A Phase 2a, Randomized, Double-Blind, Vehicle-Controlled, Single Site, Exploratory Trial to Assess the Effect of Delgocitinib Cream 20 mg/g on the Molecular Signature, Safety, and Efficacy in Adults With Frontal Fibrosing Alopecia
Phase: PHASE2
Conditions: Frontal Fibrosing Alopecia
Sponsor: LEO Pharma

Cover Page 
Study title: A Phase 2a, Randomized, Double-Blind, Vehicle-Controlled, Single Site, Exploratory Trial to Assess 
the Effect of Delgocitinib Cream 20 mg/g on the Molecular Signature, Safety, and Efficacy in Adults With Frontal 
Fibrosing Alopecia  
LEO Pharma number: EXP-2228
NCT number: NCT05332366
Date: 17-Nov-2021 

Sponsor – Protocol # 
Page 1 of 82  
 
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Confidential and proprietary. Permission should be obtained before any reproduction. 
 
 
 
PROTOCOL EXP-2228 
 
 
 
17 November 2021 
Sponsor: 
LEO Pharma A/S 
Industriparken 55 
DK-2750 Ballerup 
Denmark 
Sponsor Medical 
Expert: 
 MD, PhD;
 Translational 
Medicine 
 
Sponsor 
Representatives: 
 MD, PhD; 
Translational 
Medicine 
 MD; 
 Medical Sciences 
 MSc Stat,
 Medical Sciences 
 MSc Pharm,
 
Global Clinical Operations 
Clinical Research 
Organization: 
 
 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................ 2 
PROTOCOL VERSION HISTORY ............................................................................................... 6 
STATEMENT OF COMPLIANCE ................................................................................................ 8 
SIGNATURE PAGE ...................................................................................................................... 9 
PRINCIPAL/QUALIFIED INVESTIGATOR SIGNATURE PAGE .......................................... 11 
LIST OF ABBREVIATIONS ....................................................................................................... 12 
1 
PROTOCOL SUMMARY ............................................................................................ 14 
1.1 
Synopsis ........................................................................................................................ 14 
1.2 
Trial Diagram ................................................................................................................ 23 
1.3 
Schedule of Events ........................................................................................................ 23 
2 
INTRODUCTION ........................................................................................................ 30 
2.1 
Background ................................................................................................................... 30 
 
Frontal Fibrosing Alopecia .................................................................................. 30 
 
Delgocitinib........................................................................................................... 30 
 
Trial Rationale ...................................................................................................... 31 
2.2 
Risk/Benefit Assessment ............................................................................................... 31 
 
Known Potential Risks .......................................................................................... 31 
 
Known Potential Benefits ...................................................................................... 32 
 
Assessment of Risks and Benefits .......................................................................... 32 
 
COVID-19 Pandemic ............................................................................................ 32 
3 
OBJECTIVES AND ENDPOINTS .............................................................................. 34 
4 
TRIAL DESIGN ........................................................................................................... 36 
4.1 
Overall Design .............................................................................................................. 36 
4.2 
Scientific Rationale for Trial Design ............................................................................ 38 
4.3 
Justification for Dose .................................................................................................... 38 
4.4 
End of Trial Definition .................................................................................................. 39 
5 
TRIAL POPULATION ................................................................................................. 40 
5.1 
Inclusion Criteria ........................................................................................................... 40 
5.2 
Exclusion Criteria ......................................................................................................... 41 
5.3 
Lifestyle Considerations ............................................................................................... 43 
5.4 
Screen Failures .............................................................................................................. 44 
6 
TREATMENT .............................................................................................................. 45 
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6.1 
Trial Treatment Administered ....................................................................................... 45 
 
Treatment Interruption.......................................................................................... 45 
6.2 
Preparation/Handling/Storage/Accountability .............................................................. 46 
 
Preparation/Storage/Handling ............................................................................. 46 
 
Accountability ....................................................................................................... 46 
6.3 
Randomization .............................................................................................................. 47 
 
Blinding ................................................................................................................. 47 
 
Trial Treatment Compliance ................................................................................. 48 
6.4 
Concomitant Therapy .................................................................................................... 48 
 
Permitted Therapies .............................................................................................. 48 
 
Prohibited Therapies or Procedures .................................................................... 49 
7 
DISCONTINUATION AND LOST TO FOLLOW-UP ............................................... 50 
7.1 
Discontinuation ............................................................................................................. 51 
7.2 
Lost to Follow-Up ......................................................................................................... 52 
8 
TRIAL ASSESSMENTS AND PROCEDURES ......................................................... 53 
8.1 
Efficacy Assessments (Cohort 1 only) .......................................................................... 53 
 
Lichen Planopilaris Activity Index ........................................................................ 53 
 
Frontal Fibrosing Alopecia Severity Score .......................................................... 53 
 
Perifollicular Erythema and Scale........................................................................ 53 
 
Pruritus Numerical Rating Scale .......................................................................... 54 
 
Burning Sensation Numerical Rating Scale .......................................................... 54 
 
Pain Numerical Rating Scale ................................................................................ 54 
 
Hair Counts/Trichoscopy ...................................................................................... 54 
 
Hair Line Measurements....................................................................................... 55 
8.2 
Safety Assessments ....................................................................................................... 55 
 
Vital Signs ............................................................................................................. 55 
 
Complete Physical Examination ........................................................................... 55 
 
Brief Physical Examination .................................................................................. 55 
 
Clinical Laboratory Tests ..................................................................................... 56 
 
Electrocardiogram ................................................................................................ 57 
 
Local Tolerability Assessments ............................................................................. 57 
8.3 
Pharmacodymanic Assessments ................................................................................... 57 
 
Skin Biopsies ......................................................................................................... 58 
 
Tape Stripping ....................................................................................................... 58 
 
Skin Swabs for Microbiomes Analysis .................................................................. 59 
8.4 
Other Assessments ........................................................................................................ 59 
 
Target Area Identification..................................................................................... 59 
 
Medical Photography............................................................................................ 60 
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8.5 
Adverse Events and Serious Adverse Events (Cohort 1 Only) ..................................... 60 
 
Definition of Adverse Event .................................................................................. 60 
 
Definition of Treatment-Emergent Adverse Event ................................................ 60 
 
Definition of Serious Adverse Event ..................................................................... 60 
 
Classification of an Adverse Event ....................................................................... 61 
 
Time Period and Frequency for Event Assessment and Follow-Up ..................... 63 
 
Adverse Event Reporting....................................................................................... 64 
 
Serious Adverse Event Reporting.......................................................................... 64 
 
Pregnancy Reporting ............................................................................................ 65 
 
Adverse events of special interest (AESI) ............................................................. 66 
 
Medication error ............................................................................................... 66 
 
Misuse or Abuse ................................................................................................ 67 
 
Aggravation of condition .................................................................................. 67 
8.6 
Procedural Complications (Cohort 2 Only) .................................................................. 67 
9 
STATISTICAL CONSIDERATIONS .......................................................................... 69 
9.1 
Sample Size Determination ........................................................................................... 69 
9.2 
Populations for Analyses .............................................................................................. 69 
9.3 
Statistical Analyses ....................................................................................................... 70 
 
General Approach ................................................................................................. 70 
 
Baseline ................................................................................................................. 70 
 
Efficacy Analyses .................................................................................................. 71 
 
Safety Analyses...................................................................................................... 72 
 
Molecular Signature Changes Analyses ............................................................... 73 
 
Other Analyses ...................................................................................................... 73 
 
Planned Interim Analyses ..................................................................................... 74 
10 
REGULATORY, ETHICAL, AND TRIAL OVERSIGHT CONSIDERATIONS ...... 75 
10.1 
Local Regulations/Declaration of Helsinki ................................................................... 75 
10.2 
Ethical Review .............................................................................................................. 75 
10.3 
Informed Consent Process ............................................................................................ 75 
10.4 
Trial Discontinuation and Closure ................................................................................ 76 
10.5 
Confidentiality and Privacy .......................................................................................... 76 
10.6 
Clinical Monitoring ....................................................................................................... 77 
10.7 
Quality Assurance and Quality Control ........................................................................ 77 
10.8 
Data Handling and Record Keeping ............................................................................. 77 
10.9 
Protocol Deviations ....................................................................................................... 78 
10.10 Publication Policy ......................................................................................................... 78 
11 
REFERENCES .............................................................................................................. 79 
APPENDIX A: Lichen Planopilaris Activity Index (LPPAI) 7 .................................................... 80 
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APPENDIX B: Frontal Fibrosing Alopecia Severity Score 8 ....................................................... 81 
APPENDIX C: Numerical Rating Scale ....................................................................................... 82 
 
LIST OF TABLES 
 
Table 1: Schedule of Events for Cohort 1 (Subjects with FFA) ................................................... 25 
Table 2: Schedule of Events for Cohort 2 (Healthy Subjects) ...................................................... 29 
Table 3: Trial Treatments.............................................................................................................. 45 
Table 4: Prohibited Therapies or Procedures for Cohort 1 (Subjects with FFA) ......................... 49 
Table 5: Prohibited Therapies or Procedures for Cohort 2 (Healthy Subjects) ............................ 50 
Table 6: Perifollicular Erythema and Perifollicular Scale Severity Scale .................................... 54 
Table 7: Clinical Laboratory Testing (Cohort 1) .......................................................................... 56 
Table 8: Subject Assessment of Local Tolerability after IMP Application .................................. 57 
 
LIST OF FIGURES 
 
Figure 1: Trial Diagram ................................................................................................................ 23 
 
 
 
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PROTOCOL VERSION HISTORY 
Version 
Rationale for amendment 
Main changes to the protocol 
1.0 / 03 June 2021 
Initial version 
N/A 
2.0 / 17 November 2021 To change the Sponsor Medical 
Expert 
- 
Cover page and Signature page: The 
Sponsor Medical Expert was changed 
to 
 
To address the following FDA 
recommendations for Cohort 1: 
 
- 
To 
modify 
the 
safety 
monitoring 
during 
the 
open-label extension (OLE) 
so that subjects who initiate 
delgocitinib 
will 
be 
monitored similarly, whether 
they 
initiate 
delgocitinib 
during the OLE or the initial 
treatment period. 
 
 
 
 
 
 
- 
To add the approximate 
dimension of the lesional 
target area and to specify that 
tape 
stripping 
will 
be 
optional. 
 
 
 
 
 
 
 
- 
To evaluate thyroid function 
at screening  
 
 
 
 
 
  
- 
To allow treatment of the 
eyebrows, if affected  
 
 
 
 
 
 
- 
Synopsis, Section 1.3 (Table 1), 
Section 4.1, 
Section 
8.2.4, 
and 
Section 8.2.6: The phone call visits 
planned at Week 16 and Week 20 
were changed to on-site visits. 
Therefore, subjects will come to the 
site on 9 occasions, including at 
Week 
16 
and 
Week 
20. 
All 
assessments 
that 
were 
to 
be 
performed at the phone call visits will 
be done at the site. Some additional 
safety, 
efficacy, 
and 
other 
assessments were added at Week 16 
and Week 20 visits. 
 
- 
Synopsis, 
Section 
1.3 
(Table 1, 
footnotes c and k), Section 4.1, 
Section 8.1.7, 
Section 
8.3, 
and 
Section 8.4.1: Clarifications added 
regarding selection of the lesional 
target area(s), including dimension. 
Clarifications added regarding which 
assessments could and could not 
overlap on the lesional target area(s). 
Specifications added for the tape 
stripping collection. 
 
- 
List of abbreviations, Synopsis, 
Section 1.3 (Table 1), Section 5.2, 
and Section 8.2.4: Added thyroid-
stimulating hormone (TSH) with 
reflex free T4 at screening and related 
exclusion 
criterion 
(Exclusion 
Criterion #14). 
 
- 
Section 5.3 and Section 6.1: Clarified 
that all affected areas on the 
face/scalp can be treated, including 
the eyebrows, if affected. If eyebrows 
are treated, subjects should abstain 
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from wetting them within 2 hours 
following IMP application. 
To add the outcome categories of 
adverse events (AEs). 
 
- 
Section 8.5.4: Added the different 
outcome categories of AEs under a 
new section 8.5.4.3. 
To clarify that the Numerical 
Rating Scale questions (pruritus, 
burning sensation, and pain) will 
be specific to frontal fibrosing 
alopecia. 
- 
Appendix C: Modified the NRS 
questions so that the three questions 
are specific to frontal fibrosing 
alopecia.  
To add the Innovaderm project 
team contact information for 
SAE reporting. 
- 
Section 8.5.7: Added the Innovaderm 
project team e-mail address. 
To clarify that the use of systemic 
or 
topical 
treatment 
with 
minoxidil or systemic treatment 
with spironolactone is allowed if 
used for at least 6 months prior to 
Day 1 and continue on stable 
dosing during the study.  
- 
Synopsis, 
Section 
5.2, 
and 
Section 6.4.1, a note was added to 
specify that systemic treatment with 
minoxidil or spironolactone and 
topical treatment with minoxidil is 
allowed if used for at least 6 months 
prior to Day 1 and the subject agrees 
to continue using it on a stable dosing 
during the present study (Exclusion 
Criterion #19 and #20).  
To clarify the restrictions to be 
followed by the subjects under 
stable dose of topical minoxidil 
the day of the visits with regards 
to the application of topical 
product to the areas where the 
skin samples will be collected.   
- 
Section 5.3, the following note was 
added: In addition, for the subjects 
who are on stable dose of topical 
minoxidil for at least 6 months prior 
to Day 1 and continue using it during 
the study, they should be instructed to 
not apply it on the areas where skin 
samples will be collected on the visit 
days before the visit. 
 
 
 
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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with the protocol, International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP), and applicable local regulations. The 
principal investigator will assure that no planned deviation from, or changes to the protocol will 
take place without prior agreement from the sponsor and documented approval from the 
institutional review board (IRB)/research ethics board (REB), except where necessary to eliminate 
an immediate hazard(s) to the trial subjects. All personnel involved in the conduct of this trial have 
completed ICH GCP training. 
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IRB/REB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any subject is enrolled. Any amendment to the protocol will require 
review and approval by the IRB/REB before the changes are implemented to the trial. All changes 
to the consent form will be IRB/REB approved. 
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SIGNATURE PAGE 
The signatures below constitute the approval of this protocol and provide the necessary assurances 
that this trial will be conducted according to this protocol, applicable local regulations, and ICH 
GCP guidelines. 
 
 
 
Sponsor: 
 
 
 MD, PhD  
 Translational Medicine  
LEO Pharma A/S 
 
 
 
 
 
 Date (DD-MMM-YYYY) 
 
 MD, PhD  
 Translational Medicine 
LEO Pharma A/S 
 
 
 
 
 
 Date (DD-MMM-YYYY) 
 
 MD  
 Medical Sciences 
LEO Pharma A/S 
 
 
 
 
 
 Date (DD-MMM-YYYY) 
 
 MSc Stat  
 Medical Sciences 
LEO Pharma A/S 
 
 
 
 
 
 Date (DD-MMM-YYYY) 
 
 MSc Pharm  
 Global Clinical 
Operations 
LEO Pharma A/S 
 Date (DD-MMM-YYYY) 
18-Nov-2021 | 14:52:20 EST
22-Nov-2021 | 10:08:39 EST
22-Nov-2021 | 07:56:05 PST
22-Nov-2021 | 10:58:08 EST
22-Nov-2021 | 11:22:34 EST
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SIGNATURE PAGE (Continued) 
 
 
 
 
 
Scientific Affairs: 
 
 
 BSc 
 Scientific and Regulatory Affairs  
Innovaderm Research Inc. 
 Date (DD-MMM-YYYY) 
 
 
 
 
 
Biometrics: 
 
 
 
, MSc 
 Biometrics 
Innovaderm Research Inc. 
 
 
 
 
 
 Date (DD-MMM-YYYY) 
 
 
 
 
 
22-Nov-2021 | 11:40:46 EST
22-Nov-2021 | 12:43:02 EST
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LIST OF ABBREVIATIONS 
AD 
atopic dermatitis 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
anti-HBc 
antibody to hepatitis B core antigen 
AST 
aspartate aminotransferase 
β-hCG 
β-human chorionic gonadotropin 
BID 
twice daily 
BUN 
blood urea nitrogen 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus Disease 2019 
CRA 
clinical research associate 
CRO 
contract research organization 
CXCL9 
chemokine (C-X-C motif) ligand 9 
CXCL10 
chemokine (C-X-C motif) ligand 10 
EASI 
Eczema Area and Severity Index 
EASI75 
a 75% reduction in EASI score 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
eHFSC 
epithelial hair follicle stem cells 
EDC 
Electronic Data Capture 
ET 
early termination 
FDA 
Food and Drug Administration 
FAS  
full analysis set 
FFA 
frontal fibrosing alopecia 
FFASS 
Frontal Fibrosing Alopecia Severity Score 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl-transferase 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCT 
Hematocrit 
HCV 
hepatitis C virus 
Hgb 
Hemoglobin 
HIV 
human immunodeficiency virus 
HFIP 
hair follicule immune privilege 
IB 
Investigator Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IHC 
Immunohistochemistry 
IMP 
investigational medicinal product 
INF 
Interferon 
IRB 
institutional review board 
JAK 
Janus kinase 
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JT 
Japan Tobacco Inc. 
LDH 
lactate dehydrogenase 
LPP 
lichen planopilaris 
LPPAI 
lichen planopilaris activity index 
LTA 
local tolerability assessment 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPV 
mean platelet volume 
NA 
not applicable 
NRS 
Numerical Rating Scale 
OLE 
open-label extension 
pDC 
plasmacytoid dendritic cells 
PDE-4 
phosphodiesterase-4 
PLT 
Platelets 
PP 
per-protocol 
PUVA 
psoralen-UV-A 
PT 
preferred term 
QC 
quality control 
RBC 
red blood cell 
REB 
research ethics board 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
System Organ Class 
STAT 
signal transducer and activator of transcription 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
UV 
Ultraviolet 
vIGA-AD TS 
Validated Investigator Global Assessment for Atopic Dermatitis 
treatment success 
WBC 
white blood cell 
WOCBP 
women of childbearing potential 
WHO 
world health organization 
 
 
 
 
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1 PROTOCOL SUMMARY 
1.1 Synopsis  
Name of Sponsor/Company:  
LEO Pharma A/S 
Name of Investigational Product: 
Delgocitinib cream 20 mg/g 
Name of Active Ingredient: 
Delgocitinib 
Title of Trial:  
A Phase 2a, Randomized, Double-Blind, Vehicle-Controlled, Single Site, Exploratory Trial to Assess 
the Effect of Delgocitinib Cream 20 mg/g on the Molecular Signature, Safety, and Efficacy in Adults 
with Frontal Fibrosing Alopecia 
Phase of Development:  
Phase 2a 
Trial Site:  
This trial will be conducted at 1 site located in the United States 
 
