Body Temperature 
Safety 
X 
Note: For AE tables ending with "x," separate tables will be provided for the DBVC period, OLE period, and the treatment 
periods (ie, DBVC and OLE periods). For laboratory and vital sign tables ending with "x," separate tables will be provided for 
the DBVC and the OLE periods. 
Figures 
Figure No. 
Title 
Population 
Efficacy 
4.1.1.1 
Proportion of Participants Achieving ITCH4 in Treatment Periods 
ITT 
4.1.1.2 
Proportion of Participants Achieving ITCH4 by Baseline ITCH NRS Score in 
Treatment Periods 
ITT 
4.1.1.3 
Proportion of Participants Achieving ITCH4 by Baseline IGA Score in Treatment 
Periods 
ITT 
4.1.1.4 
Proportion of Participants Achieving ITCH4 by Baseline Age Group in Treatment 
Periods 
ITT 
4.1.1.5 
Proportion of Participants Achieving ITCH4 by Baseline Duration of Disease in 
Treatment Periods 
ITT 
4.1.1.6 
Proportion of Participants Achieving ITCH4 by Pre and Postmenopausal Status in 
Treatment Periods 
ITT 
4.1.1.7 
Forest Plot of Response Rate Difference in Achieving ITCH4 at Week 12  
ITT 
4.1.2.1 
Mean and Standard Error Plot of By-Visit Itch NRS Score in Treatment Periods 
ITT 
4.1.2.2 
Mean and Standard Error Plot of Change From Baseline in By-Visit Itch NRS Score 
in Treatment Periods 
ITT 


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Figure No. 
Title 
Population 
4.1.3.1 
Mean and Standard Error Plot of Daily Itch NRS Score From Day 1 to Day 28 
ITT 
4.1.3.2 
Mean and Standard Error Plot of Change From Baseline in Daily Itch NRS Score 
From Day 1 to Day 28 
ITT 
4.1.4 
Kaplan-Meier Curve of Time to ITCH4 in the DBVC Period 
ITT 
4.2.1.1 
Mean and Standard Error Plot of Total CLISSCO in Treatment Periods 
ITT 
4.2.1.2 
Mean and Standard Error Plot of Change From Baseline in Total CLISSCO in 
Treatment Periods 
ITT 
4.2.1.3 
Mean and Standard Error Plot of Percentage Change From Baseline in Total 
CLISSCO Score in Treatment Periods 
ITT 
4.3.1.1 
Mean and Standard Error Plot of By-Visit Skin Pain NRS Score in Treatment 
Periods 
ITT 
4.3.1.2 
Mean and Standard Error Plot of Change From Baseline in By-Visit Skin Pain NRS 
Score in Treatment Periods 
ITT 
4.3.1.3 
Mean and Standard Error Plot of Percentage Change From Baseline in By-Visit Skin 
Pain NRS Score in Treatment Periods 
ITT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.10.1.1 
Mean and Standard Error Plot of Total % BSA in Treatment Periods 
ITT 
4.10.1.2 
Mean and Standard Error Plot of Change From Baseline in Total % BSA in 
Treatment Periods 
ITT 
4.10.1.3 
Mean and Standard Error Plot of Percentage Change From Baseline in Total % BSA 
in Treatment Periods 
ITT 


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Listings 
Listing No. 
Title 
2.1 Demographic and Baseline Characteristics 
2.1.1 
Participant Enrollment and Disposition Status 
2.1.2 
Participant Inclusion and Exclusion Criteria Violations 
2.2 Protocol Deviations 
2.2.1 
Protocol Deviations and Violations 
2.3 Data Excluded From 
 Efficacy, and/or Safety Analyses 
2.3 
Analysis Populations 
2.4 Demographic and Baseline Characteristics (Including Prior and Concomitant Medications) 
2.4.1 
Demographic and Baseline Characteristics  
2.4.2 
Baseline Disease Characteristics 
2.4.3 
Medical History  
2.4.4 
Prior and Concomitant Medications 
2.4.5 
Prior Medications for Lichen Sclerosus 
2.5 Drug Exposure and Compliance 
2.5.1 
Study Drug Exposure and Compliance in the DBVC Period 
2.5.2 
Study Drug Exposure in the OLE Period 
2.6 Efficacy  
2.6.1.1 
By-Visit Itch NRS Score 
2.6.1.2 
Daily Itch NRS Score 
2.6.2 
CLISSCO 
2.6.3.1 
By-Visit Skin Pain NRS Score 
2.6.3.2 
Daily Skin Pain NRS Score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.7 Adverse Events 
2.7.1 
Adverse Events 
2.7.2 
Adverse Events Leading to Study Drug Discontinuation 
2.7.3 
Serious Adverse Events 
2.7.4 
Treatment-Related Adverse Events 
2.7.5 
Adverse Events With a Fatal Outcome 
2.7.6 
Adverse Events Leading to Interruption of Study Drug 
2.7.8 
Grade 3 or Higher Adverse Events 
2.7.9 
Application Site Reactions 
2.8 Laboratory Data 
2.8.1.1 
Clinical Laboratory Values – Hematology 
2.8.1.2 
Clinical Laboratory Values – Chemistry 
2.8.1.4 
Abnormal Clinical Laboratory Values – Hematology 
2.8.1.5 
Abnormal Clinical Laboratory Values – Chemistry 


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Listing No. 
Title 
Vital Signs 
2.8.2.1 
Vital Signs 
2.8.2.2 
Abnormal Vital Sign Values 
2.8.2.3 
Alert Vital Sign Values