Clinical trial NCT04598269
Conditions: Atopic Dermatitis
Sponsor: Aclaris Therapeutics, Inc.
Start date: 2020-09-30; Completion date: 2021-04-22
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a first-in-human, randomized, double-blind, parallel-group, vehicle-controlled study to evaluate the efficacy, safety, tolerability, and PK of ATI-1777 solution following twice-daily applications to target areas of participants with moderate or severe atopic dermatitis (AD).

Detailed description:
Participants underwent screening evaluations to determine eligibility up to 30 days prior to randomization. Participants who meet all the entry criteria were randomized on Day 1 to active or vehicle treatment. Participants applied study drug (ATI-1777 topical solution 2.0% w/w or vehicle) twice daily for 4 weeks with weekly study visits and were to return 2 weeks after the last dose of study medication for a Post treatment Follow-up (PTFU) Visit.

Arms: arm 1: ATI-1777 topical solution 2.0% w/w, twice daily arm 2: Vehicle topical solution, twice daily
Interventions: intervention 1: ATI-1777 intervention 2: Vehicle
Intervention descriptions: intervention 1: ATI-1777 topical solution 2.0% w/w intervention 2: Vehicle topical solution containing no ATI-1777

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
Version Date: 28-Jan-2021 
Page 1 of 93 
CLINICAL STUDY PROTOCOL 
Title: 
A Phase 2a, Multicenter, Randomized, Double-
blind, Vehicle-controlled, Parallel-group Study to 
Determine the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of ATI-1777 in 
Adult Patients with Moderate or Severe Atopic 
Dermatitis 
Protocol number: 
ATI-1777-AD-201 
Study phase:  
Phase 2a  
Test product:  
ATI-1777 
IND number: 
141,358 
Sponsor:  
Aclaris Therapeutics, Inc. 
640 Lee Road 
Suite 200 
Wayne, Pennsylvania 19087 
USA 
Phone: 
 
Contract research organization:  PRA Health Sciences, Inc. 
4130 Park Lake Avenue 
Suite 400 
Raleigh, North Carolina 27612 
USA 
Phone: 
 
Protocol version and date:  
Version 4, 28-Jan-2021 
This study will be performed in compliance with the principles of Good Clinical Practice. 
This document is a confidential communication of Aclaris Therapeutics, Inc. Acceptance 
of this document constitutes agreement by the recipient that no unpublished information 
contained herein shall be published or disclosed without prior written approval, except 
that this document will be disclosed to the appropriate institutional review board(s) 
(IRBs) under the condition that they keep it confidential. 
NCT #: NCT04598269


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
Protocol Version and Date: Version 4, 28-Jan-2021 
Page 2 of 93
 
 
Confidential 
 
 
PROTOCOL SIGNATURE PAGE – SPONSOR 
This protocol has been reviewed and approved by the representative listed below. Any 
modification of the protocol must be agreed upon by the sponsor and the investigator and 
must be documented in writing. 
Aclaris Therapeutics, Inc. representative: 
 
 
 
 
Date 
 
DocuSign Envelope ID: 133CEE5E-BEFC-4653-90E7-FA53BF9872F8
1/28/2021


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
Protocol Version and Date: Version 4, 28-Jan-2021 
Page 3 of 93
 