Boston, MA). 
Number of Subjects (planned):  
• 
Cohort 1 
- Approximately 30 subjects with frontal fibrosing alopecia (FFA) will be randomized in this 
cohort. 
• 
Cohort 2 
- Approximately 5 healthy postmenopausal female subjects will be included in this cohort. 
Duration of Trial:  
• 
Cohort 1 
- The maximum trial duration per subject is approximately 30 weeks, including up to 30 days 
for the screening period, 12 weeks for the vehicle-controlled treatment period, 12 weeks for 
the open-label extension (OLE), and approximately 2 weeks for the safety follow-up period. 
• 
Cohort 2 
- The maximum trial duration per subject is approximately 6 weeks, including up to 30 days for 
the screening period, 1 day for the skin samples collection, and up to 14 days for the optional 
follow-up period. 
Investigational Medicinal Product, Dosage, and Mode of Administration:  
Delgocitinib cream 20 mg/g and matching vehicle (delgocitinib cream vehicle). 
• 
 Cohort 1 
- Subjects will be randomized in a 1:1 ratio on Day 1 to apply delgocitinib cream 20 mg/g or 
vehicle cream twice daily (BID) for 12 weeks during the vehicle-controlled treatment period. 
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Name of Sponsor/Company:  
LEO Pharma A/S 
Name of Investigational Product: 
Delgocitinib cream 20 mg/g 
Name of Active Ingredient: 
Delgocitinib 
After the vehicle-controlled treatment period, subjects will continue into the OLE and will 
apply delgocitinib cream 20 mg/g BID for 12 weeks. 
• 
Cohort 2 
- No investigational product will be administered in Cohort 2. 
Objectives: 
Primary: 
The primary objective is: 
• 
To assess molecular signature changes following topical application of delgocitinib cream 20 mg/g 
in subjects with FFA. 
Secondary: 
The secondary objective is: 
• 
To evaluate the safety and tolerability of delgocitinib cream 20 mg/g following topical application 
in subjects with FFA during the vehicle-controlled treatment period. 
Exploratory: 
The exploratory objectives are: 
• 
To evaluate the safety and tolerability of delgocitinib cream 20 mg/g during the OLE. 
• 
To evaluate the preliminary efficacy of delgocitinib cream 20 mg/g following topical application 
in subjects with FFA. 
Endpoints: 
Primary Endpoint: 
• 
Change in expression of chemokine (C-X-C motif) ligand 9 (CXCL9), chemokine (C-X-C motif) 
ligand 10 (CXCL10), and interferon (IFN)-γ from baseline to Week 12. 
Secondary Endpoint: 
• 
Number of treatment-emergent adverse events (TEAEs) from baseline to Week 12.  
Exploratory Endpoints: 
Exploratory safety endpoint: 
• 
Number of TEAEs during the OLE (up to Week 26) 
Exploratory efficacy endpoints during the vehicle-controlled treatment period: 
• 
Change in Lichen Planopilaris Activity Index (LPPAI) score from baseline to Weeks 4, 8, and 12. 
• 
Change in Frontal Fibrosing Alopecia Severity Score (FFASS) from baseline to Weeks 4, 8, and 
12. 
• 
Change in target area perifollicular erythema score from baseline to Weeks 4, 8, and 12. 
• 
Change in target area perifollicular scale score from baseline to Weeks 4, 8, and 12. 
• 
Change in pruritus Numerical Rating Scale (NRS) score from baseline to Days 2, 3, 4, 5, 6, 7, 8, 
and Weeks 4, 8, and 12. 
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Name of Sponsor/Company:  
LEO Pharma A/S 
Name of Investigational Product: 
Delgocitinib cream 20 mg/g 
Name of Active Ingredient: 
Delgocitinib 
• 
Change in burning sensation NRS score from baseline to Days 2, 3, 4, 5, 6, 7, 8, and Weeks 4, 8, 
and 12. 
• 
Change in pain NRS score from baseline to Days 2, 3, 4, 5, 6, 7, 8, and Weeks 4, 8, and 12. 
• 
Proportion of subjects with a 3-point reduction* in pruritus NRS score from baseline to Days 2, 3, 
4, 5, 6, 7, 8, and Weeks 4, 8, and 12. 
• 
Proportion of subjects with a 4-point reduction* in pruritus NRS score from baseline to Days 2, 3, 
4, 5, 6, 7, 8, and Weeks 4, 8, and 12. 
• 
Proportion of subjects with a 3-point reduction* in burning sensation NRS score from baseline to 
Days 2, 3, 4, 5, 6, 7, 8, and Weeks 4, 8, and 12. 
• 
Proportion of subjects with a 4-point reduction* in burning sensation NRS score from baseline to 
Days 2, 3, 4, 5, 6, 7, 8, and Weeks 4, 8, and 12. 
• 
Proportion of subjects with a 3-point reduction* in pain NRS score from baseline to Days 2, 3, 4, 
5, 6, 7, 8, and Weeks 4, 8, and 12. 
• 
Proportion of subjects with a 4-point reduction* in pain NRS score from baseline to Days 2, 3, 4, 
5, 6, 7, 8, and Weeks 4, 8, and 12. 
• 
Change in target area hair counts/trichoscopy via fotofinder trichovision from baseline to Week 12. 
Exploratory efficacy endpoints during the OLE: 
• 
These efficacy outcomes will be measured at scheduled visits after Week 12: LPPAI, FFASS, 
target area perifollicular scale score, target area perifollicular erythema score, pruritus NRS, 
burning sensation NRS, pain NRS, and target area hair counts/trichoscopy via fotofinder 
trichovision. 
* Note: Only subjects with a baseline NRS score ≥3 will be included in the respective endpoints on proportion of 
subjects with a 3-point reduction. Only subjects with a baseline NRS score ≥4 will be included in the respective 
endpoints on proportion of subjects with a 4-point reduction. 
Trial Design: 
A Phase 2a, randomized, double-blind, vehicle-controlled, single-site, exploratory trial of delgocitinib 
cream 20 mg/g in subjects with FFA. 
The trial will consist of 2 cohorts: Cohort 1 will include approximately 30 subjects with FFA and 
Cohort 2 will include approximately 5 healthy postmenopausal female subjects. Both cohorts can be 
conducted in parallel.  
Cohort 1: 
All subjects will read and sign an informed consent form (ICF) prior to any trial-related activities being 
performed. Subjects who fulfill all of the inclusion criteria and none of the exclusion criteria will be 
randomized into the trial. After a screening period of no more than 30 days (from Day -30 to Day -1), 
eligible subjects will be randomized (1:1) on Day 1 to apply delgocitinib cream 20 mg/g or vehicle cream 
BID for 12 weeks during the vehicle-controlled treatment period. All subjects who complete the 
vehicle-controlled treatment period will then continue into the OLE and apply delgocitinib cream 
20 mg/g BID for 12 weeks. The OLE period will be followed by a 2-week safety follow-up period. For 
scheduled trial visits, subjects will come to the site on 9 occasions: screening, Day 1, Week 4, Week 8, 
Week 12, Week 16, Week 20, Week 24, and Week 26/early termination (ET).  
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Confidential and proprietary. Permission should be obtained before any reproduction. 
Name of Sponsor/Company:  
LEO Pharma A/S 
Name of Investigational Product: 
Delgocitinib cream 20 mg/g 
Name of Active Ingredient: 
Delgocitinib 
On Day 1, a lesional target area on the scalp (eg, frontal, periauricular, or temporal area) that will be 
treated with the investigational medicinal product (IMP) will be identified. To allow for the hair 
count/trichoscopy assessment and all samples collection (ie, skin biopsies, tape stripping, and skin 
swabs) the lesional target area should be approximately 3 cm x 6 cm (or equivalent). However, as tape 
strips can be collected from the same area where trichoscopy/hair counts is performed or can be collected 
adjacent/close to the lesional target area (refer to Section 8.3.2 for details), a smaller lesional target area 
may be acceptable. If needed, two small target areas (totalling approximately the same size) could also 
be selected to allow for skin samples collection and hair count/trichoscopy assessment. If two lesional 
target areas are selected, they should be of similar severity.  
The following skin samples will be collected during the trial to assess molecular signature changes: 
- 
Skin biopsies for transcriptomic and immunohistochemistry (IHC) analyses (n=3): 
o Day 1: 2 skin biopsies (4-mm) will be collected prior to the first IMP application (1 from 
a lesional hair follicle within the target area and 1 from a non lesional hair follicle [eg, on 
the occipital scalp]). 
o Week 12: 1 skin biopsy (4-mm) will be collected from a hair follicle within the lesional 
target area (outside the scar of previous biopsies). 
- 
Skin swabs for microbiome analysis (n=3): 
o Day 1: 2 skin microbiome samples will be collected prior to the first IMP application 
(1 from the target area [lesional skin] and 1 from an uninvolved occipital scalp area). 
o Week 12: 1 skin microbiome sample will be collected at the same location of the lesional 
skin of the target area. 
- 
Adhesive tape strips samples for transcriptomic analysis (n=3): 
o Day 1: skin tape strips will be collected prior to the first IMP application from lesional 
skin and from non lesional skin (eg, on the occipital scalp). 
o Week 12: skin tape strips will be collected at the same location of the lesional skin.  
Note: Every effort should be made to collect tape strip samples in all subjects however, 
adhesive tape strip collection is optional and will be collected per investigator’s judgement 
(based on available skin area on the scalp). 
Safety will be assessed by collecting adverse events (AEs), recording vital signs, performing complete 
and brief physical examinations, and evaluating clinical laboratory results and local tolerability 
assessments (LTA). 
Efficacy will be assessed using LPPAI, FFASS, evaluation of the perifollicular erythema and 
perifollicular scale, pruritus NRS, burning sensation NRS, pain NRS, and hair counts/trichoscopy 
(eg, number of hairs, hair diameter, and hair density). Hair line measurements (ie, lateral canthus [right 
and left] to hairline, lower glabellar crease to hair line, top of frontalis muscle to hair line, and mid brow 
to hair line [right and left]) will also be done. 
Medical photographs of the lesional target area and the entire scalp (including the frontal hair line and 
right and left hair line areas) will be taken with the fotofinder device during the trial. 
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Confidential and proprietary. Permission should be obtained before any reproduction. 
Name of Sponsor/Company:  
LEO Pharma A/S 
Name of Investigational Product: 
Delgocitinib cream 20 mg/g 
Name of Active Ingredient: 
Delgocitinib 
Cohort 2: 
All subjects will read and sign an ICF prior to any trial-related activities being performed. Subjects who 
fulfill all of the inclusion criteria and none of the exclusion criteria will be accepted into the trial. After 
a screening period of no more than 30 days (from Day -30 to Day -1), eligible subjects will be asked to 
come at the site for skin samples collection. Screening and skin samples collection on Day 1 can be 
performed on the same day (if subjects do not have a washout period) or on two separate visits, at the 
investigator’s discretion. No investigational product will be administered in Cohort 2. For scheduled trial 
visits, subjects will come to the site on up to 3 occasions: screening, Day 1, and optional follow-up visit. 
The following skin samples will be collected: 
- 
Skin biopsies (n=2): 
o Day 1: 2 skin biopsies (4-mm) that include hair follicles will be collected on healthy 
skin at similar matched areas of subjects with FFA (ie, 1 from frontal scalp area and 
1 from occipital scalp area) 
- 
Adhesive tape strips (n=1): 
o Day 1: skin tape strips will be collected on non-hair bearing healthy skin at a similar 
matched area of subjects with FFA (ie, on the forehead, as close as possible to the frontal 
scalp area). 
- 
Skin swabs for microbiome analysis (n=2): 
o Day 1: 2 skin microbiome samples will be collected on healthy skin at similar matched 
areas of subjects with FFA (ie, 1 from frontal scalp area and 1 from occipital scalp area). 
For Cohort 2 only, safety will be assessed by review of any procedural complications and changes in 
health observed after skin samples collection. 
Inclusion/Exclusion Criteria: 
Inclusion criteria:  
In order to be eligible to participate in this trial, a subject must meet all of the following criteria, either 
at the screening and Day 1 visits or only at one of the specified visits (screening or Day 1) as noted in 
the criterion: 
Inclusion criteria for all subjects: 
1. Subject is willing to participate and is capable of giving informed consent. Note: Consent must be 
obtained prior to any trial-related procedures.  
2. Subjects must be willing to comply with all trial procedures and must be available for the duration 
of the trial. 
Inclusion criteria for Cohort 1 only (subjects with FFA): 
3. Male or female subject aged 18 years of age or older at the time of consent.  
4. Female subject of childbearing potential has had a negative serum pregnancy test at screening and 
negative urine pregnancy test at Day 1.  
5. Subject has clinically confirmed diagnosis of FFA based on investigator’s judgment. 
6. Subject has a target area with a perifollicular erythema score ≥ 2 and a perifollicular scale score ≥ 2 
at Screening and Day 1. 
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Confidential and proprietary. Permission should be obtained before any reproduction. 
Name of Sponsor/Company:  
LEO Pharma A/S 
Name of Investigational Product: 
Delgocitinib cream 20 mg/g 
Name of Active Ingredient: 
Delgocitinib 
7. For subject who uses make-up, moisturizers, creams, lotions, cleansers, and/or sunscreens on the 
face, subject has used the same product brands/types for a minimum period of 4 weeks prior to 
Day 1, agrees not to change brand/type or frequency of use throughout the trial, agrees not to apply 
those products on the treated area during the trial, and agrees not to use make-up, moisturizers, 
creams, lotions, cleansers, and/or sunscreens on the face on the clinic visit days before the visit. 
8. Subject is willing to maintain a consistent hair style and hair style regimen, including shampoo and 
hair products (including hair dye, process, and timing to hair appointments), and to refrain from 
weaves or extensions throughout the course of the trial and for 4 weeks prior to Day 1. 
Note: Hair dying and shaving of scalp is allowed during the trial but not within 48 hours prior to a 
trial visit. 
9. For female subject of childbearing potential involved in any sexual intercourse that could lead to 
pregnancy: the subject must agree to use an effective contraceptive method from at least 4 weeks 
prior to Day 1 until at least 4 weeks after the last IMP application. Effective contraceptive methods 
include hormonal contraceptives (eg, combined oral contraceptive, progesterone-only hormonal 
contraception [associated with or without inhibition of ovulation as the primary mode of action], 
patch, vaginal ring, injectable, or implant), intrauterine devices or intrauterine systems, vasectomized 
partner(s) (provided his vasectomy was performed ≥4 months prior to Screening), tubal ligation or 
a barrier method of contraception (eg, male condom, female condom, cervical cap, diaphragm, 
contraceptive sponge) in conjunction with spermicide.  
Note: Subjects must have been on a stable dose of hormonal contraceptives for at least 4 weeks 
before Day 1.  
Note: The above list of contraceptive methods does not apply to subjects who are abstinent for at 
least 4 weeks before Day 1 and will continue to be abstinent from penile-vaginal intercourse 
throughout the trial.  The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject. Periodic abstinence 
(calendar, symptothermal, post-ovulation methods) is not acceptable. 
Note: A female subject of nonchildbearing potential is defined as follows:  
– 
Female subject who has had surgical sterilization (hysterectomy, bilateral oophorectomy, or 
bilateral salpingectomy) 
– 
Female subject who has had a cessation of menses for at least 12 months prior to the screening 
visit without an alternative medical cause 
Inclusion criteria for Cohort 2 only (healthy subjects): 
10. Female subject aged 45 years of age or older at the time of consent.  
11. Female is postmenopausal as defined below: 
– 
Female subject who has had surgical sterilization (hysterectomy, bilateral oophorectomy, or 
bilateral salpingectomy) 
– 
Female subject who has had a cessation of menses for at least 12 months prior to the screening 
visit without an alternative medical cause. 
12. Subject is in good general health, according to the investigator’s judgment based on vital signs, 
medical history, and brief physical examination.   
 
 
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Confidential and proprietary. Permission should be obtained before any reproduction. 
Name of Sponsor/Company:  
LEO Pharma A/S 
Name of Investigational Product: 
Delgocitinib cream 20 mg/g 
Name of Active Ingredient: 
Delgocitinib 
Exclusion criteria: 
A subject who meets any of the following criteria at the screening and/or Day 1 visits, as applicable, will 
be excluded from participation in this trial: 
Exclusion criteria for all subjects: 
1. Subject is a female who is breastfeeding, pregnant, or who is planning to become pregnant during 
the trial. 
2. Subject has received any marketed or investigational biological agent within 12 weeks or 5 half-lives 
(whichever is longer) prior to Day 1. 
3. Subject is currently receiving a nonbiological investigational product or device or has received one 
within 4 weeks prior to Day 1. 
4. Subject has had excessive sun exposure or has used tanning booths within 4 weeks prior to Day 1 or 
is not willing to minimize natural and artificial sunlight exposure during the trial. Use of sunscreen 
products (except on treated areas for subjects in Cohort 1) and protective apparel are recommended 
when sun exposure cannot be avoided. 
5. Subject has a history of an allergic reaction or significant sensitivity to lidocaine or other local 
anesthetics. 
6. Subject has a history of hypertrophic scarring or keloid formation in scars or suture sites. 
Exclusion criteria for Cohort 1 only (subjects with FFA): 
7. History of other scalp/hair disease including discoid lupus erythematosus and central centrifugal 
cicatricial alopecia. 
Note: Subjects with lichen planopilaris/FFA overlap are not to be excluded. 
8. Presence of active dermatologic condition that might interfere with FFA diagnosis and/or interfere 
with the trial assessments such as seborrheic dermatitis, psoriasis, or telogen effluvium. 
9. Subject who has undergone scalp reduction surgery or hair transplantation. 
10. Use of adhesive wigs during the trial. 
11. Subject is known to have immune deficiency or is immunocompromised. 
12. Subject has a history of cancer or lymphoproliferative disease within 5 years prior to Day 1. Subjects 
with successfully treated nonmetastatic cutaneous squamous cell or basal cell carcinoma and/or 
localized carcinoma in situ of the cervix are not to be excluded. 
13. Subject had a major surgery within 8 weeks prior to Day 1 or has a major surgery planned during 
the trial. 
14. Subject has uncontrolled hypo- or hyperthyroidism or has both thyroid-stimulating hormone (TSH) 
and free T4 levels outside normal range at screening.   
15. Subject has any clinically significant medical condition or physical/laboratory/ECG/vital signs 
abnormality that would, in the opinion of the investigator, put the subject at undue risk or interfere 
with interpretation of trial results. 
16. Subject has positive results for hepatitis B surface antigens (HBsAg), antibodies to hepatitis B core 
antigens (anti-HBc), hepatitis C virus (HCV), or human immunodeficiency virus (HIV).  
17. Subject has used treatment with agents (including natural products or nutritional supplement such as 
Viviscal, Nutrafol, and/or biotin) that may affect hair regrowth in the last 4 weeks prior to Day 1. 
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. 
Confidential and proprietary. Permission should be obtained before any reproduction. 
Name of Sponsor/Company:  
LEO Pharma A/S 
Name of Investigational Product: 
Delgocitinib cream 20 mg/g 
Name of Active Ingredient: 
Delgocitinib 
18. Subject has used intralesional scalp corticosteroids or platelet rich plasma injection in the last 
4 weeks prior to Day 1. 
19. Subject has used systemic treatment with immunosuppressive/modulating medication or medication 
that could affect FFA (eg, corticosteroids, methotrexate, minoxidil, hydroxychloroquine, retinoids, 
calcineurin inhibitor, tetracyclines, pioglitazone, spironolactone, or 5-α-reductase-inhibitors) within 
4 weeks prior to Day 1.  
Note: Intranasal corticosteroids and inhaled corticosteroids are allowed. Eye and ear drops 
containing corticosteroids are also allowed. 
Note: Standard doses of systemic antihistamines are allowed. 
Note: Use of systemic treatment with minoxidil or spironolactone is allowed if used for at least 
6 months prior to Day 1 and the subject agrees to continue using it on a stable dosing during the 
present study. 
20. Subject has used any topical medicated treatment that could affect FFA within 2 weeks prior to 
Day 1, including, but not limited to, topical corticosteroids, calcineurin inhibitors, minoxidil, 
phosphodiesterase-4 (PDE-4) inhibitors. 
Note: Use of topical treatment with minoxidil is allowed if used for at least 6 months prior to Day 1 
and the subject agrees to continue using it on a stable dosing during the present study. 
21. Subject has received treatment with Janus kinase (JAK) inhibitors (systemic or topical) within 
4 weeks prior to Day 1. 
22. Subject has received any ultraviolet (UV)-B phototherapy (including tanning beds), excimer laser, 
or any other phototherapy within 4 weeks prior to Day 1. 
23. Subject has had psoralen-UV-A (PUVA) treatment within 4 weeks prior to Day 1. 
24. Subject has a known or suspected allergy to delgocitinib or any component of the IMP. 
25. Subject has a history of an allergic reaction or significant sensitivity to hypoallergenic ink. 
26. Subject has a known history of clinically significant drug or alcohol abuse in the last year prior to 
Day 1. 
Exclusion criteria for Cohort 2 only (healthy subjects): 
27. Subject has a history of skin disease or presence of skin condition that, in the opinion of the 
investigator, would interfere with the trial assessments.  
28. Subject has any clinically significant medical condition or physical/vital signs abnormality that 
would, in the opinion of the investigator, put the subject at undue risk or interfere with interpretation 
of trial results. 
29. Subject has a known history of chronic infectious disease (e.g., hepatitis B, hepatitis C, or HIV). 
30. Subject has used a topical medicated treatment on the targeted skin sites within 2 weeks prior to skin 
samples collection (Day 1).   
Statistical methods:  
Continuous variables will be summarized in tables and will include the number of subjects, mean, 
standard deviation (SD), median, minimum, maximum, first (Q1) and third (Q3) quartiles. Categorical 
variables will be presented in tables as frequencies and percentages.  
Molecular Signature Changes Analyses: 
A Mixed Effect Model Repeated Measurement (MMRM) will be used to detect any overall differences 
in the treatment effect at Week 12 compared to baseline in the molecular measurements. This formulation 
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. 
Confidential and proprietary. Permission should be obtained before any reproduction. 
Name of Sponsor/Company:  
LEO Pharma A/S 
Name of Investigational Product: 
Delgocitinib cream 20 mg/g 
Name of Active Ingredient: 
Delgocitinib 
intrinsically models the within patient correlation structure as in the case of a paired t-test. This approach 
introduces less bias than restricting the analysis for those patients who completed the trial. Time points 
(baseline, Week 12), treatment group (active, vehicle, and healthy), and tissue (lesional and non-lesional) 
will be considered as fixed factors, while participant ID will be included as random factor. 
Safety Analyses:  
Safety data will be summarized descriptively per cohort. No missing data will be imputed, and no 
inferential statistics are planned. For Cohort 1, the safety analysis will include reported AEs, including 
TEAEs, and other safety information (ie. clinical laboratory evaluations and vital signs). For Cohort 2, 
the safety analysis will include reported procedural complications. 
Efficacy Analyses:  
The comparison between the groups for the exploratory efficacy endpoints involving change from 
baseline will be done using a MMRM, where the absolute change from baseline will be the dependent 
variable; the treatment group, the visit, and an interaction term for the treatment-by-visit will be the fixed 
effects; and the baseline value will be the covariate. 
The other efficacy endpoints involving proportions of pruritus NRS, burning sensation NRS, and pain 
NRS will be analyzed using a Chi-square test. 
Sample Size Consideration: 
From Del Duca et al. (2020) paper1, the difference in log2-fold changes (SD*) between FFA patients and 
healthy controls are reported to 4.851 (4.411), 5.298 (5.512) and 4.559 (4.891) for CXCL9, CXCL10 
and IFN-γ, respectively. 
A sample 30 subjects are randomized in an equal manner (1:1) to delgocitinib cream 20 mg/g or vehicle 
cream. It is expected that a reduction of at least 90% from baseline to Week 12 for the delgocitinib cream 
20 mg/g treated subjects compared to only 5% in the vehicle group, normalized to healthy controls, will 
be observed. 
With the above assumptions, the trial should have at least 80% disjunctive power, i.e. a statistically 
significant difference (tested at 5% one-sided level in an independent two-sample t-test) can be shown 
with at least 80% probability, in at least one of the genes, assuming no correlation between the tests and 
same level of variation as reported in the Del Duca et al. (2020) paper1. 
 
*Derived from the reported p-values coming from a t-test comparing lesional FFA biopsy data (N=12) to data from 
healthy controls (N=8). 
 
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1.2 Trial Diagram 
Figure 1: Trial Diagram 
Cohort 1 and Cohort 2 can be conducted in parallel. 
Cohort 1: 
Abbreviations: BID, twice daily; OLE, open-label extension. 
Cohort 2: 
Notes: For Cohort 2 only, screening and skin samples collection on Day 1 can be performed on the same day at the 
investigator’s discretion, if no medication washout is required and the lifestyle considerations are fulfilled. The 
optional follow-up period will occur 10 to 14 days after Day 1, to remove biopsy sutures, if needed.  
1.3 Schedule of Events 
The screening evaluation will only be performed after the subject has agreed to participate and has 
signed and dated the ICF. No treatment or trial-related procedures will be initiated before the 
informed consent is signed. The Day 1 visit must be performed, at the latest, 30 days after the 
screening visit. For Cohort 2 only (healthy subjects), the sample collections on Day 1 can be 
performed on the same day as the screening visit or on separate visits as per the schedule of events, 
at the investigator’s discretion. 
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The screening evaluation will be performed according to the inclusion and exclusion criteria. If 
the subject fulfills all inclusion criteria and no exclusion criteria, he or she may be included in the 
trial.  
Table 1 and Table 2 provide a description of the procedures to be performed at each visit for 
Cohort 1 and Cohort 2, respectively. 
Unless specified otherwise, the trial assessments scheduled during the trial visits must be 
performed before the IMP application for subjects in Cohort 1. If assessments are scheduled for 
the same nominal time, then the assessments should occur in the following order: 
•
Patient-reported outcomes
•
Investigator assessments
•
Vital signs
•
Medical photographs
•
Collection of skin samples
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Table 1: Schedule of Events for Cohort 1 (Subjects with FFA) 
Trial Visits 
Screening 
Treatment Period 
Follow-
Up 
ET 
Vehicle-Controlled 
OLE 
Day 1 
Week 4 
Week 8 
Week 12 Week 16 Week 20 Week 24 Week 26 
- 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
- 
Window (days) 
-30 to -1 
- 
2 
2 
2 
4 
4 
4 
4 
- 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
Medical and surgical history 
X 
X 
 
 
 
 
 
 
 
 
Inclusion-exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Pregnancy testa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory tests 
(biochemistry and hematology) 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
TSH and reflex free T4 
X 
 
 
 
 
 
 
 
 
 
Serology (HBV [HBsAg, 
anti-HBc], HCV, HIV) 
X 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
Complete Physical examination 
X 
 
 
 
X 
 
 
X 
X 
X 
Brief Physical examination 
 
X 
X 
X 
 
X 
X 
 
 
 
Vital signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Identification of a lesional target 
area on the scalp and of a non 
lesional area (eg. occipital scalp)c 
X 
X 
 
 
 
 
 
 
 
 
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Trial Visits 
Screening 
Treatment Period 
Follow-
Up 
ET 
Vehicle-Controlled 
OLE 
Day 1 
Week 4 
Week 8 
Week 12 Week 16 Week 20 Week 24 Week 26 
- 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
- 
Window (days) 
-30 to -1 
- 
2 
2 
2 
4 
4 
4 
4 
- 
Perifollicular erythema and scale 
evaluation of the lesional target 
area 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pruritus NRSd 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Burning Sensation NRSd 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pain NRSd 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
LPPAI 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
FFASS 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Hair counts/Trichoscopy 
 
X 
 
 
X 
 
 
X 
 
X 
Hair line measurementse  
 
X 
 
 
X 
 
 
X 
 
X 
Medical photographsf 
 
X 
 
 
X 
 
 
X 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
IMP application at site 
 
X 
X 
X 
X 
X 
X 
 
 
 
IMP application BIDg 
 
X-------------------------------------------------------------------------------X 
 
 
IMP distribution 
 
X 
X 
X 
X 
X 
X 
 
 
 
IMP collection and/or 
accountability and/or compliance 
 
 
X 
X 
X 
X 
X 
X 
 
X 
Subject diary 
distribution/collection/review 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Local tolerability assessmentsh 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
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Trial Visits 
Screening 
Treatment Period 
Follow-
Up 
ET 
Vehicle-Controlled 
OLE 
Day 1 
Week 4 
Week 8 
Week 12 Week 16 Week 20 Week 24 Week 26 
- 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
- 
Window (days) 
-30 to -1 
- 
2 
2 
2 
4 
4 
4 
4 
- 
Skin biopsies collectioni,j 
 
X 
 
 
X 
 
 
 
 
 
Adhesive skin tape strip samplesk 
 
X 
 
 
X 
 
 
 
 
 
Skin microbiome samplesl 
 
X 
 
 
X 
 
 
 
 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: anti-HBc, antibody to hepatitis B core antigen; BID, twice daily; ET, early termination; FFA, frontal fibrosing alopecia; FFASS, Frontal Fibrosing 
Alopecia Severity Score; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IMP, 
investigational medicinal product; LPPAI, lichen planopilaris activity index; NRS, Numerical Rating Scale; OLE, open-label extension; TSH, thyroid-stimulating 
hormone; V, visit. 
a For female subjects of childbearing potential, serum pregnancy test at screening and urine pregnancy test at other specified visits.  
b Including height and weight. Height will be measured only at screening.  
c The lesional target area should be treated with the IMP and should be approximately 3 cm x 6 cm (or equivalent). However, a smaller lesional target area can 
be selected if tape stripping is performed from the same area where trichoscopy/hair counts is performed or if sample is collected adjacent/close to the lesional 
target area (refer to Section 8.3.2 for details). If needed, two small lesional target areas (totalling approximately the same size) could be selected to allow for 
skin samples collection. 
d Subjects will complete their NRS at home on a daily basis starting approximately 7 days prior to Day 1 and up to Day 8. On Day 1, the NRS will be 
completed at the site prior to the first IMP application. After Day 8, the NRS will be completed at the site at the specified visits only.  
e Hair line measurements of lateral canthus (right and left) to hairline, lower glabellar crease to hair line, top of frontalis muscle to hair line, and mid brow to hair 
line (right and left). 
f Medical photographs of the target area and the entire scalp (including the frontal hair line and right and left hair line areas). 
g The morning application will be on site on visit days. Other IMP applications will be done at home. The first application of the OLE (delgocitinib cream 
20 mg/g) is on the morning of Week 12, after all efficacy assessments and skin sample collections are completed. The last application of the OLE is the 
evening prior to the Week 24 visit. No IMP application will be done on the day of the Week 24 visit. 
h Local tolerability assessments will be done by subjects. On Day 1 and Week 12, the local tolerability assessment will be done approximately 30 minutes after 
the IMP application at the site, with a recall period of 30 minutes. At other visits, the subject’s local tolerability assessment will be done before the IMP 
application with a recall period of 7 days (worst over the last 7 days).  
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Trial Visits 
Screening 
Treatment Period 
Follow-
Up 
ET 
Vehicle-Controlled 
OLE 
Day 1 
Week 4 
Week 8 
Week 12 Week 16 Week 20 Week 24 Week 26 
- 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
- 
Window (days) 
-30 to -1 
- 
2 
2 
2 
4 
4 
4 
4 
- 
i On Day 1, 2 skin biopsies (4-mm) will be collected prior to the first IMP application (1 from a lesional hair follicle within the target area and 1 from a non 
lesional hair follicle [eg, on the occipital scalp]). On Week 12, 1 skin biopsy (4-mm) will be collected from a hair follicle within the lesional target area (outside 
the scar of previous biopsies).  
j Within 10 to 14 days after biopsy collection, suture may be removed, if needed. An additional visit(s) may be necessary for suture removal only, if suture 
removal is needed after Day 1 and/or Week 12. 
k On Day 1, optional skin tape strips will be collected prior to the first IMP application from lesional skin and from non lesional skin (eg, on the occipital scalp). 
The lesional skin tape strip should ideally be collected from the target area but can also be collected adjacent/close to the target area, as long as it includes a 
portion of lesional skin and is treated with the IMP. On Week 12, skin strips will be collected at the same location of the lesional skin. Every effort should be 
made to collect tape strip samples in all subjects however, adhesive tape strip collection is optional and will be collected per investigator judgement (based on 
available skin area on the scalp). 
l On Day 1, skin swab for microbiome analysis will be collected prior to the first IMP application (1 from the target area [lesional skin] and 1 from an uninvolved 
occipital scalp area). On Week 12, skin microbiome will be collected at the same location of the lesional skin of the target area.  
 
 
 
 
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Table 2: Schedule of Events for Cohort 2 (Healthy Subjects) 
Trial Visits 
Screening 
Sample Collection Day 
Follow-Up (Optional) 
V1 
V2 
V3 
Window (days) 
-30 to -1 
- 
10 to 14 days after Day 1 
Informed consent  
X 
 
 
Demographics  
X 
 
 
Medical and surgical history 
X 
X 
 
Inclusion-exclusion criteria 
X 
X 
 
Brief physical examination 
X 
X 
 
Vital signsa 
X 
X 
 
Skin biopsies collectionb 
 
X 
 
Suture removal (if applicable) 
 
 
X 
Adhesive skin tape strip samplesc 
 
X 
 
Skin microbiome samplesd 
 
X 
 
Concomitant medication 
X 
X 
X 
Procedural complications evaluation 
X 
X 
X 
Abbreviation: V, visit. 
Note: Screening and Day 1 can be performed on the same day (if subjects do not have a washout period for any of the medications or procedures listed in the 
exclusion criterion or lifestyle considerations) and the scheduled assessments on these two days can be completed only once in this case. 
a Including height and weight. Height will be measured only at screening.  
b Two skin biopsies (4-mm) that include hair follicles will be collected on healthy skin at similar matched areas of subjects with FFA (ie., 1 from frontal area and 
1 from occipital scalp area).   
c Skin tape strips will be collected on non-hair bearing healthy skin at a similar matched area of subjects with FFA (ie, on the forehead, as close as possible to the 
frontal scalp area).  
d Two skin swab samples for microbiome analysis will be collected on healthy skin at similar matched areas of subjects with FFA (ie, 1 on frontal scalp area and 
1 from occipital scalp area).  
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2 INTRODUCTION 
2.1 Background 
 Frontal Fibrosing Alopecia 
Frontal fibrosing alopecia (FFA) was first described in 1994 and is a type of primary lymphocytic 
cicatricial alopecia that is often considered a clinical variant of lichen planopilaris (LPP) due to 
their shared histopathologic features.2 This variant of LPP is most commonly found in 
postmenopausal women and is increasing in prevalence.3 FFA is characterized by the recession of 
the frontal, temporal, or frontotemporal hairline; the clinical pattern is distinct and usually includes 
eyebrow hair loss, as well as other associated symptoms. Pruritus, facial papules, eyelash loss, 
body hair involvement, and trichodynia may also occur in addition to the frontotemporal recession 
and eyebrow loss classically seen.2  
Early diagnosis and prompt treatment are critical as FFA is a progressive disorder that can result 
in permanent hair loss. However, even with aggressive therapy, FFA may progress. There are a 
limited number of published guidelines for the treatment of FFA and there is no consensus or 
standard treatment regimen for FFA.2 Intralesional corticosteroids may achieve some disease 
stabilization, with associated adverse effects such as pain and skin atrophy, and topical 
corticosteroids are often not effective.1 In addition, no therapeutic interventions selectively target 
cellular or molecular key elements of FFA pathogenesis.4  
The etiology and pathogenesis of FFA are not completely understood and remain areas of active 
investigation. The inflammatory cell infiltrate surrounding lesional hair follicles, namely around 
the bulge and infundibulum, is characterized by an increase in CD8+ GranzymeB+ cytotoxic T 
cells and plasmacytoid dendritic cells (pDC), with elevated levels of the chemokine receptor 
CXCR3 expression.4 The available evidence suggests a key role for interferon (IFN)-γ in inducing 
hair follicule immune privilege (HFIP) bulge collapse and subsequent immune-mediated epithelial 
hair follicle stem cells (eHFSC) destruction observed in FFA.4 Therapeutically, bulge immune 
privilege protection/restoration or neutralizing IFN-γ may help to better manage this highly 
treatment-resistant cicatricial alopecia.  
 Delgocitinib 
Delgocitinib is a novel pan-Janus kinase (JAK) inhibitor. After a cytokine binds to its receptor, the 
JAK family is activated intracellularly, and promotes growth and activation of a variety of cells 
(eg, lymphocytes) via phosphorylation of the downstream substrate signal transducer and activator 
of transcription (STAT). The JAK family is essential for the physiological activity of cytokines 
and plays a critical role in the pathogenesis of diseases with an immunoinflammatory component.5  
The JAK-STAT pathway is a promising target for the treatment of disorders with an 
immunoinflammatory component. Several JAK inhibitors (such as ruxolitinib, baricitinib, and 
tofacitinib) are in clinical development or are already approved for oral or topical treatment of 
various chronic inflammatory conditions. Delgocitinib ointment (that was developed by Japan 
Tobacco In. [JT]) has been approved for topical treatment of children aged 2 years and older and 
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adults with atopic dermatitis (AD) in Japan and delgocitinib cream has shown promising efficacy 
in inflammatory skin diseases such as chronic hand eczema and AD.5  
Based on the nonclinical and clinical data currently available, delgocitinib has the potential to 
become a novel local-acting, selective immunosuppressive agent suitable for the topical treatment 
of inflammatory dermatological diseases such as FFA.5 
 Trial Rationale 
FFA demonstrated significant upregulation of T helper 1/IFN (IFN-γ, CXCL9/CXCL10), the 
JAK-STAT pathway (STAT1, JAK3) and fibrosis-related products (vimentin, fibronectin).1 The 
increased expression of IFN-γ-inducible chemokines (CXCL9, CXC10, and CXC11) and cognate 
receptor 3 (CXCR3) in lesional FFA bulge epithelium suggest that the CXCL9/10/11-CXCR3 
signaling system plays a major role in attracting the inflammatory cell infiltrate in FFA. Interfering 
with the JAK-STAT signaling pathway may be a novel approach to suppress aberrant immune 
responses in patients with FFA.6  
It is hypothesized that delgocitinib cream 20 mg/g will reduce INF-γ driven inflammation in 
subjects with FFA. In the present trial, the molecular signature changes following topical 
application of delgocitinib cream 20 mg/g in subjects with FFA will be evaluated. The safety and 
preliminary efficacy of delgocitinib cream in subjects with FFA will also be evaluated. 
2.2 Risk/Benefit Assessment 
 Known Potential Risks 
A total of 15 clinical trials, 1 with oral delgocitinib (sponsored by JT), 11 with delgocitinib 
ointment (7 sponsored by JT and 4 sponsored by LEO Pharma A/S), and 3 with delgocitinib cream 
(sponsored by LEO Pharma A/S), have been completed and 2 clinical trials with delgocitinib cream 
are currently ongoing (sponsored by LEO Pharma A/S). In total, 54 subjects were dosed orally 
with delgocitinib (at doses between 1 and 100 mg) and 1635 subjects were exposed topically to 
delgocitinib ointment (1165 subjects at concentrations between 0.3 and 30 mg/g) or delgocitinib 
cream (470 subjects at concentrations between 1 and 20 mg/g). 
Delgocitinib ointment and delgocitinib cream were well tolerated in the conducted clinical trials 
and systemic exposure to delgocitinib has been low. No clinical indication of any phototoxic 
potential was observed for delgocitinib cream when single occlusive application of delgocitinib 
was followed by light exposure in healthy subjects. Potential risks to humans that could arise from 
use of delgocitinib cream are local skin infection, and acneiform eruptions, which have been 
reported in clinical trials with delgocitinib ointment. Only few serious adverse events (SAEs) were 
reported in the completed clinical trials. Except for one, all SAEs were considered not related to 
treatment. There was no pattern in the reported preferred terms (PT). The one related SAE was an 
event of Kaposi’s varicelliform eruption reported in a JT trial with delgocitinib ointment in 
Japanese subjects. The subject experiencing this event was hospitalized, and the event was 
resolved. 
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Generally, no clinically significant changes in laboratory test values, in systolic blood pressure, 
diastolic blood pressure, pulse rate, or body temperature were observed in subjects exposed to 
delgocitinib cream. Lymphocytopenia was observed in oral nonclinical toxicity studies and is 
considered a potential clinical consequence of systemic levels of delgocitinib. Lymphocytopenia 
is therefore considered an important potential risk for delgocitinib cream. 
Further information related to nonclinical and clinical studies is available in the Investigator 
Brochure (IB).5 
 Known Potential Benefits 
For Cohort 1, it is anticipated that subjects randomized to the active investigational medicinal 
product (IMP) during the vehicle--controlled treatment period and all subjects continuing into the 
OLE will see an improvement or a stabilization in their FFA condition as a result of participating 
in this Phase 2a trial. 
For Cohort 2, there are no anticipated benefits for subjects participating in the trial, other than the 
benefit of medical evaluation at screening and throughout the trial. 
Participation in this trial may help generate future benefit for larger groups of patients with FFA. 
 Assessment of Risks and Benefits 
All previous data demonstrated in nonclinical and clinical trials are considered sufficient to expect 
a positive benefit/risk ratio for the treatment of FFA with delgocitinib cream 20 mg/g, and therefore 
to initiate this trial. 
The risks to subjects in this trial will be minimized by compliance with the eligibility criteria, 
proper trial design, and close monitoring. 
 COVID-19 Pandemic 
Initiating and conducting clinical trials during Coronavirus Disease 2019 (COVID-19) pandemic, 
presents numerous challenges. Control measures in place in different regions may impact the 
ability to adhere to some of the trial procedures described in this protocol. Due to challenges that 
include but are not limited to participant preferences, site closures, travel restrictions, and 
quarantines, some modifications to trial conduct during the COVID-19 pandemic may be 
necessary to ensure trial continuity and safety of the participants and trial staff.  Adequate 
benefit/risk analyses should be applied relative to the completion of study procedures. Recognizing 
the flexibility required to manage the impact of the pandemic on this clinical trial, additional details 
may be added to study manual(s) and communicated to the site, as needed.   
Taking into account the modifications to trial conduct that could occur to minimize risk related to 
COVID-19 in this trial, the potential risks to participate in this trial during the pandemic are 
justified by the anticipated benefits that may be afforded to subjects with FFA. 
In addition, it is not believed that treatment with delgocitinib cream will put subjects at an 
increased risk for viral infections, including SARS-CoV-2. Vaccination for COVID-19 will be 
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allowed during the study, if needed, without changes in currently planned trial procedures and IMP 
applications. 
 
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3 OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
Primary 
 
To assess molecular 
signature changes 
following topical 
application of delgocitinib 
cream 20 mg/g in subjects 
with FFA 
Primary endpoint: 
• Change in expression of CXCL9, CXCL10, and IFN-γ from 
baseline to Week 12. 
Secondary 
 
To evaluate the safety and 
tolerability of delgocitinib 
cream 20 mg/g following 
topical application in 
subjects with FFA during 
the vehicle-controlled 
treatment period. 
Safety endpoint during the vehicle-controlled treatment period: 
• Number of TEAEs from baseline to Week 12.  
 
Exploratory  
 
To evaluate the safety and 
tolerability of delgocitinib 
cream 20 mg/g during the 
OLE. 
Exploratory safety endpoint: 
• Number of TEAEs during the OLE (up to Week 26) 
To evaluate the 
preliminary efficacy of 
delgocitinib cream 
20 mg/g following topical 
application in subjects 
with FFA. 
Exploratory efficacy endpoints during the vehicle-controlled 
treatment period: 
• Change in LPPAI score from baseline to Weeks 4, 8, and 12. 
• Change in FFASS score from baseline to Weeks 4, 8, and 12. 
• Change in target area perifollicular erythema score from 
baseline to Weeks 4, 8, and 12. 
• Change in target area perifollicular scale score from baseline 
to Weeks 4, 8, and 12. 
• Change in pruritus NRS score from baseline to Days 2, 3, 4, 
5, 6, 7, 8, and Weeks 4, 8, and 12. 
• Change in burning sensation NRS score from baseline to 
Days 2, 3, 4, 5, 6, 7, 8, and Weeks 4, 8, and 12. 
• Change in pain NRS score from baseline to Days 2, 3, 4, 5, 
6, 7, 8, and Weeks 4, 8, and 12. 
• Proportion of subjects with a 3-point reduction* in pruritus 
NRS score from baseline to Days 2, 3, 4, 5, 6, 7, 8, and 
Weeks 4, 8, and 12. 
• Proportion of subjects with a 4-point reduction* in pruritus 
NRS score from baseline to Days 2, 3, 4, 5, 6, 7, 8, and 
Weeks 4, 8, and 12. 
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OBJECTIVES 
ENDPOINTS 
• Proportion of subjects with a 3-point reduction* in burning 
sensation NRS score from baseline to Days 2, 3, 4, 5, 6, 7, 8, 
and Weeks 4, 8, and 12. 
• Proportion of subjects with a 4-point reduction* in burning 
sensation NRS score from baseline to Days 2, 3, 4, 5, 6, 7, 8, 
and Weeks 4, 8, and 12. 
• Proportion of subjects with a 3-point reduction* in pain NRS 
score from baseline to Days 2, 3, 4, 5, 6, 7, 8, and Weeks 4, 
8, and 12. 
• Proportion of subjects with a 4-point reduction* in pain NRS 
score from baseline to Days 2, 3, 4, 5, 6, 7, 8, and Weeks 4, 
8, and 12. 
• Change in target area hair counts/trichoscopy via fotofinder 
trichovision from baseline to Week 12. 
Exploratory efficacy endpoints during the OLE: 
• These efficacy outcomes will be measured at scheduled visits 
after Week 12: LPPAI, FFASS, target area perifollicular 
scale score, target area perifollicular erythema score, pruritus 
NRS, burning sensation NRS, pain NRS, and target area hair 
counts/trichoscopy via fotofinder trichovision. 
Abbreviations: CXCL9, chemokine (C-X-C motif) ligand 9; 10, chemokine (C-X-C motif) ligand 10; 
FFA, frontal fibrosing alopecia; FFASS, Frontal Fibrosing Alopecia Severity Score; INF, interferon, 
LPPAI, Lichen Planopilaris Activity Index; NRS, Numerical Rating Scale; TEAE, treatment-emergent adverse 
event. 
* Only subjects with a baseline NRS score ≥3 will be included in the respective endpoints on proportion of 
subjects with a 3-point reduction. Only subjects with a baseline NRS score ≥4 will be included in the respective 
endpoints on proportion of subjects with a 4-point reduction. 
 
 
 
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4 TRIAL DESIGN 
4.1 Overall Design 
A Phase 2a, randomized, double-blind, vehicle-controlled, single-site, exploratory trial of 
delgocitinib cream 20 mg/g in subjects with FFA. 
The trial will consist of 2 cohorts: Cohort 1 will include approximately 30 subjects with FFA and 
Cohort 2 will include approximately 5 healthy postmenopausal female subjects. Both cohorts can 
be conducted in parallel.  
Cohort 1: 
All subjects will read and sign an informed consent form (ICF) prior to any trial-related activities 
being performed. Subjects who fulfill all of the inclusion criteria and none of the exclusion criteria 
will be randomized into the trial. After a screening period of no more than 30 days (from Day -30 
to Day -1), eligible subjects will be randomized (1:1) on Day 1 to apply delgocitinib cream 20 mg/g 
or vehicle cream BID for 12 weeks during the vehicle-controlled treatment period. All subjects 
who complete the vehicle-controlled treatment period will then continue into the OLE and apply 
delgocitinib cream 20 mg/g BID for 12 weeks. The OLE period will be followed by a 2-week 
safety follow-up period. For scheduled trial visits, subjects will come to the site on 9 occasions: 
screening, Day 1, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, and Week 26/early 
termination (ET).  
On Day 1, a lesional target area on the scalp (eg, frontal, periauricular, or temporal area) that be 
treated with the IMP will be identified. To allow for the hair count/trichoscopy assessment and all 
samples collection (ie, skin biopsies, tape stripping, and skin swabs) the lesional target area should 
be approximately 3 cm x 6 cm (or equivalent). However, as tape strips can be collected from the 
same area where trichoscopy/hair counts is performed or can be collected adjacent/close to the 
lesional target area (refer to Section 8.3.2 for details), a smaller lesional target area may be 
acceptable. If needed, two small target areas (totalling approximately the same size) could also be 
selected to allow for skin samples collection and hair count/trichoscopy assessment. If two lesional 
target areas are selected, they should be of similar severity.    
The following skin samples will be collected during the trial to assess molecular signature changes: 
- 
Skin biopsies for transcriptomic and immunohistochemistry (IHC) analyses (n=3): 
o Day 1: 2 skin biopsies (4-mm) will be collected prior to the first IMP application 
(1 from a lesional hair follicle within the target area and 1 from a non lesional hair 
follicle [eg, on the occipital scalp]). 
o Week 12: 1 skin biopsy (4-mm) will be collected from a hair follicle within the 
lesional target area (outside the scar of previous biopsies). 
- 
Skin swabs for microbiome analysis (n=3): 
o Day 1: 2 skin microbiome samples will be collected prior to the first IMP 
application (1 from the target area [lesional skin] and 1 from an uninvolved 
occipital scalp area). 
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o Week 12: 1 skin microbiome sample will be collected at the same location of the 
lesional skin of the target area. 
- 
Adhesive tape strips samples for transcriptomic analysis (n=3): 
o Day 1: skin tape strips will be collected prior to the first IMP application from 
lesional skin and from a nonlesional skin (eg, on the occipital scalp). 
o Week 12: skin tape strips will be collected at the same location of the lesional skin.  
Note: Every effort should be made to collect tape strip samples in all subjects however, 
adhesive tape strip collection is optional and will be collected per investigator’s 
judgement (based on available skin area on the scalp). 
Safety will be assessed by collecting adverse events (AEs), recording vital signs, performing 
complete and brief physical examinations, and evaluating clinical laboratory results and local 
tolerability assessments (LTA). 
Efficacy will be assessed using LPPAI, FFASS, evaluation of the perifollicular erythema and 
perifollicular scale, pruritus NRS, burning sensation NRS, pain NRS, and hair counts/trichoscopy 
(eg, number of hairs, hair diameter, and hair density). Hair line measurements (ie, lateral canthus 
[right and left] to hairline, lower glabellar crease to hair line, top of frontalis muscle to hair line, 
and mid brow to hair line [right and left]) will also be done. 
Medical photographs of the lesional target area and the entire scalp (including the frontal hair line 
and right and left hair line areas) will be taken with the fotofinder device during the trial. 
Cohort 2: 
All subjects will read and sign an ICF prior to any trial-related activities being performed. Subjects 
who fulfill all of the inclusion criteria and none of the exclusion criteria will be accepted into the 
trial. After a screening period of no more than 30 days (from Day -30 to Day -1), eligible subjects 
will be asked to come at the site for skin samples collection. Screening and skin samples collection 
on Day 1 can be performed on the same day (if subjects do not have a washout period) or on two 
separate visits, at the investigator’s discretion. No investigational product will be administered in 
Cohort 2. For scheduled trial visits, subjects will come to the site on up to 3 occasions: screening, 
Day 1, and optional follow-up visit. 
The following skin samples will be collected: 
- 
Skin biopsies (n=2): 
o Day 1: 2 skin biopsies (4-mm) that include hair follicles will be collected on healthy 
skin at similar matched areas of subjects with FFA (ie, 1 from frontal scalp area 
and 1 from occipital scalp area) 
- 
Adhesive tape strips (n=1): 
o Day 1: skin tape strips will be collected on non-hair bearing healthy skin at a similar 
matched area of subjects with FFA (ie, on the forehead, as close as possible to the 
frontal scalp area). 
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- 
Skin swabs for microbiome analysis (n=2): 
o Day 1: 2 skin microbiome samples will be collected on healthy skin at similar 
matched areas of subjects with FFA (ie, 1 from frontal scalp area and 1 from 
occipital scalp area). 
For Cohort 2 only, safety will be assessed by review of any procedural complications and changes 
in health observed after skin samples collection.  
No interim analysis is planned in this trial. 
4.2 Scientific Rationale for Trial Design  
This is an exploratory trial to interrogate the effect of delgocitinib cream 20 mg/g on the molecular 
signature of active FFA. Frontal fibrosing alopecia demonstrated significant upregulation of 
T helper 1/IFN (IFN-γ, CXCL9/CXCL10), the JAK-STAT pathway (STAT1, JAK3) and 
fibrosis-related products (vimentin, fibronectin). Delgocitinib is a novel pan- JAK inhibitor. It is 
hypothesized that delgocitinib cream 20 mg/g will reduce INF-γ driven inflammation in subjects 
with FFA. The proposed design is considered appropriate for assessing the molecular signature 
changes, the safety, as well as preliminary efficacy of delgocitinib cream 20 mg/g in subjects with 
FFA.  
In this Phase 2a trial, the vehicle-controlled treatment period will be randomized to ensure random 
allocation of subjects to treatment arms to reduce bias. Because efficacy assessments of FFA have 
a high degree of subjectivity, the trial will be double-blinded. The highest degree of patient and 
assessor blinding should be sought to achieve credible inference. It is also important to have a 
vehicle control in the Phase 2a trial to control for confounding factors, such as potential 
investigator bias, and to ensure that the statistical procedures can be appropriately applied. After 
completion of the vehicle-controlled treatment period, all subjects will have the opportunity to 
continue into the OLE and to receive the active drug for a period of 12 weeks.  
Inclusion of 5 healthy postmenopausal female subjects to collect skin samples will allow 
comparison of the molecular and cellular fingerprint to that of subjects with FFA. 
4.3 Justification for Dose 
The justification for the delgocitinib dose is based on the findings from the Phase 2b trial in 
subjects with AD. Delgocitinib cream was tested at 4 different strengths (1, 3, 8, and 20 mg/g) 
BID for up to 8 weeks in subjects with AD. A statistically significant dose-response was 
established for the primary endpoint (change in Eczema Area and Severity Index [EASI] from 
baseline to Week 8), and the secondary endpoints (Validated Investigator Global Assessment for 
Atopic Dermatitis treatment success [vIGA-AD TS] at Week 8 and EASI75 [a 75% reduction in 
EASI score] at Week 8). The highest treatment effect (compared to cream vehicle) was seen with 
delgocitinib cream 20 mg/g. 
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4.4 End of Trial Definition 
A subject is considered to have completed the trial if he or she has completed all phases of the 
trial, including the last visit or the last scheduled procedure shown in the Schedule of Events, 
Table 1 (for Cohort 1) and Table 2 (for Cohort 2). 
The end of the trial is defined as completion of the last visit or procedure shown in the schedule of 
event for the last enrolled subject in Cohort 1 and Cohort 2. 
 
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5 TRIAL POPULATION  
5.1 Inclusion Criteria 
In order to be eligible to participate in this trial, a subject must meet all of the following criteria, 
either at the screening and Day 1 visits or only at one of the specified visits (screening or Day 1) 
as noted in the criterion:  
Inclusion criteria for all subjects: 
1. Subject is willing to participate and is capable of giving informed consent. Note: Consent must 
be obtained prior to any trial-related procedures.  
2. Subjects must be willing to comply with all trial procedures and must be available for the 
duration of the trial. 
Inclusion criteria for Cohort 1 only (subjects with FFA): 
3. Male or female subject aged 18 years of age or older at the time of consent.  
4. Female subject of childbearing potential has had a negative serum pregnancy test at screening 
and negative urine pregnancy test at Day 1.  
5. Subject has clinically confirmed diagnosis of FFA based on investigator’s judgment. 
6. Subject has a target area with a perifollicular erythema score ≥ 2 and a perifollicular scale score 
≥ 2 at Screening and Day 1. 
7. For subject who uses make-up, moisturizers, creams, lotions, cleansers, and/or sunscreens on 
the face, subject has used the same product brands/types for a minimum period of 4 weeks 
prior to Day 1, agrees not to change brand/type or frequency of use throughout the trial, agrees 
not to apply those products on the treated area during the trial, and agrees not to use make-up, 
moisturizers, creams, lotions, cleansers, and/or sunscreens on the face on the clinic visit days 
before the visit. 
8. Subject is willing to maintain a consistent hair style and hair style regimen, including shampoo 
and hair products (including hair dye, process, and timing to hair appointments), and to refrain 
from weaves or extensions throughout the course of the trial and for 4 weeks prior to Day 1. 
Note: Hair dying and shaving of scalp is allowed during the trial but not within 48 hours prior 
to a trial visit 
9. For female subject of childbearing potential involved in any sexual intercourse that could lead 
to pregnancy: the subject must agree to use an effective contraceptive method from at least 
4 weeks prior to Day 1 until at least 4 weeks after the last IMP application. Effective 
contraceptive methods include hormonal contraceptives (eg, combined oral contraceptive, 
progesterone-only hormonal contraception [associated with or without inhibition of ovulation  
as the primary mode of action], patch, vaginal ring, injectable, or implant), intrauterine devices 
or intrauterine systems, vasectomized partner(s) (provided his vasectomy was performed 
≥4 months prior to Screening), tubal ligation or a barrier method of contraception (eg, male 
condom, female condom, cervical cap, diaphragm, contraceptive sponge) in conjunction with 
spermicide.  
Note: Subjects must have been on a stable dose of hormonal contraceptives for at least 4 weeks 
before Day 1.  
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Note: The above list of contraceptive methods does not apply to subjects who are abstinent for 
at least 4 weeks before Day 1 and will continue to be abstinent from penile-vaginal intercourse 
throughout the trial.  The reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the clinical trial and the preferred and usual lifestyle of the subject. Periodic 
abstinence (calendar, symptothermal, post-ovulation methods) is not acceptable. 
Note: A female subject of nonchildbearing potential is defined as follows:  
– 
Female subject who has had surgical sterilization (hysterectomy, bilateral oophorectomy, 
or bilateral salpingectomy) 
– 
Female subject who has had a cessation of menses for at least 12 months prior to the 
screening visit without an alternative medical cause  
Inclusion criteria for Cohort 2 only (healthy subjects): 
10. Female subject aged 45 years of age or older at the time of consent.  
11. Female is postmenopausal as defined below: 
– 
Female subject who has had surgical sterilization (hysterectomy, bilateral oophorectomy, 
or bilateral salpingectomy) 
– 
Female subject who has had a cessation of menses for at least 12 months prior to the 
screening visit without an alternative medical cause. 
12. Subject is in good general health, according to the investigator’s judgment based on vital signs, 
medical history, and brief physical examination.  
5.2 Exclusion Criteria 
A subject who meets any of the following criteria at the screening and/or Day 1 visits, as 
applicable, will be excluded from participation in this trial: 
Exclusion criteria for all subjects: 
1. Subject is a female who is breastfeeding, pregnant, or who is planning to become pregnant 
during the trial. 
2. Subject has received any marketed or investigational biological agent within 12 weeks or 
5 half-lives (whichever is longer) prior to Day 1. 
3. Subject is currently receiving a nonbiological investigational product or device or has received 
one within 4 weeks prior to Day 1. 
4. Subject has had excessive sun exposure or has used tanning booths within 4 weeks prior to 
Day 1 or is not willing to minimize natural and artificial sunlight exposure during the trial. Use 
of sunscreen products (except on treated areas for subjects in Cohort 1) and protective apparel 
are recommended when sun exposure cannot be avoided. 
5. Subject has a history of an allergic reaction or significant sensitivity to lidocaine or other local 
anesthetics. 
6. Subject has a history of hypertrophic scarring or keloid formation in scars or suture sites. 
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Exclusion criteria for Cohort 1 only (subjects with FFA): 
7. History of other scalp/hair disease including discoid lupus erythematosus and central 
centrifugal cicatricial alopecia. 
Note: Subjects with lichen planopilaris/FFA overlap are not to be excluded.  
8. Presence of active dermatologic condition that might interfere with FFA diagnosis and/or 
interfere with the trial assessments such as seborrheic dermatitis, psoriasis, or telogen 
effluvium. 
9. Subject who has undergone scalp reduction surgery or hair transplantation. 
10. Use of adhesive wigs during the trial. 
11. Subject is known to have immune deficiency or is immunocompromised. 
12. Subject has a history of cancer or lymphoproliferative disease within 5 years prior to Day 1. 
Subjects with successfully treated nonmetastatic cutaneous squamous cell or basal cell 
carcinoma and/or localized carcinoma in situ of the cervix are not to be excluded. 
13. Subject had a major surgery within 8 weeks prior to Day 1 or has a major surgery planned 
during the trial. 
14. Subject has uncontrolled hypo- or hyperthyroidism or has both thyroid-stimulating hormone 
(TSH) and free T4 levels outside normal range at screening.  
15. Subject has any clinically significant medical condition or physical/laboratory/ECG/vital signs 
abnormality that would, in the opinion of the investigator, put the subject at undue risk or 
interfere with interpretation of trial results. 
16. Subject has positive results for hepatitis B surface antigens (HBsAg), antibodies to hepatitis B 
core antigens (anti-HBc), hepatitis C virus (HCV), or human immunodeficiency virus (HIV).  
17. Subject has used treatment with agents (including natural products or nutritional supplement 
such as Viviscal, Nutrafol, and/or biotin) that may affect hair regrowth in the last 4 weeks prior 
to Day 1. 
18. Subject has used intralesional scalp corticosteroids or platelet rich plasma injection in the last 
4 weeks prior to Day 1. 
19. Subject has used systemic treatment with immunosuppressive/modulating medication or 
medication that could affect FFA (eg, corticosteroids, methotrexate, minoxidil, 
hydroxychloroquine, 
retinoids, 
calcineurin 
inhibitor, 
tetracyclines, 
pioglitazone, 
spironolactone, or 5-α-reductase-inhibitors) within 4 weeks prior to Day 1.  
Note: Intranasal corticosteroids and inhaled corticosteroids are allowed. Eye and ear drops 
containing corticosteroids are also allowed. 
Note: Standard doses of systemic antihistamines are allowed. 
Note: Use of systemic treatment with minoxidil or spironolactone is allowed if used for at least 
6 months prior to Day 1 and the subject agrees to continue using it on a stable dosing during 
the present study. 
20. Subject has used any topical medicated treatment that could affect FFA within 2 weeks prior 
to Day 1, including, but not limited to, topical corticosteroids, calcineurin inhibitors, minoxidil, 
phosphodiesterase-4 (PDE-4) inhibitors. 
Note: Use of topical treatment with minoxidil is allowed if used for at least 6 months prior to 
Day 1 and the subject agrees to continue using it on a stable dosing during the present study. 
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21. Subject has received treatment with JAK inhibitors (systemic or topical) within 4 weeks prior 
to Day 1. 
22. Subject has received any ultraviolet (UV)-B phototherapy (including tanning beds), excimer 
laser, or any other phototherapy within 4 weeks prior to Day 1. 
23. Subject has had psoralen-UV-A (PUVA) treatment within 4 weeks prior to Day 1. 
24. Subject has a known or suspected allergy to delgocitinib or any component of the 
investigational product. 
25. Subject has a history of an allergic reaction or significant sensitivity to hypoallergenic ink. 
26. Subject has a known history of clinically significant drug or alcohol abuse in the last year prior 
to Day 1. 
Exclusion criteria for Cohort 2 only (healthy subjects): 
27. Subject has a history of skin disease or presence of skin condition that, in the opinion of the 
investigator, would interfere with the trial assessments.  
28. Subject has any clinically significant medical condition or physical/vital signs abnormality that 
would, in the opinion of the investigator, put the subject at undue risk or interfere with 
interpretation of trial results. 
29. Subject has a known history of chronic infectious disease (e.g., hepatitis B, hepatitis C, or 
HIV). 
30. Subject has used a topical medicated treatment on the targeted skin sites within 2 weeks prior 
to skin samples collection (Day 1). 
 
5.3 Lifestyle Considerations 
Cohort 1: 
For subject who uses make-up, moisturizers, creams, lotions, cleansers, and/or sunscreens on the 
face, the same product brands/types should be used for a minimum period of 4 weeks prior to 
Day 1. Subject should continue to use the same brand/type or frequency of use throughout the trial, 
but should not apply those products on the treated area during the trial.  On clinic visit days, 
subjects should not use make-up, moisturizers, creams, lotions, cleansers, and/or sunscreens on the 
face on the clinic visit days before the visit. In addition, for the subjects who are on stable dose of 
topical minoxidil for at least 6 months prior to Day 1 and continue using it during the study, they 
should be instructed to not apply it on the areas where skin samples will be collected on the visit 
days before the visit. 
Subject should maintain a consistent hair style and hair style regimen, including shampoo and hair 
products (including hair dye, process, and timing to hair appointments), and should refrain from 
weaves or extensions throughout the course of the trial and for 4 weeks prior to Day 1. Hair dying 
and shaving of scalp is allowed during the trial but not within 48 hours prior to a trial visit. Subjects 
will be informed to wash their scalp/hair approximately 48 hours prior the visits on Day 1 and 
Week 12 and then to keep their hair free of products until these visits (ie, the visits where skin 
microbiome will be collected). For other visits (Weeks 4, 8, and 24 [or ET, as applicable]), subjects 
will be informed that they should not apply hair products before the visits.  
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The IMP should be applied after hair washing if this coincides with time for IMP application. 
Subjects should abstain from wetting the hair and eyebrows (if eyebrows are treated) within 
2 hours following IMP application. Subjects should also wait at least 30 minutes after IMP 
application to wear protective apparel (eg, hat) or non-adhesive hair piece/wig that cover treated 
areas. 
Subjects should abstain from physical activity that can cause significant sweating within 2 hours 
following IMP application.   
Subjects should avoid eye contact with the IMPs. 
Cohort 2: 
On the Day 1 visit, subjects should not use make-up, moisturizers, creams, lotions, cleansers, 
and/or sunscreens on the face before the visit.  
Subjects will be informed to wash their scalp/hair approximately 48 hours prior to the Day 1 visit 
and then to keep their hair free of products until the visit. 
5.4 Screen Failures 
Screen failures are defined as individuals who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the IMP. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure subjects, to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements, and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAEs. 
Individuals who do not meet the criteria for participation in this trial (screen failure) may be 
rescreened once, if deemed acceptable by the investigator. Rescreened subjects should be assigned 
a different subject number than the initial screening. All procedures planned at the screening visit, 
including signature of a new consent form, will be performed. 
 
 
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6 TREATMENT 
6.1 Trial Treatment Administered 
No IMP will be administered in Cohort 2. For Cohort 1, the vehicle-controlled treatment period 
involves a comparison of delgocitinib cream 20 mg/g administered topically BID with a vehicle 
(delgocitinib cream vehicle). During the OLE, all subjects will apply delgocitinib cream 20 mg/g 
BID. All IMPs will be provided by the sponsor. 
On Day 1, trial staff will instruct subjects on proper application of IMP. On Day 1, Week 4, 
Week 8, Week 12, Week 16, and Week 20, the morning application of the IMP will be at the site 
under the supervision of trial staff. Other IMP applications will be self-administered by the subject 
at home. The last IMP application will be the evening prior to the Week 24 visit. No IMP 
application will be done on the day of the Week 24 visit. Typically, dosing will occur in the 
morning and evening, with approximately 12 hours between doses. The IMP will be applied to all 
affected areas on the face/scalp (ie, frontal scalp area, including the lesional target area, and 
eyebrows, if affected) as a thin layer. The original lesional area(s) identified at Day 1 and any new 
lesions (or increase in original lesional area) on the face/scalp must be treated until Week 24. The 
IMP should be applied after hair washing if this coincides with time for IMP application, and the 
hair should be dry before application. Subjects will be instructed to wash their hands with soap 
and water after IMP application and to wait at least 30 minutes before covering the treated areas.  
Table 3: Trial Treatments 
 
Trial Treatments 
Product name 
Delgocitinib 
Delgocitinib Vehicle 
Dosage form 
Cream 
Cream 
Unit dose 
strength(s)/Dosage level(s) 
20 mg/g 
NA 
Route of Administration  
Topical 
Topical 
Dosing instructions 
Applied BID to all affected areas on 
the face/scalp (ie, frontal scalp and 
eyebrows, if affected) for 12 weeks 
during the vehicle-controlled 
treatment period and for 12 weeks 
during the OLE. 
Applied BID to all affected areas 
on the face/scalp (ie, frontal 
scalp and eyebrows, if affected) 
for 12 weeks during the vehicle-
controlled treatment period. 
Physical description 
The drug product is a white to 
almost white cream 
Vehicle is identical to the active 
cream. 
Source of procurement 
LEO Pharma A/S 
LEO Pharma A/S 
Abbreviations: BID, twice daily; NA, not applicable; OLE, open-label extension. 
The contents of the label will be in accordance with all applicable regulatory requirements. 
 Treatment Interruption  
In the event of an AE or laboratory abnormality, individual subject trial treatment may be 
temporarily interrupted based on the investigator’s judgment and preferably following a discussion 
with the Medical Monitor.  
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Treatment may be resumed at the discretion of the principal investigator in consultation with the 
Medical Monitor. 
The investigator may suspend trial treatment at any time, even without consultation with the 
Medical Monitor if the urgency of the situation requires immediate action and if it is determined 
to be in the subject’s best interest. However, the Medical Monitor should be contacted as soon as 
possible for all cases of study drug interruption. Resumption of trial treatment after temporary 
discontinuation should always be discussed with the Medical Monitor. 
The information pertaining to interruption of trial medication and the reasons for it must be 
recorded in the case report form. 
6.2 Preparation/Handling/Storage/Accountability 
 Preparation/Storage/Handling  
All IMPs must be stored in a secure environmentally controlled and monitored area in accordance 
with the labelled storage conditions with access limited to the investigator and authorized site staff. 
The IMPs may only be supplied by authorized site staff and may only be given to subjects enrolled 
into the Cohort 1 of the trial.   
Investigational medicinal products will be dispensed by the site to the subject in Cohort 1 at the 
visits specified in Table 1. Subjects are to return all IMPs (used and unused) to the site. The tubes 
will be weighed prior to dispensing and upon return, and the weight will be recorded in the source 
documents and electronic case report form (eCRF). Each subject will be instructed on the 
importance of returning IMP at the next trial visit and on taking the product as prescribed. If a 
subject does not return IMP, he or she will be instructed to return it as soon as possible. 
More details on the application methods are described in the study manual. 
 Accountability  
The investigator is responsible for maintaining accurate records of the IMP received initially and 
of the IMP dispensed/used. Any IMP accidentally or deliberately destroyed, or returned to the 
sponsor or designee will be accounted for. Any discrepancies between amounts dispensed and 
returned will be explained. At the conclusion of the trial, all used and unused investigational 
products and all medication containers will be returned or destroyed as per approved arrangements 
by the Sponsor.   
All IMP accountability forms and treatment logs must be retained in the investigator’s study files. 
Product inventory and accountability records will be maintained, as per ICH GCP. These records 
must be available for inspection at any time by the sponsor, its designees, or by regulatory agencies. 
Further guidance and information for final disposition of IMPs are provided in the study manual. 
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6.3 Randomization 
At the site, each screened subject will be assigned a subject identifier number during screening 
that will be used on all subject documentation. The subject identifier number will contain the site 
number (ie, 01) and the subject number and will be assigned in numerical order at the screening 
visit based on chronological order of screening dates (e.g., 01-010 for the 10th subject screened). 
In Cohort 1, approximately 30 subjects will be randomized 1:1 to delgocitinib cream 20 mg/g or 
vehicle cream.  
Further guidance and information about randomization assignment can be obtained in the study 
manual. The randomization number is to be recorded at the appropriate location in the source 
document and eCRF. 
In Cohort 2, no randomization scheme will be used since no IMP will be applied.  
 Blinding 
The vehicle-controlled treatment period of Cohort 1 will be double-blinded. At all times, treatment 
and randomization information will be kept confidential and will not be released to the 
investigator, the trial staff, the contract research organization (CRO), or the sponsor’s trial team 
until after the conclusion of the trial. 
While the safety of a subject always comes first, it is still important to carefully consider if 
unblinding is necessary to ensure a subject’s safety. An emergency unblinding request can be made 
by the investigator, health care professionals who are not members of the trial staff, or authorized 
LEO Pharma personnel. 
Provisions are in place for 24-hour emergency unblinding of individual subject treatment. If 
emergency unblinding is required, the investigator or delegated site staff can directly contact the 
emergency unblinding facility via a corresponding local emergency unblinding telephone number, 
that can be found in the Investigator Site File. 
The investigator or delegated site staff will need to provide the trial ID, the subject ID and the 
randomization code number of the subject to the emergency unblinding facility who will 
immediately reveal the individual treatment allocation. 
For a requester who is not a member of the site staff (eg, a physician in an emergency room), the 
local contact number for the emergency unblinding facility will be provided on the subject card to 
be used if the investigator or delegated site staff cannot be reached. Like the investigator or 
delegated site staff, the requester needs to provide the trial ID, the subject ID and the randomization 
code number to the emergency unblinding facility, that will immediately reveal the individual 
treatment allocation. 
The emergency unblinding facility will clarify that the requester requires immediate unblinding 
without further medical consultation. 
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Unblinding should only be done in case of an emergency and when it is essential for effective 
treatment of the subject. Most often, trial drug discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat the subject. The Sponsor is to be informed 
immediately about any unblinding event. 
Documentation of any unblinding should include the name of the trial personnel performing the 
unblinding, the date of the unblinding and the reasons that led to unblinding. It has to be reported 
on the blind break form filed in the Investigators site file. In addition, AEs or SAEs related to the 
unblinding have to be reported appropriately. 
LEO Pharma Global Safety will receive a set of emergency envelopes, including the identity of 
the product codes for potential unblinding for regulatory purpose. 
The subject for whom the blind has been broken will be discontinued from the trial and undergo 
the ET procedures. In cases where there are ethical reasons to have the subject remain in the trial, 
the investigator must obtain specific approval from the sponsor or its designee for the subject to 
continue in the trial. The primary reason for discontinuation (the event or condition which led to 
the unblinding) will be recorded. 
 Trial Treatment Compliance 
Trial treatment compliance will be monitored at each visit. Adherence to treatment will be assessed 
by direct questioning, review of the subject’s diary, and by maintaining adequate IMP dispensing 
and return records. The date and time of each dose administered in the clinic will be recorded. 
Subjects who are significantly noncompliant with treatment will be counseled and could be 
discontinued from the trial, at the discretion of the investigator, following consultation with the 
sponsor. A subject will also be considered significantly noncompliant if he or she intentionally or 
repeatedly takes more than the prescribed amount of IMP in the same time frame, as judged by the 
investigator.   
6.4 Concomitant Therapy 
All medications (including over-the-counter drugs, vitamins, herbal/natural products, and 
antacids) taken within 4 weeks prior to screening and throughout the trial must be recorded. In 
addition, the use of any prohibited medications must be recorded within the timeframe described 
in the exclusion criteria. 
Medication entries may be captured as generic or trade names. Trade names should be used for 
combination drugs. Entries should include as much as possible of the following information: the 
dose, unit, frequency of administration, route of administration, start date, end date, and indication. 
If the medication is stopped or the dosage is changed, these details must be recorded. 
 Permitted Therapies 
The following therapies are permitted: 
• 
Intranasal corticosteroids and inhaled corticosteroids are allowed. Eye and ear drops containing 
corticosteroids are also allowed.   
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• 
Standard doses of systemic antihistamines are allowed. 
• 
Use of systemic treatment with minoxidil or spironolactone is allowed if used for at least 
6 months prior to Day 1 and the subject agrees to continue using it on a stable dosing during 
the present study.  
• 
Use of topical treatment with minoxidil is allowed if used for at least 6 months prior to Day 1 
and the subject agrees to continue using it on a stable dosing during the present study. 
• 
Use of sunscreen products, except on treated areas, and protective apparel are permitted when 
sun exposure cannot be avoided. Of note, subjects should wait at least 30 minutes after IMP 
application to wear protective apparel (eg, hat) or non-adhesive hair piece/wig that cover 
treated areas.  
• 
Vaccination for COVID-19 will be allowed during the trial. 
 Prohibited Therapies or Procedures 
For subjects in Cohort 1, Table 4 lists prohibited medications that are not to be used from the 
defined washout periods before the first application of the IMP at the Day 1 visit through the last 
trial visit.  
Subjects in Cohort 1 who start prohibited medications or therapies that could have an impact on 
FFA during the trial will be withdrawn from trial treatment. Subjects who start prohibited 
medications or therapies for other reasons during the trial may be withdrawn from trial treatment 
if an impact on efficacy assessment or safety of the subjects is expected. If in any doubt, 
investigators are advised to discuss medications with the medical monitor.   
For subjects in Cohort 2, Table 5 lists prohibited medications that are not to be used from the 
defined washout periods before the Day 1 visit.  
Table 4: Prohibited Therapies or Procedures for Cohort 1 (Subjects with FFA) 
Prohibited medications, products, and procedures 
Washout period prior to 
first dose (Day 1)  
Scalp reduction surgery or hair transplantation 
- 
Any marketed or investigational biological agent 
12 weeks or 5 half-lives 
(whichever is longer) 
Major surgery 
8 weeks 
Nonbiological investigational product or device  
4 weeks 
Treatment with agents (including natural products or nutritional 
supplement such as Viviscal, Nutrafol, and/or biotin) that may affect hair 
regrowth 
4 weeks 
Intralesional scalp corticosteroids or platelet rich plasma injection 
4 weeks 
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Prohibited medications, products, and procedures 
Washout period prior to 
first dose (Day 1)  
Systemic treatments with immunosuppressive/modulating medication or 
medication that could affect FFA (eg, corticosteroids, methotrexate, 
minoxidil, 
hydroxychloroquine, 
retinoids, 
calcineurin 
inhibitor, 
tetracyclines, pioglitazone, spironolactone, or 5-α-reductase inhibitors)  
4 weeks  
 
JAK inhibitors (systemic or topical) 
4 weeks 
PUVA treatment, UV-B phototherapy (including tanning beds) or 
excimer laser, any other phototherapy, excessive sun exposure or has 
used tanning booths 
4 weeks 
Topical medicated treatment that could affect FFA including, but not 
limited to topical corticosteroids, calcineurin inhibitors, minoxidil, 
PDE-4 inhibitors 
2 weeks 
Adhesive wigs 
During the trial 
Abbreviations: PDE-4, phosphodiesterase-4; FFA, frontal fibrosing alopecia; IMP, investigational medicinal 
product; JAK, Janus-Kinase; PUVA, psoralen-UV-A; UV, ultraviolet. 
Table 5: Prohibited Therapies or Procedures for Cohort 2 (Healthy Subjects) 
Prohibited medications, products, and procedures 
Washout period prior to 
Day 1  
Any marketed or investigational biological agent 
12 weeks or 5 half-lives 
(whichever is longer) 
Nonbiologial investigational product or device  
4 weeks 
Excessive sun exposure or has used tanning booths 
4 weeks 
Topical medicated treatment on the targeted skin sites 
2 weeks 
7 DISCONTINUATION AND LOST TO FOLLOW-UP 
Subjects have the right to withdraw from the trial at any time for any reason without penalty. The 
investigator also has the right to withdraw subjects from the trial if he or she feels it is in the best 
interest of the subject or if the subject is uncooperative or noncompliant.  
Should a subject decide to withdraw, all efforts will be made to complete and report the 
observations as thoroughly as possible, particularly the examinations outlined in the ET visit (for 
Cohort 1 only). 
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The investigator or one of his or her staff members should contact the subject to determine as 
accurately as possible the primary reason for the withdrawal.  
A complete final evaluation at the time of the subject’s withdrawal should be made with an 
explanation of why the subject is withdrawing from the trial. If the reason for removal of a subject 
is an AE (or a procedural complication for subjects in Cohort 2) or an abnormal laboratory test 
result, the principal specific event or test will be recorded. 
If a subject withdraws from the trial, he/she may request destruction of any samples taken and not 
tested, and the investigator must document this in the site study records. 
7.1 Discontinuation 
For Cohort 1, subjects who discontinue the trial after the first dose will be asked, if they agree, to 
come for a last assessment (ET visit). Subjects who are discontinued for safety reasons may be 
asked to come for additional follow-up visits, at the investigator’s discretion, after the ET visit to 
ensure appropriate medical care and AEs follow-up. 
Subjects who discontinue will not be replaced.  
Reasons for discontinuation include the following: 
• 
The investigator decides that the subject should be withdrawn. If this decision is made because 
of an SAE, the IMP is to be discontinued in that subject immediately and appropriate measures 
are to be taken. The investigator will notify the sponsor immediately. 
• 
If an application site reaction occurs, the investigator should use his or her best medical 
judgement as to whether to continue subject’s treatment.  
• 
The attending physician requests that the subject be withdrawn from the trial. 
• 
The subject, for any reason, requires treatment with another therapeutic agent that has been 
demonstrated to be effective for treatment of the trial indication. In this case, discontinuation 
from the trial occurs immediately upon introduction of the new agent. 
• 
The subject is lost to follow-up. In this case, a reasonable attempt to contact the subject and 
ascertain his or her status must be made, and these attempts must be documented. 
• 
The subject becomes pregnant at any time during the trial.  
• 
Other: the subject may withdraw from the trial for any other reason, including withdrawal of 
consent. 
• 
The sponsor or regulatory authorities, for any reason, stop the trial. In this case, all subjects 
will be discontinued from the trial. The investigator will immediately, on discontinuance of 
the trial by the sponsor, in its entirety or at a clinical trial site, inform both the subjects and the 
research ethics board of the discontinuance, provide them with the reasons for the 
discontinuance and advise them in writing of any potential risks to the health of subjects or 
other persons. 
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7.2 Lost to Follow-Up 
A subject will be considered lost to follow-up if he or she fails to return for scheduled visits and is 
unable to be contacted by the trial site staff.  
The following actions must be taken if a subject fails to return to the clinic for a required trial visit: 
• 
The site will attempt to contact the subject and reschedule the missed visit. The site will 
then counsel the subject on the importance of maintaining the assigned visit schedule and 
ascertain if the subject wishes to or should continue in the trial. 
• 
Before a subject is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the subject (where possible, three telephone calls and, if 
necessary, a certified letter to the subject’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject’s medical record or 
trial file. 
• 
If all attempts to contact the subject fail, he or she will be considered to have withdrawn 
from the trial with a primary reason of lost to follow-up. 
 
 
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8 TRIAL ASSESSMENTS AND PROCEDURES 
8.1 Efficacy Assessments (Cohort 1 only) 
Clinical evaluations of FFA will be performed by an experienced and qualified dermatologist 
(board certified or equivalent) or other suitably qualified and experienced designee. To assure 
consistency and reduce variability, the same assessor should perform all assessments on a given 
subject whenever possible. 
 Lichen Planopilaris Activity Index 
The LPPAI will be assessed at the visits specified in Table 1. It is a quantitative measure of disease 
activity.7 The LPPAI records symptoms (pruritus, pain, burning), signs (erythema, perifollicular 
erythema and scale), a measure of activity (the anagen pull test), and spreading of the condition. 
These subjective and objective measures have been assigned a numeric value to establish a disease 
activity score. The weights given to the symptoms (30%), signs (30%), anagen pull test (25%), 
and presence of spreading (15%) led to the equation: LPPAI (0-10) = (pruritus + pain + burning)/3 
+ (scalp erythema + perifollicular erythema + perifollicular scale)/3 + 2.5 (pull test) + 1.5 
(spreading/2). Symptoms and signs are recorded on a 4-point scale: 0 = absent (negative), 1 = mild 
(+/-), 2 = moderate (+), and 3 = severe (++,+++). The anagen pull test, when present, is a reliable 
measure of local disease activity. It involves taking hold of 10 to 20 hairs between the thumb, 
second and third fingers at the scalp end of the hair shafts, and pulling firmly away from the scalp 
with a perpendicular force to slide the fingers to the ends of the hair. The result is recorded both 
as a binary value (0 for no anagen hairs and 1 for the presence of anagen hairs) and as anagen 
hairs/total hairs pulled. Last is the assessment of disease extension, recorded as 0 (no spreading) 
versus 1 (indeterminate) versus 2 (spreading). When the hair loss is difficult to judge, the issue of 
extension is recorded as indeterminate. A detailed procedure of LPPAI score calculation is 
provided in Appendix A.  
 Frontal Fibrosing Alopecia Severity Score 
The FFASS will be assessed at the visits specified in Table 1. This index is based on the evaluation 
of the relevant clinical features in FFA.8 Those features are the grade of frontal and temporal 
hairline recession (from 1 to 5), grade of eyebrow loss (none, partial, or total), severity and extent 
of perifollicular erythema and hyperkeratosis, and severity and frequency of pruritus and pain 
associated with FFA. The resulting severity scores range from 0 to 25, with higher scores 
indicating greater FFA severity. The clinical features included in the FFASS are grouped into two 
categories: extent of alopecia (up to 21 points) and inflammation (up to 4 points). A detailed 
procedure of FFASS score calculation is provided in Appendix B.  
 Perifollicular Erythema and Scale 
The perifollicular erythema and perifollicular scale of the selected lesional target area will be 
assessed visually at the visits specified in Table 1. Each clinical finding (ie, perifollicular erythema 
and perifollicular scale) will be scored using the 4-point severity scale7,9 presented in Table 6. To 
be eligible for this trial, subjects must have a lesional target area with a perifollicular erythema 
score ≥ 2 and a perifollicular scale score ≥ 2 at Screening and Day 1. 
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Table 6: Perifollicular Erythema and Perifollicular Scale Severity Scale 
Score 
Description 
0 
Absent/None 
1 
Mild 
2 
Moderate 
3 
Severe/Intense 
 Pruritus Numerical Rating Scale  
The intensity of pruritus due to FFA will be recorded using a NRS.10,11 It will be assessed daily 
starting approximately 7 days prior to Day 1 and up to Day 8. Thereafter, it will be assessed only 
at the visits specified in Table 1. This will be evaluated by asking subjects to assign a numerical 
score representing of the worst intensity over the last 24 hours of their symptoms on a scale from 
0 to 10, with 0 indicating no symptoms and 10 indicating the worst imaginable symptoms. The 
NRS of pruritus is presented in Appendix C.  
 Burning Sensation Numerical Rating Scale 
The intensity of burning sensation due to FFA will be recorded using an NRS. It will be assessed 
daily starting approximately 7 days prior to Day 1 and up to Day 8. Thereafter, it will be assessed 
only at the visits specified in Table 1. This will be evaluated by asking subjects to assign a 
numerical score representing of the worst intensity over the last 24 hours of their symptoms on a 
scale from 0 to 10, with 0 indicating no symptoms and 10 indicating the worst imaginable 
symptoms. The NRS of burning sensation is presented in Appendix C.  
 Pain Numerical Rating Scale 
The intensity of pain due to FFA will be recorded using an NRS12,13. It will be assessed daily 
starting approximately 7 days prior to Day 1 and up to Day 8. Thereafter, it will be assessed only 
at the visits specified in Table 1. This will be evaluated by asking subjects to assign a numerical 
score representing of the worst intensity over the last 24 hours of their symptoms on a scale from 
0 to 10, with 0 indicating no symptoms and 10 indicating the worst imaginable symptoms. The 
NRS of pain is presented in Appendix C.  
 Hair Counts/Trichoscopy 
Hair counts/trichoscopy will be performed at the visits specified in Table 1. Trichoscopy should 
be performed on the lesional target area, and should not overlap with the site of skin microbiome 
collection. Trichoscopy could overlap with the site of tape stripping or biopsy if needed, but should 
be performed first. The number of hairs, hair diameter, and hair density will be measured via 
fotofinder trichovision.  
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 Hair Line Measurements 
Hair line measurements will be performed at the visits specified in Table 1. Lateral canthus (right 
and left) to hairline, lower glabellar crease to hair line, top of frontalis muscle to hair line, and mid 
brow to hair line (right and left) will be measured using a disposable paper ruler. 
8.2 Safety Assessments 
 Vital Signs 
The following vital signs will be recorded at the visits specified in Table 1 (Cohort 1) and Table 2 
(Cohort 2) with the subject in a seated position, after having sat calmly for at least 5 minutes: 
systolic and diastolic blood pressure (mmHg), pulse (bpm), and body temperature (°C).  
Weight (kg) and height (cm) will be collected at the screening visit. Weight (kg) will also be 
collected at other visits specified in Table 1 (Cohort 1) and Table 2 (Cohort 2). 
If deemed appropriate by the investigator, clinically significant findings in the vital signs will 
exclude a subject from trial participation. For Cohort 1 only, any abnormal finding related to vital 
signs that the investigator considers to be clinically significant must be recorded as an AE. 
 Complete Physical Examination 
For subjects in Cohort 1 only, the following sites/systems will at least be included in the complete 
physical examination, which will be performed at the visits specified in Table 1:  
• General appearance 
• Dermatological (except FFA) 
• Head, eyes, ears, nose, throat (HEENT) 
• Respiratory 
• Cardiovascular 
• Abdominal 
• Neurological 
• Musculoskeletal 
• Lymphatic 
Information for all physical examinations must be included in the source document. If deemed 
appropriate by the investigator, clinically significant findings in the physical examination will 
exclude a subject from trial participation. Any significant change will be reported as an AE in the 
source document and eCRF.   
 Brief Physical Examination  
The following sites/systems will at least be included in the brief physical examination that will be 
performed at the visits specified in Table 1 (Cohort 1) and Table 2 (Cohort 2):  
• General appearance 
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• Dermatological (except FFA) 
• Respiratory 
• Cardiovascular 
• Abdominal 
If deemed appropriate by the investigator based on the subject’s condition, a complete physical 
examination as described in Section 8.2.2 can be performed instead of a brief examination. 
Information for all physical examinations must be included in the source document. If deemed 
appropriate by the investigator, clinically significant findings in the physical examination will 
exclude a subject from trial participation. For Cohort 1 only, any significant change will be 
reported as an AE in the source document and eCRF.  
 Clinical Laboratory Tests 
For subject in Cohort 1 only, laboratory tests will be performed at the visits specified in Table 1. 
The tests will include hematology with differential, a standard chemistry panel (chemistry includes 
liver function tests), TSH with reflex free T4 (screening), serum pregnancy test (screening) or 
urine pregnancy test (at other visits) for women of childbearing potential (WOCBP). The specific 
tests in these panels are listed in Table 7. 
Table 7: Clinical Laboratory Testing (Cohort 1) 
Laboratory Testing 
Tests Included 
Hematology  
HCT, Hgb, MCH, MCHC, MCV, MPV, PLT, RBC, WBC, and differentials 
(neutrophils, lymphocytes, monocytes, eosinophils, and basophils relative 
and absolute) 
Biochemistry 
Albumin, alkaline phosphatase, ALT, AST, chloride, creatinine (enzymatic), 
GGT, glucose random, LDH, potassium, sodium, total bilirubin, 
triglycerides, urea (BUN), uric acid 
Urine pregnancy test 
For female subjects of childbearing potential (at each visit, except screening) 
Laboratory tests 
required at screening 
only 
β-hCG for female subjects of childbearing potential  
Serology (HBV (HBsAg, anti-HBc), HCV, HIV)  
TSH with reflex free T4 (ie, free T4 will be performed only if TSH value is 
abnormal) 
Abbreviations: ALT, alanine aminotransferase; anti-HBc, antibody to hepatitis B core antigen; AST, aspartate 
aminotransferase; β-hCG, β-human chorionic gonadotropin; BUN, blood urea nitrogen; GGT, gamma-glutamyl-
transferase; HBsAg, hepatitis B surface antigens; HBV, hepatitis B virus; HCT, hematocrit; HCV, hepatitis C virus; 
Hgb, hemoglobin; HIV, human immunodeficiency virus; LDH,  lactate dehydrogenase; MCH, mean corpuscular 
hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; MPV, mean 
platelet volume; PLT, platelets; RBC, red blood cell (count); TSH, thyroid-stimulating hormone; WBC, white blood 
cell (count). 
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In case of a screening laboratory value abnormality, the test can be repeated once within the 
original screening time window, if the investigator believes there is a reasonable possibility that 
the subject would be eligible if re-tested. 
If deemed appropriate by the investigator, clinically significant findings in clinical laboratory 
testing will exclude a subject from trial participation. Any clinically significant value will be 
reported as an AE.  
 Electrocardiogram 
For subjects in Cohort 1, a twelve-lead ECG will be performed as a safety assessment at the visit 
specified in Table 1. Clinically significant findings in the ECG should exclude a subject from study 
participation (as deemed appropriate by the investigator). Any clinically significant value will be 
reported as an AE.  
 Local Tolerability Assessments 
For subjects in Cohort 1, subject local tolerability assessments will be performed at the visits 
specified in Table 1. On Day 1 and Week 12, the assessment will be performed approximately 
30 minutes after the IMP application at the site with a recall period of 30 minutes. At other visits, 
the subject’s local tolerability assessment will be done before the IMP application with a recall 
period of 7 days (worst over the last 7 days). The subject will evaluate stinging/burning at the 
application site using the scale described in Table 8. 
Table 8: Subject Assessment of Local Tolerability after IMP Application 
Grade 
Stinging/Burning 
0 (none) 
No stinging or burning. 
1 (mild) 
Slight warm, tingling sensation, not really bothersome. 
2 (moderate) 
Definitive warm, tingling sensation, that is somewhat bothersome. 
3 (severe) 
Hot, tingling/stinging sensation that has caused definite discomfort. 
Abbreviation: IMP, investigational medicinal product. 
The subject’s assessment of local tolerability may be reported as an AE at the discretion of the 
investigator, even if the investigator does not suspect a local skin reaction related to application of 
IMP (reporting of stinging/burning by the subject). 
8.3 Pharmacodymanic Assessments 
For subjects in Cohort 1, skin microbiome samples and skin biopsies will be collected in all 
subjects. Adhesive tape strip samples collection is optional and will be performed per 
investigator’s judgement (based on available skin area on the scalp). However, every effort should 
be made to collect tape strip samples in all subjects. 
For subjects in Cohort 1, it is preferred that the skin microbiome samples, tape strips (when 
applicable), and skin biopsies come from the same lesional target area. If needed, a second lesional 
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target area could be selected to allow for skin samples collection and the hair count/trichoscopy 
assessment. If two lesional target areas are selected, they should be of similar severity. 
In addition, lesional skin biopsies should be as close as possible from the area of the skin tape 
stripping and preferably from the target area. Lesional skin tape strips could be collected from the 
same area where trichoscopy/hair counts is performed. Other assessments need to be done on 
different areas of the lesional target area(s) (ie, they should not overlap). 
 Skin Biopsies 
The skin will be cleaned, disinfected, and anesthetized before skin biopsies are performed. Sterile 
gauze will be used to absorb any bleeding. The biopsy sites will be sutured if necessary. 
Details about the collection, processing, handling, storage and shipping of biopsy samples will be 
provided in the laboratory manual. 
Cohort 1: 
On Day 1, all subjects will have 2 skin biopsies (4-mm) collected prior to the first IMP application 
(1 from a lesional hair follicle within the target area and 1 from a non lesional hair follicle [eg, on 
the occipital scalp]). On Week 12, 1 skin biopsy (4-mm) will be collected from a hair follicle 
within the lesional target area (outside the scar of previous biopsies). Each biopsy will be split in 
half. One part will be used for IHC and the other part will be used for gene expression analysis.  
Cohort 2: 
On Day 1, all healthy subjects will have 2 skin biopsies (4-mm) that include hair follicles collected 
on healthy skin at similar matched areas of subjects with FFA (ie, 1 from frontal scalp area and 
1 from occipital scalp area). Each biopsy will be split in half. One part will be used for IHC and 
the other part will be used for gene expression analysis.  
 Tape Stripping 
Tape stripping is a non-invasive procedure where superficial skin cells is collected using tape 
strips. For each sampled site, approximately 20 tape strips units will be placed and removed from 
the exact same site one after the other. 
Details about the collection, handling, storage and shipping of tape stripping samples will be 
provided in the laboratory manual. 
Cohort 1: 
Adhesive tape strip collection is optional for subjects in Cohort 1 and will be collected per 
investigator’s judgement (based on available skin area on the scalp). However, every effort should 
be made to collect tape strip samples in all subjects. 
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On Day 1, skin tape strips will be collected prior to the first IMP application from lesional skin 
and from nonlesional skin (eg, on the occipital scalp). On Week 12, skin tape strips will be 
collected at the same location of the lesional skin. 
Lesional tape strip samples should ideally be collected in the lesional target area. However, if the 
lesional target area is not large enough to accommodate the tape stripping, tape strips can be 
collected adjacent/close to the target area. The tape strip area can be a combination of lesional and 
non lesional skin (or peri-lesional skin) on the scalp, as long as this area will be treated with the 
IMP. If possible, tape stripping should be performed on non-hair bearing skin.  
Cohort 2: 
On Day 1, skin tape strips will be collected on non-hair bearing healthy skin at a similar matched 
area of subjects with FFA (ie, on the forehead, as close as possible to the frontal scalp area).  
 Skin Swabs for Microbiomes Analysis 
Collection of skin microbiome samples is a non-invasive procedure where a swab is passed along 
the skin. Skin swabs for microbiome analysis must be collected prior to the tape stripping and skin 
biopsies. 
Details about the collection, handling, storage and shipping of microbiome samples will be 
provided in the laboratory manual. 
Cohort 1: 
On Day 1, skin swab for microbiome analysis will be collected for all subjects prior to the first 
IMP application (1 from the target area [lesional skin] and 1 from an uninvolved occipital scalp 
area). On Week 12, skin microbiome will be collected at the same location of the lesional skin of 
the target area. 
Cohort 2: 
Two skin swab samples for microbiome analysis will be collected on healthy skin at similar 
matched areas of subjects with FFA (ie, 1 on frontal scalp area and 1 from occipital scalp area). 
8.4 Other Assessments 
 Target Area Identification 
For subjects in Cohort 1 only, a lesional target area on the scalp (eg, frontal, periauricular, or 
temporal area) and a non lesional area on the scalp (eg, occipital scalp) will be identified. The 
lesional target area will be within the lesional treated area of FFA and should be the most active 
area with regards to erythema and scaling as per investigator’s judgment. To be eligible for this 
trial, subjects must have a lesional target area with a perifollicular erythema score ≥ 2 and a 
perifollicular scale score ≥ 2 on Day 1.  
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To allow for the hair count/trichoscopy assessment and all samples collection (ie, skin biopsies, 
tape stripping, and skin swabs), the lesional target area should be approximately 3 cm x 6 cm (or 
equivalent). However, as tape strips can be collected from the same area where trichoscopy/hair 
counts is performed or can be collected adjacent/close to the lesional target area (refer to 
Section 8.3.2 for details), a smaller lesional target area may be acceptable. If needed, two small 
target areas (totalling approximately the same size) could also be selected to allow for skin samples 
collection and hair count/trichoscopy assessment. If two lesional target areas are selected, they 
should be of similar severity.  
In order to mark the lesional target area on the scalp, two 1-2 mm permanent tattoos will be made 
on the scalp by using a disposable 30-gauge needle to inject non-toxic ink in the epidermis of the 
skin. 
A note on the location of the lesional target area should be made in the source document. 
 Medical Photography  
For subjects in Cohort 1 only, medical photographs of the lesional target area and the entire scalp  
(including the frontal hair line and right and left hair line areas) will be performed at the visits 
specified in Table 1. Photographs should be taken prior to IMP application and skin sample 
collections (ie, skin biopsies, tape stripping, and skin microbiome). Photographs will be taken with 
the fotofinder device. Care will be taken to use the same magnification, and the same settings for 
each photograph at each visit in order to obtain comparable pictures.  
Photographs will be identified as follows: trial number, subject number, visit name, and date. 
Photographs will be kept as electronic files on site and will be transmitted to the sponsor for review.  
8.5 Adverse Events and Serious Adverse Events (Cohort 1 Only) 
 Definition of Adverse Event  
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and that does not necessarily have a causal relationship with this treatment. An AE can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an IMP, whether or not considered related to the 
IMP. 
 Definition of Treatment-Emergent Adverse Event  
A TEAE is any condition that was not present prior to treatment with the IMP but appeared 
following treatment, was present at treatment initiation but worsened during treatment, or was 
present at treatment initiation but resolved and then reappeared while the individual was on 
treatment (regardless of the intensity of the AE when the treatment was initiated). 
 Definition of Serious Adverse Event  
A SAE is any untoward medical occurrence that, at any dose has any of the following 
consequences: 
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• 
Results in death 
• 
Is life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is a medically important condition. Events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed 
in the definition above. Examples are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias, and convulsions 
that do not result in hospitalization, development of drug dependency, or drug 
abuse. 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event that hypothetically 
might have caused death if it were more severe. 
Note: Hospitalization for procedures or treatments planned prior to the subject consented to trial 
participation does not constitute an AE and should therefore not be reported as AE or SAE. 
Hospitalization for elective treatment of a pre-existing condition which did not worsen from the 
subject consented to trial participation is not considered an AE and should therefore not be reported 
as AE or SAE, even if not planned before consent to trial participation. Hospitalization for routine 
scheduled treatment or monitoring not associated with any aggravation of the condition does not 
constitute an AE and should therefore not be reported as AE or SAE. Hospitalization for 
administrative purpose does not constitute an AE and should therefore not be reported as AE or 
SAE. Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization, the event is an SAE. When in doubt as to whether hospitalization occurred, the AE 
should be considered serious. 
 Classification of an Adverse Event 
8.5.4.1 Relationship to Trial Treatment 
The investigator will establish causality of the AE to the experimental treatment. The investigator 
should take into account the subject’s history, most recent physical examination findings, and 
concomitant medications.  
The following definitions will be used to determine causality of an AE:  
• 
Not related: Temporal relationship of the onset of the AE, relative to the experimental 
treatment, is not reasonable, or another cause can explain the occurrence of the AE. Does 
not reappear or worsen upon re-challenge. 
• 
Probably Related: Follows a reasonable temporal sequence from administration of the IMP. 
Could not be reasonably explained by the subject’s clinical state, environmental or toxic 
factors, or other therapies administered to the subject. Follows a known pattern of response 
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to the IMP. Disappears or decreases on cessation or reduction in dose of the IMP. 
Reappears or worsens upon re-challenge. 
• 
Possibly Related: Follows a reasonable temporal sequence from the administration of the 
IMP. Could also be reasonably explained by the subject’s clinical state, environmental or 
toxic factors, or other therapies administered to the subject. Follows a known pattern of 
response to the IMP. 
8.5.4.2 Adverse Event Severity 
The intensity of an AE is an estimate of the relative severity of the event made by the investigator 
based on his or her clinical experience and familiarity with the literature. The following definitions 
are to be used to rate the severity of an AE: 
• 
Mild: The symptom is barely noticeable to the subject and does not influence performance 
of daily activities. Treatment is not ordinarily indicated. 
• 
Moderate: The symptom is sufficiently severe to make the subject uncomfortable, and 
performance of daily activities is influenced. Treatment may be necessary. 
• 
Severe: The symptom causes severe discomfort, and daily activities are significantly 
impaired or prevented. Treatment may be necessary. 
 
If the AE worsens in severity, the new severity, including date of severity change, should be 
recorded. 
8.5.4.3 Outcome 
The outcome of the event according to the investigator’s clinical judgement should be classified 
using the categories below. 
Recovered/ 
resolved 
The event has stopped. The stop date of the event must be recorded. 
Recovering/ 
resolving 
The subject is clearly recovering from an event. The event is not yet completely 
resolved.  
Not 
recovered/ 
not resolved 
Event is still ongoing.  
Recovered/ 
resolved with 
sequelae 
The event has reached a state where no further changes are expected and the 
residual symptoms are assumed to persist. An example is hemiparesis after 
stroke. 
 
The stop date of the event must be recorded. In case of an SAE, the sequelae 
should be specified. 
Fatal 
The subject has died as a consequence of the event. Date of death is recorded as 
stop date for the AE. 
Unknown 
Unknown to investigator, e.g. subject lost to follow-up. 
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8.5.4.4 Expectedness 
Global Safety at LEO Pharma will assess the expectedness of each SAE in relation to the IMP. 
The relevant reference safety information document for this clinical trial is the delgocitinib cream 
Investigator’s Brochure, Ed. 4, section 7.3. 
 Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an AE or SAE may come to the attention of trial personnel during trial visits 
and interviews of a trial subject presenting for medical care, or upon review by a trial monitor. 
At all visits, the subject will be asked a non-leading question by the investigator about AEs, 
eg,: ‘How have you felt since I saw you last?’. It is important that the investigator also observes 
the subject for any changes not reported by the subject and records these changes. 
All AEs, including cutaneous and systemic reactions, will be captured on the appropriate eCRF. 
Information to be collected includes event description, date of onset, clinician’s assessment of 
severity, relationship to IMP (assessed only by those with the training and authority to make a 
diagnosis, ie, the investigator), and date of resolution/stabilization of the event. All AEs occurring 
while on trial must be documented appropriately regardless of relationship.  
Trial site personnel will note the occurrence and nature of each subject’s medical condition(s) 
present prior to the informed consent signature in the appropriate section of the source document 
and eCRF. During the trial, site personnel will note any change in the condition(s) and the 
occurrence and nature of any AE.  
Any medical condition that is present prior to informed consent signature will be considered as 
part of medical history and not reported as an AE. However, if the trial subject’s condition 
deteriorates after the consent signature, it will be recorded as an AE. 
Should a subject experience an AE/SAE at any time after the informed consent signature until the 
end of participation in the trial, the event will be recorded as an AE in the source document and 
eCRF. The investigator is responsible for appropriate medical care of subjects during the trial. All 
non-serious AEs will be followed until the last subject’s visit, unless additional follow up is 
required per medical judgment. If an SAE is ongoing at the end of trial, the subject will be followed 
up until the event is resolved or stable. For SAEs which have stabilized and from which the subject 
cannot be expected to recover during the trial or the safety follow-up period, e.g. chronic or 
stabilized conditions, the final outcome at the investigator’s discretion should be reported as 
‘recovering/resolving’ or ‘not recovered/not resolved’. In addition, a statement detailing why the 
subject cannot be expected to recover during the trial, e.g. that the SAE has stabilized or is chronic, 
should be added to the narrative description of the SAE on the SAE form. Follow-up frequency 
will be performed at the discretion of the investigator.  
Whenever possible, clinically significant abnormal laboratory results are to be reported using the 
diagnostic that resulted in the clinically significant abnormal laboratory results and not the actual 
abnormal test. 
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In the event the subject experiences a skin reaction that an allergic contact dermatitis is suspected, 
the event should be documented as an AE and the medication given, if any, recorded. The subject 
may be re-challenged using the assigned trial medication (patch test in the back) to confirm or rule 
out contact dermatitis.  
 Adverse Event Reporting 
Investigators are responsible for monitoring the safety of subjects who are participating in this trial 
and for alerting the sponsor to any event that seems unusual, even if this event may be considered 
an unanticipated benefit to the subject.  
The AE term (verbatim) must be in precise English medical terminology (that is, not necessarily 
the exact words used by the subject). Whenever possible, a specific diagnosis should be stated (eg, 
‘allergic contact dermatitis’). 
For cutaneous AEs, the location of the AE relative to the treatment area will be recorded: 
• Lesional/perilesional (≤2 cm from the border of lesion(s) treated with IMP). 
• Distant (>2 cm from the border of lesion(s) treated with IMP). 
The duration of the AE must be reported by the start date and stop date of the event, unless the 
event is ongoing. If the event is ongoing, it will be marked as ongoing. In addition, it will be 
recorded if the AE started prior to first administration of IMP. 
Action taken with IMP: any action taken with IMP as a consequence of the AE must be recorded 
(dose not changed, drug withdrawn, not applicable, unknown). Withdrawal from trial due to this 
AE: it must be recorded whether the AE led to withdrawal from the trial. Other action taken: any 
other action taken as a result of the AE must be recorded (none, concomitant medication, 
concurrent procedure). 
 Serious Adverse Event Reporting 
Global Safety at LEO Pharma will be the pharmacovigilance unit responsible for the overall 
pharmacovigilance process for this trial. All SAEs, related to the trial treatment or not, occurring 
during the course of the trial must be reported on an SAE form (paper) to Global Safety at LEO 
Pharma (see below contact information) immediately without undue delay within 24 hours of the 
knowledge of the occurrence (this refers to any AE that meets one or more of the aforementioned 
serious criteria). This report should contain amongst others an assessment of available information 
on seriousness, severity, causal relationship to the IMP or trial procedure, the action taken, the 
outcome to date, and a narrative description of the course of the event. For more details regarding 
reporting of any SAE, please see the guidance text on the SAE form. Additionally, Global Safety 
at LEO Pharma may request further information in order to fully assess the SAE. The investigator 
must forward such information to LEO Pharma upon request by fax or e-mail (see contacts details 
below). The Innovaderm project team should also be informed of any SAE at the same time as 
Global Safety at LEO Pharma using the below contact information. 
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By signing and dating the SAE form, the investigator acknowledges that he/she is aware of the 
SAE and has assessed the causal relationship of the IMP(s) and any of the other medications to the 
SAE. 
The SAE reporting period ends at the end of the follow-up period. SAEs occurring after the 
completion of the clinical trial should not be routinely sought or recorded. However, such events 
should be reported to Global Safety at LEO Pharma and the Innovaderm project team (see contact 
details below) if the investigator becomes aware of them. 
Reporting should be done by sending the completed SAE form to the following e-mail addresses 
(faxing can also be done as a second option in case e-mailing is not possible). 
Safety Contact Information: Global Safety at LEO Pharma  
E-mail: drug.safety@leo-pharma.com 
Fax: +45 7226 3287 
AND 
Innovaderm project team:  
E-mail: EXP2228_SAE@innovaderm.com  
Global Safety at LEO Pharma will inform the LEO medical monitor within 1 business day of 
awareness of a new SAE. Global Safety at LEO Pharma will process and evaluate all SAEs as 
soon as the reports are received. For each SAE received, Global Safety at LEO Pharma will make 
a determination as to whether the criteria for expedited reporting to relevant regulatory authorities 
have been met.  
Global Safety at LEO Pharma will manage the expedited reporting of relevant safety information 
to concerned regulatory agencies in accordance with local laws and regulations.  
Investigators will be notified of the evolving safety profile of the IMP on an ongoing basis using 
documents such as Investigator Periodic Safety Update and/or any revised version of the IB. 
The investigator must notify the local IRB(s)/IEC(s) of SAEs, as required by current applicable 
legislation for the concerned country. 
 Pregnancy Reporting 
If a female subject becomes pregnant during the trial and up to 4 weeks after the end of the trial, 
the subject should inform the site as soon as possible. Upon confirmation of the pregnancy, the 
female subject will be discontinued from the trial. The investigator must complete a trial-specific 
pregnancy form upon confirmation of a pregnancy and send it to Global Safety at LEO Pharma 
within 24 hours of confirmation of the pregnancy (contact information to be used is the same as 
for SAE reporting) using the (paper) pregnancy form (part I). Pregnancy is not itself an AE or 
SAE; however, maternal/fetal complications or abnormalities will be recorded as AEs or SAEs, as 
appropriate. The investigator will follow the pregnancy until completion or until pregnancy 
termination and, in the case of a live-born offspring, to 1 month of age in that infant. The 
investigator should notify Global Safety at LEO Pharma and Innovaderm using the (paper) 
pregnancy form (part II) within 24 hours of first knowledge of the outcome as a follow-up to the 
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initial pregnancy form. All pregnancies should be reported to the sponsor and, when applicable, to 
the ethics committee. 
 Adverse events of special interest (AESI) 
An AESI is an event type of scientific and medical concern specific for the product or development 
program, for which additional monitoring may be appropriate. Such an event might warrant further 
investigation in order to further characterize it. 
Deep vein thrombosis/Pulmonary embolism is considered AESI in this trial and will require 
additional details to be recorded. LEO Pharma may request that the investigator forward additional 
test results, as appropriate. An AESI may be serious or non-serious. Serious AESIs require 
expedited reported via the SAE form as described in Section 8.5.7 in addition to the requirements 
specified below.  
The additional information that will be collected is:  
• Risk factors such as:  
o Previous thromboembolism (record as medical history) 
o Family history of deep vein thrombosis/pulmonary embolism or other 
cardiovascular/blood-clotting disorders 
o Genetic disorders that might increase the risk for thrombosis (record as medical 
history) 
o History of cancer (record as medical history) 
o Recent venous catheter placement (record as medical history) 
o Current smoker (record as tobacco smoking history) 
o Hormonal contraception/hormonal replacement therapy (record as concomitant 
medication) 
o Trauma or surgery (record as per protocol) 
o Immobilisation (e.g. prolonged bed rest or sitting for long periods) 
o None 
• Method of verification may include: 
o Clinical evaluation 
o Image-verified 
o Laboratory test(s) 
 Medication error 
Medication error refers to any unintentional error in the dispensing or administration of an IMP. 
Medication errors include accidental overdose or underdose, inappropriate schedule of product 
administration, incorrect route of product administration, wrong product administered, and expired 
product administered. 
Accidental overdose or underdose where a clinical consequence occurred or could have occurred 
should be recorded based on investigator judgement. 
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Inappropriate schedule of product administration where a clinical consequence occurred or could 
have occurred should be recorded based on investigator judgement. 
Treatment non-compliance (including missed doses) where no clinical consequence occurred or 
could have occurred should not be recorded as medication errors. See Section 6.3.2 for recording 
of treatment compliance. 
Medication error must be recorded on the AE form in the eCRF. In addition, any clinical 
consequences of the medication error must be recorded as separate AEs on the AE form. If the AE 
originating from the medication error qualifies as an SAE, expedited reporting is required 
(Section 8.5.7). 
 Misuse or Abuse 
The terms misuse and abuse are similar in that they both represent the intentional use of a drug in 
a way other than defined in the protocol. 
Misuse refers to situations where the IMP is intentionally and inappropriately used for therapeutic 
purposes not in accordance with the protocol. 
Abuse refers to intentional use of an IMP for what could be considered desirable non-therapeutic 
effects (e.g. sedative, stimulant, euphoric effects). 
Misuse and abuse must be recorded on the AE form in the eCRF. In addition, any clinical 
consequences of misuse or abuse must be recorded as separate AEs on the AE form. If the AE 
originating from the misuse or abuse qualifies as an SAE, expedited reporting is required 
(Section 8.5.7). 
 Aggravation of condition 
Any clinically significant aggravation/exacerbation/worsening of any medical condition(s) 
compared to screening must be reported as an (S)AE in accordance with Section 8.5.5. 
Worsening of FFA is captured by efficacy assessments and will not be recorded as an AE.   
8.6 Procedural Complications (Cohort 2 Only) 
For subjects in Cohort 2, procedural complications will be reported instead of AEs.  
For the purpose of this trial, a procedural complication is defined as any untoward medical event 
experienced by a subject that has signed an ICF for the trial, such as infection, bleeding, and/or 
pain, that the investigator believes to be causally related to the trial procedures performed at Day 1 
visit or at the optional visit. Subjects will receive appropriate treatment as needed for any 
procedural complications that arise. 
For the purpose of this trial, a serious procedural complication is any untoward medical event 
related to the trial procedures that has any of the following consequences: 
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• Results in death 
• Is life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event that hypothetically 
might have caused death if it were more severe. 
Any medical condition that is present prior to the first sample collection on Day 1 will be 
considered as part of medical history and not reported as a procedural complication. Should a 
subject experience an event that he believes to be causally related to the trial procedure performed 
on Day 1 or at the optional follow-up visit (after sample collection), the event will be recorded as 
a procedural complication. Any procedural complications whether observed by site personnel or 
reported spontaneously by the subject will be described in the source document and eCRF.  
Any serious procedural complication (this refers to any procedural complication that meets one or 
more of the aforementioned serious criteria) occurring during the trial must be reported on a serious 
procedural complication form as per the instructions in Section 8.5.7.  
 
 
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9 STATISTICAL CONSIDERATIONS  
9.1 Sample Size Determination 
From Del Duca et al. (2020) paper1, the difference in log2-fold changes (SD*) between FFA 
patients and healthy controls are reported to 4.851 (4.411), 5.298 (5.512) and 4.559 (4.891) for 
CXCL9, CXCL10 and IFN-γ, respectively. 
A sample 30 subjects are randomized in an equal manner (1:1) to delgocitinib cream 20 mg/g or 
vehicle cream. It is expected that a reduction of at least 90% from baseline to Week 12 for the 
delgocitinib cream 20 mg/g treated subjects compared to only 5% in the vehicle group, normalized 
to healthy controls, will be observed. 
With the above assumptions, the trial should have at least 80% disjunctive power, i.e. a statistically 
significant difference (tested at 5% one-sided level in an independent two-sample t-test) can be 
shown with at least 80% probability, in at least one of the genes, assuming no correlation between 
the tests and same level of variation as reported in the Del Duca et al. (2020) paper1. 
*Derived from the reported p-values coming from a t-test comparing lesional FFA biopsy data (N=12) to data from 
healthy controls (N=8).  
9.2 Populations for Analyses 
Cohort 1: 
Efficacy will be evaluated on the basis of the full analysis set (FAS). A supportive analysis will 
also be conducted on the per-protocol (PP) analysis set. 
Full analysis set (FAS): All subjects randomised and exposed to IMP will be included in the FAS 
and will be analysed based on the randomised treatment allocation. Exclusions from the FAS can 
be considered in special cases as described in ICH E9, Section 5.2.1, Full Analysis Set. If it is 
decided to exclude a subject from the FAS, a justification addressing ICH E9 will be given. 
PD analysis set: This analysis set is a subset of the FAS and will include all subjects who have at 
least one assessment of PD parameters. 
Per-protocol (PP) analysis set: This analysis set will include all subjects who were randomized, 
who received at least one dose of IMP and who at least one post dose efficacy measurement with 
no major protocol deviations affecting the efficacy evaluations. All subjects will be analyzed 
according to the treatment group that they actually received during the vehicle-controlled period. 
Safety analysis set (vehicle-controlled treatment period): This analysis set will include all subjects 
who received at least one dose of the IMP. All subjects will be analyzed according to the treatment 
group that they actually received during the vehicle-controlled period. 
Safety analysis set (OLE): This analysis set will include all subjects who entered the OLE and 
received at least one dose of delgocitinib 20 mg/g during the OLE.  
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Cohort 2: 
Safety analysis set: This analysis set will include all subjects who had at least one skin sample 
collected.  
9.3 Statistical Analyses 
 General Approach 
Continuous variables will be summarized in tables and will include the number of subjects, mean, 
standard deviation (SD), median, minimum, maximum, first (Q1) and third (Q3) quartiles. 
Categorical variables will be presented in tables as frequencies and percentages.  
All details regarding the efficacy and safety variable definitions, analyses strategy, statistical 
justification, and techniques for handling missing values will be detailed in a separate statistical 
analysis plan (SAP) that will be prepared before the database is locked and any analyses are 
undertaken. Any deviation(s) from the SAP will be described and justified in the final report, as 
appropriate. Statistical analysis related to molecular signature changes/PD analyses (ie, skin 
biopsies, tape strips, and skin microbiome) will be described in a separate SAP prepared by the 
specialty laboratory in charge of these analyses. 
All statistical tests will be two-sided and will be performed with a significant level of 0.05, unless 
otherwise specified in the SAP. 
 Baseline 
Baseline will be defined separately for the vehicle-controlled treatment period and OLE as follows: 
• Vehicle-controlled treatment period: 
For both the safety and exploratory efficacy analyses, the baseline will be defined as the last 
non-missing assessment prior to the first trial treatment dose (including unscheduled 
assessments). If the last non-missing assessment is performed on the same date as the first trial 
treatment and time is not available, the assessment will be considered as baseline, except for 
AEs and medications starting on the first trial treatment dose date which will be considered 
post-baseline. 
• Open-label extension period: 
For the safety analyses, the OLE baseline will be defined as the last non-missing assessment 
prior to the first delgocitinib cream 20 mg/g dose.  This definition will be used for summarizing 
the change from the OLE baseline for the subject who entered OLE period.    
For the exploratory efficacy analyses, the baseline will be defined as the last non-missing 
assessment prior to the first trial treatment dose (including unscheduled assessments) from the 
vehicle-controlled treatment period for all subjects. 
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Change from baseline is defined for both the vehicle-controlled treatment period and OLE as the 
post-baseline value minus the baseline value unless otherwise specified. Percent change from 
baseline will be calculated as follows: Percent change from baseline = (Change from baseline / 
Baseline) x 100   
For the pruritus NRS, burning sensation NRS, and pain NRS, the baseline scores will be defined 
as the average of all non-missing daily 24-hour NRS scores reported over the last 7 days prior to 
randomization (prior to the first application of the IMP). 
 Efficacy Analyses 
9.3.3.1 Vehicle-Controlled Treatment Period 
The comparison between the groups for the exploratory efficacy endpoints will be done using a 
mixed model repeated measures (MMRM), where the change from baseline will be the dependent 
variable; the treatment group, the visit, and an interaction term for the treatment-by-visit will be 
the fixed effects; and the baseline value will be the covariate. 
The exploratory efficacy endpoints involving change from baseline will be analyzed at each time 
point using the same approach (i.e., MMRM) as described for the primary efficacy analysis.  
The other efficacy endpoints involving proportions of pruritus NRS, burning sensation NRS, and 
pain NRS will be analyzed using a Chi-squared test at each visit.  
The primary efficacy analysis will be done using the FAS, and the PP analysis set will be used as 
supportive analysis. No imputation will be performed for the continuous endpoints subjected to an 
MMRM. 
For the analyses of binary data, imputation of the last observation carried forward (LOCF) for any 
missing value will be performed.  
9.3.3.2 Open-Label Extension Period 
These efficacy outcomes will be measured at scheduled visits after Week 12. The following 
endpoints will be assessed in the OLE: 
• Continuous variables: observed value and change (percent) from baseline in LPPAI, 
FFASS, target area perifollicular scale score, target area perifollicular erythema score, 
pruritus NRS, burning sensation NRS, pain NRS, and target area hair counts/trichoscopy 
via fotofinder trichovision.  
The above endpoints will be summarized by visit using descriptive statistics with following 
considerations: 
• Summaries will be provided for 1) treatment group in OLE and for 2) randomized treatment 
groups in the vehicle-controlled treatment period. 
• Change from baseline in continuous variables will be analyzed using change from 
vehicle-controlled treatment period baseline. 
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 Safety Analyses 
9.3.4.1 Vehicle-Controlled Treatment Period 
Cohort 1: 
All safety data, including AEs and SAEs will be presented and tabulated according to the Medical 
Dictionary for Regulatory Activities (MedDRA) classification. Descriptions of AEs will include 
the start date, the stop date (if it resolved), the severity and seriousness of the AE, the causality of 
the AE to IMP, and the outcome. The focus in this protocol will be the number of 
treatment-emergent adverse events (TEAEs). 
Adverse events will be considered in vehicle-controlled treatment period or OLE depending on the 
onset date – if the AE onset date was before Week 12, the AE will be considered as a 
vehicle-controlled treatment period AE. If the AE had an onset on or after Week 12, the AE will 
be considered as an OLE AE.  
Reported AEs will be summarized by the number of subjects reporting the events, as well as by 
System Organ Class (SOC), PT, severity, seriousness, and relationship to IMP. For the summary 
of AEs by severity, each subject will be counted only once within a SOC or a PT by using the AEs 
with the highest intensity within each category for each analysis. For the summary of AEs by 
relationship to IMP, each subject will be counted only once within a SOC or a PT by using the 
AEs with the greatest reported relationship within each category. For the summary of AEs by 
relationship to IMP and severity, each subject will be counted only once within a SOC or a PT by 
using (1) the greatest reported relationship followed by (2) the highest reported intensity. 
All information pertaining to AEs noted during the trial will be listed by subject, detailing 
verbatim, SOC, PT, start date, stop date, intensity, outcome, and relationship to IMP. The AE onset 
will also be shown relative (in number of days) to the day of IMP administration. Serious adverse 
events will be tabulated by treatment group, relationship to the IMP, and a reference to the 
occurrence of the SAEs to the relative day of dosing. 
AESIs will be listed. No narratives for AESIs will be written in the study report.  
Results from laboratory analyses and vital signs will be tabulated by treatment and visit using 
descriptive statistics. The value at each visit as well as the change from baseline will be presented 
descriptively. 
Clinically significant changes in laboratory analyses and vital signs, and new findings on local 
tolerability assessments and physical examination will be recorded as AEs. 
Concomitant medications will be coded with the world health organization (WHO)-Drug 
Dictionary and listed by subject. Summary of medication classes will also be tabulated. 
No inferential statistics will be done on safety variables. 
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Cohort 2: 
Procedural complications will be presented and tabulated according to MedDRA classification. 
Descriptions of procedural complications will include the start date, the stop date (if it resolved), 
the severity and seriousness of the procedural complication, and the outcome.  
Reported procedural complications will be summarized by the number of subjects reporting the 
events, as well as by SOC, PT, severity, and seriousness. For the summary of procedural 
complications by severity, each subject will be counted only once within a SOC or a PT by using 
the procedural complications with the highest intensity within each category for each analysis.  
All information pertaining to procedural complications noted during the trial will be listed by 
subject, detailing verbatim, SOC, PT, start date, stop date, intensity, and outcome. The procedural 
complication onset will also be shown relative (in number of days) to the Day 1 skin sample 
collection.  
9.3.4.2 Open-Label Extension Period 
Safety analyses will follow general considerations in previous Section 9.3.4.1 with the following 
exceptions: 
• Summaries will be provided for 1) treatment group in the OLE and for 2) randomized 
treatment groups in vehicle-controlled treatment period. 
• Change from baseline will be analyzed using change from vehicle-controlled treatment 
period baseline for subjects who received delgocitinib during the vehicle-controlled 
treatment period, and change from OLE baseline for subjects who received placebo during 
the vehicle-controlled treatment period. 
Only descriptive statistics will be presented. 
 Molecular Signature Changes Analyses 
Molecular signature changes analyses will be evaluated on the basis of the PD analysis set. A 
MMRM will be used to detect any overall differences in the treatment effect at Week 12 compared 
to baseline in the molecular measurements. This formulation intrinsically models the within patient 
correlation structure as in the case of a paired t-test. This approach introduces less bias than 
restricting the analysis for those patients who completed the trial. Time points (baseline, Week 
12), treatment group (active, vehicle, and healthy), and tissue (lesional and non-lesional) will be 
considered as fixed factors, while participant ID will be included as random factor. 
 Other Analyses 
Descriptive summaries of baseline characteristics, including demographic data, prior and 
concomitant therapy, and subject disposition will be presented. In addition, a list of subjects who 
discontinued from the trial will be provided. 
Protocol deviations will be summarized by treatment and category. 
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 Planned Interim Analyses 
No interim analysis is planned in this trial. 
 
 
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10 REGULATORY, ETHICAL, AND TRIAL OVERSIGHT 
CONSIDERATIONS 
10.1  Local Regulations/Declaration of Helsinki 
This trial will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and that are consistent with ICH Tripartite Guideline for GCP and the 
applicable laws and regulations of the country in which the research is conducted, whichever 
affords the greater protection to the individual. 
10.2  Ethical Review  
It is the understanding of the sponsor that this protocol (and any amendments) as well as 
appropriate consent procedures, will be reviewed and approved by a REB/IRB. This board must 
operate in accordance with the current federal regulations. If the site has a local ethics committee, 
a letter or certification of approval will be sent by the investigator to the sponsor (or CRO) before 
initiation of the trial and also whenever subsequent modifications to the protocol are made. 
10.3  Informed Consent Process 
An ICF describing in detail the trial treatment (for Cohort 1 only), trial procedures, and risks will 
be given to the subject, along with an assent form when required. 
It is the responsibility of the investigator, or a person designated by the investigator (if acceptable 
by local regulation), to obtain written informed consent from each individual participating in this 
trial, after adequate explanation of the aims, methods, objectives, and potential hazards of the trial. 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
trial and continues throughout the individual’s trial participation. Consent forms will be IRB/REB 
approved, and the subject will be asked to read and review the document. The investigator will 
explain the research trial to the subject and answer any questions that may arise. A verbal 
explanation will be provided in terms suited to the subject’s comprehension of the purposes, 
procedures, and potential risks of the trial and of his or her rights as a research subject. Subjects 
will have the opportunity to carefully review the written consent form and ask questions prior to 
signing. The subjects should have the opportunity to discuss the trial with their family or surrogates 
or think about it prior to agreeing to participate. 
The subject will sign the informed consent document prior to any procedures being done 
specifically for the trial. Subjects must be informed that participation is voluntary and that they 
may withdraw from the trial at any time for any reason, without prejudice. A copy of the signed 
informed consent document will be given to the subjects for their records. The informed consent 
process will be conducted and documented in the source document (including the date), and the 
form signed, before the subject undergoes any trial-specific procedures. 
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The rights and welfare of the subjects will be protected by emphasizing to them that the quality of 
their medical care will not be adversely affected if they decline to participate in this trial. 
If new safety information results in significant changes in the risk/benefit assessment, or if any 
new information becomes available that may affect the willingness of a subject to continue to 
participate, the consent form should, if necessary, be reviewed and updated by the IRB/REB. All 
subjects (including those already being treated) should be informed of the new information, given 
a copy of the revised form, and asked to give their consent to continue in the trial. 
10.4  Trial Discontinuation and Closure 
This trial may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for trial suspension or termination, will be 
provided by the suspending or terminating party to trial subjects, investigators, the sponsor, and 
regulatory authorities. If the trial is prematurely terminated or suspended, the principal 
investigators will promptly inform trial subjects and the IRB/REB, and will provide the reason(s) 
for the termination or suspension. Trial subjects will be contacted, as applicable, and be informed 
of changes to trial visit schedule. 
Circumstances that may warrant termination or suspension of the trial include, but are not limited 
to the following: 
• 
Determination of unexpected, significant, or unacceptable risk to subjects 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete or evaluable 
• 
Scientific or corporate reasons 
The trial may resume once concerns about safety, protocol compliance, and data quality are 
addressed and satisfy the sponsor, IRB/REB, and/or FDA. 
10.5  Confidentiality and Privacy  
Subject confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor and their interventions. This confidentiality is extended to cover testing of 
biological samples in addition to the clinical information relating to subjects. Therefore, the trial 
protocol, documentation, data, and all other information generated will be held in strict confidence. 
The investigator must assure that the subjects’ anonymity will be maintained and that subjects’ 
identities are protected from unauthorized parties. On CRF or other documents submitted to the 
sponsor, subjects should not be identified by their names, but by an identification code. The 
investigator should keep a subject log relating codes with the names of subjects. The investigator 
should maintain in strict confidence documents not for submission to LEO Pharmaceutical A/S 
(e.g., subjects’ written consent forms). 
All research activities will be conducted in a setting as private as possible. 
The study monitor, other authorized representatives of the sponsor, and representatives of the IRB, 
regulatory agencies, or pharmaceutical company supplying IMP may inspect all documents and 
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records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the subjects in this trial. The clinical site will 
permit access to such records. 
The trial subject’s contact information will be securely stored at each clinical site for internal use 
during the trial. At the end of the trial, all records will continue to be kept in a secure location for 
as long a period as dictated by the applicable legal or regulatory requirements, the reviewing IRB, 
institutional policies, or sponsor requirements. 
10.6  Clinical Monitoring 
Clinical site monitoring will be conducted to ensure that the rights and well-being of trial subjects 
are protected; that the reported trial data are accurate, complete, and verifiable; and that the conduct 
of the trial is in compliance with the currently approved protocol/amendment(s), ICH GCP 
guidelines, and with applicable regulatory requirement(s). Details of clinical site monitoring will 
be documented in a Monitoring Plan. Centralized monitoring, which consist of remote review of 
accumulating data from all sites, will be performed as detailed in the Centralized Monitoring Plan.  
10.7  Quality Assurance and Quality Control 
Each clinical site will perform internal quality management of trial conduct, data and biological 
specimen collection, documentation, and completion. 
Quality control (QC) procedures will be implemented beginning with the data entry system, and 
data QC checks, which will be run on the database, will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
During the trial, the sponsor or its representative will conduct monitoring visits at regular intervals. 
The monitoring visits will be conducted to ensure protocol adherence, quality of data, accuracy of 
entries on the eCRFs, IMP accountability, compliance with regulatory requirements, and continued 
adequacy of the site and its facilities. 
The site may be audited, monitored, or inspected by a quality assurance officer named by the 
sponsor, by the REB or IRB, and/or by the regulatory authorities. The investigator will be given 
notice before an audit occurs and will be expected to cooperate with any audit and provide 
assistance and documentation (including source data) as requested. The site will provide direct 
access to all trial-related sites, source data/documents, and reports for the purpose of monitoring 
and auditing by the sponsor and inspection by local and regulatory authorities. 
10.8 Data Handling and Record Keeping 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
The investigator must maintain adequate and accurate records to enable the conduct of the trial to 
be fully documented and the trial data to be subsequently verified. These documents should be 
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classified into two separate categories: investigator’s study files and subject clinical source 
documents. 
The investigator must maintain source documents for each subject in the trial. These source 
documents will consist of case and visit notes (clinical medical records) containing demographic 
and medical information and the results of any tests or assessments. All information on the eCRFs 
must be traceable to the source documents in the subject’s file. Data not requiring a written or 
electronic record will be defined before trial start and will be recorded directly on the eCRFs, 
which will be documented as being the source data. 
The records should be retained by the investigator according to ICH guidelines, local regulations, 
or as specified in the Clinical Trial Agreement, whichever retention period is longer. 
Subject data will be entered by site personnel using Medrio, a web-based EDC and reporting 
system. This application will be set up for remote entry. Medrio Inc. is the developer and owner 
of Medrio. The EDC software has been fully validated and conforms to Title 21 of the Code of 
Federal Regulations, Part 11 requirements. Investigator site staff will not be given access to the 
EDC system until they have been fully trained. Designated investigator staff will enter the data 
required by the protocol into the eCRFs using this web-based application. Automatic validation 
programs check for data discrepancies in the eCRFs and, by generating appropriate error messages, 
allow modification or verification of the entered data by the investigator staff before confirming 
the data. The investigator must certify that the data are complete and accurate by applying an 
electronic signature to the eCRFs. 
The data collected will be encoded and stored electronically in a database system. Validated data 
may subsequently be transferred to the sponsor. 
10.9 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol requirements. The 
non-compliance may be either on the part of the subject, the investigator, or the trial site staff. As 
a result of deviations, corrective actions are to be developed by the site and implemented promptly. 
The clinical research associate (CRA) must ensure that a prompt action is taken to secure 
compliance. If a non-compliance that significantly affects or has the potential to significantly affect 
human subject protection or reliability of trial results is discovered, the CRO and the Sponsor 
should perform a root cause analysis and implement appropriate corrective and preventive actions. 
Protocol deviations must be sent to the reviewing IRB per their policies. The investigator is 
responsible for knowing and adhering to the reviewing IRB requirements. 
10.10 Publication Policy 
The publication policy will be addressed in the Research and Financial Agreement with the site, 
and all details outlined in the agreement will apply to this protocol. The trial will be registered on 
ClinicalTrials.Gov prior to the first subject being dosed. 
 
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Final Protocol Version 2.0: 17 November 2021 
 
. 
Confidential and proprietary. Permission should be obtained before any reproduction. 
11 REFERENCES 
1. 
Del Duca E, Ruano Ruiz J, Pavel AB, et al. Frontal fibrosing alopecia shows robust T 
helper 1 and Janus kinase 3 skewing. Br J Dermatol. 2020;183(6):1083-1093. 
2. 
Imhof R, Tolkachjov SN. Optimal Management of Frontal Fibrosing Alopecia: A Practical 
Guide. Clin Cosmet Investig Dermatol. 2020;13:897-910. 
3. 
Pham CT, Hosking AM, Cox S, Mesinkovska NA. Therapeutic response of facial papules 
and inflammation in frontal fibrosing alopecia to low-dose oral isotretinoin. JAAD Case 
Rep. 2020;6(5):453-456. 
4. 
Harries MJ, Meyer K, Chaudhry I, et al. Lichen planopilaris is characterized by immune 
privilege collapse of the hair follicle's epithelial stem cell niche. J Pathol. 2013;231(2):236-
247. 
5. 
Investigator's Brochure Delgocitinib Cream. In. Vol Edition no. 04: LEO Pharma A/S; 22-
Jan-2021. 
6. 
Tavakolpour S, Mahmoudi H, Abedini R, Kamyab Hesari K, Kiani A, Daneshpazhooh M. 
Frontal fibrosing alopecia: An update on the hypothesis of pathogenesis and treatment. Int 
J Womens Dermatol. 2019;5(2):116-123. 
7. 
Chiang C, Sah D, Cho BK, Ochoa BE, Price VH. Hydroxychloroquine and lichen 
planopilaris: efficacy and introduction of Lichen Planopilaris Activity Index scoring 
system. J Am Acad Dermatol. 2010;62(3):387-392. 
8. 
Saceda-Corralo D, Moreno-Arrones OM, Fonda-Pascual P, et al. Development and 
validation of the Frontal Fibrosing Alopecia Severity Score. J Am Acad Dermatol. 
2018;78(3):522-529. 
9. 
Doche I, Romiti R, Hordinsky MK, Valente NS. "Normal-appearing" scalp areas are also 
affected in lichen planopilaris and frontal fibrosing alopecia: An observational 
histopathologic study of 40 patients. Exp Dermatol. 2020;29(3):278-281. 
10. 
Phan NQ, Blome C, Fritz F, et al. Assessment of pruritus intensity: prospective study on 
validity and reliability of the visual analogue scale, numerical rating scale and verbal rating 
scale in 471 patients with chronic pruritus. Acta Derm Venereol. 2012;92(5):502-507. 
11. 
Verweyen E, Stander S, Kreitz K, et al. Validation of a Comprehensive Set of Pruritus 
Assessment Instruments: The Chronic Pruritus Tools Questionnaire PRURITOOLS. Acta 
Derm Venereol. 2019;99(7):657-663. 
12. 
Hawker GA, Mian S, Kendzerska T, French M. Measures of adult pain: Visual Analog 
Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain 
Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain 
Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of 
Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken). 
2011;63 Suppl 11:S240-252. 
13. 
Haefeli M, Elfering A. Pain assessment. Eur Spine J. 2006;15 Suppl 1:S17-24. 
14. 
European Parliament Union. European CoT. Directive 2001/20/EC of the European 
Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations 
and administrative provisions of the Member States relating to the implementation of good 
clinical practice in the conduct of clinical trials on medicinal products for human use. EMA 
ed 2001. 2001. 
 
 
 
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Final Protocol Version 2.0: 17 November 2021 
 
. 
Confidential and proprietary. Permission should be obtained before any reproduction. 
APPENDIX A: Lichen Planopilaris Activity Index (LPPAI) 7 
 
 
 
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Final Protocol Version 2.0: 17 November 2021 
 
. 
Confidential and proprietary. Permission should be obtained before any reproduction. 
APPENDIX B: Frontal Fibrosing Alopecia Severity Score 8  
 
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Final Protocol Version 2.0: 17 November 2021 
 
. 
Confidential and proprietary. Permission should be obtained before any reproduction. 
APPENDIX C: Numerical Rating Scale  
Pruritus NRS 
On scale from 0 (“no itch”) to 10 (“worst imaginable itch”), how was your worst itch due to 
your frontal fibrosing alopecia in the past 24 hours? Please select one number.   
Numeric Rating Scale  
 
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
 
 
 
 
No itch 
Worst imaginable itch 
 
 
Modified from: http://www.pruritussymposium.de/numericalratingscale.html 
 
Burning Sensation NRS 
On scale from 0 (“no burning sensation”) to 10 (“worst imaginable burning sensation”), how 
was your worst burning sensation due to your frontal fibrosing alopecia in the past 24 hours? 
Please select one number.   
Numeric Rating Scale  
 
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
 
 
 
 
No burning sensation 
          Worst imaginable burning sensation 
 
 
Pain NRS 
On scale from 0 (“no pain”) to 10 (“worst imaginable pain”), how was your worst pain due 
to your frontal fibrosing alopecia in the past 24 hours? Please select one number.   
Numeric Rating Scale  
 
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
 
 
 
 
No pain 
Worst imaginable pain 
 
 
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