 
Confidential 
 
 
PROTOCOL SIGNATURE PAGE – INVESTIGATOR 
I have read this protocol, which has been agreed by Aclaris Therapeutics, Inc. and, given 
approval/favorable opinion by the IRB, and I agree that it contains all necessary details 
for my staff and I to conduct this study as described. I will provide copies of the protocol 
and any amendments to all study personnel under my supervision and provide access to 
all information provided by Aclaris Therapeutics, Inc. or their specified designees. I will 
discuss the material with the study personnel to ensure that they are fully informed about 
the study. 
I understand that information contained in or pertaining to this protocol is confidential 
and should not be disclosed, other than to those directly involved in the execution or the 
ethical review of the study, without written authorization from Aclaris Therapeutics, Inc. 
It is, however, permissible to provide information to a patient in order to obtain consent. 
I agree to conduct this study according to this protocol and to comply with its 
requirements, subject to ethical and safety considerations and guidelines, and to conduct 
the study in accordance with the Declaration of Helsinki, International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP), and applicable 
regional regulatory requirements. 
I agree to comply with the procedures described for data recording and reporting and to 
permit monitoring and auditing by Aclaris Therapeutics, Inc. and inspection by the 
appropriate regulatory authorities. 
I agree to make my patients’ study records available to Aclaris Therapeutics, Inc. 
personnel, their representatives, and relevant regulatory authorities in order to verify data 
that I have entered into the electronic case report forms (eCRFs). I will retain the study-
related essential documents until Aclaris Therapeutics, Inc. indicates that they are no 
longer needed. I am aware of my responsibilities as an investigator as provided by 
Aclaris Therapeutics, Inc. 
I understand that Aclaris Therapeutics, Inc. may decide to suspend or prematurely 
terminate the study at any time for whatever reason; such a decision will be 
communicated to me in writing. Conversely, should I decide to withdraw from execution 
of the study, I will communicate my intention immediately in writing Aclaris 
Therapeutics, Inc. 


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
Protocol Version and Date: Version 4, 28-Jan-2021 
Page 4 of 93
 
 
Confidential 
 
 
Investigator: 
 
 
 
 
Name 
 
 
Title 
 
Institution 
 
 
 
Signature 
 
Date 
 


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
Protocol Version and Date: Version 4, 28-Jan-2021 
Page 5 of 93
 
 
Confidential 
 
 
SERIOUS ADVERSE EVENT CONTACT INFORMATION 
In the event of a serious adverse event (SAE), the investigator will send a safety report 
form within 24 hours of becoming aware of the SAE to: 
ProPharma Group  
FAX: 
  
Email:
 
 


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
Protocol Version and Date: Version 4, 28-Jan-2021 
Page 6 of 93
 
 
Confidential 
 
 
SUMMARY OF CHANGES 
The changes introduced under Version 4 of the protocol (dated 28-Jan-2021) are being 
made to increase study enrollment to more accurately reflect the expected frequency of 
evaluable subjects and update the statistical methods to more accurately reflect the 
planned statistical analyses. 
 
Text Affected 
Changes 
Protocol Summary – 
Planned number of patients 
Sentence 1 
Revised: 
It is planned to enroll approximately 4250 patients. 
Protocol Summary –  
Statistical method 
Determination of sample 
size 
Sentences 1 and 2 
Revised: 
Data from 34 patients provides 9095.6% power to detect a 
statistically significant difference between the treatment 
groups in the primary endpoint (percent change from baseline 
in EASI scores). This power calculation is based upon a 1-
sided treatment contrast within a 1-way ANOVA model and 
assumes group means of 65% and 20% for ATI-1777 and 
vehicle, respectively. 
Protocol Summary –  
Statistical methods 
Efficacy Analyses 
Revised: 
All efficacy summaries will be conducted on both the FAS 
and PP populations. All p-values for efficacy will be based on 
a 1-sided hypothesis test of the superiority of ATI-1777 to 
vehicle. 
The primary efficacy analysis will be the treatment 
comparison between ATI-1777 and vehicle for the percent 
change from baseline in EASI scores at Week 4. This 
treatment comparison will be made within the context of a 
Mixed Model Repeated Measures analysis where the EASI 
scores over time are treated as repeated measures within a 
given patient. Treatment group, time (study visit), and 
treatment by time interaction will enter the model as 
categorical factors, baseline EASI score and/or baseline 
severity of AD will be included as a continuous covariate, and 
patient ID will enter the model as a random effect. Treatment 
group model-based means and model-based differences in 
treatment groups will be provided along with corresponding 
9590% confidence intervals and 1-sided p-values.  
Treatment comparisons between ATI-1777 and vehicle for 
each of the continuous efficacy endpoints that are conducted 
over time (Change in IGA, BSA, and PP-NRS) will be 
analyzed using a similar model as described for the primary 
endpoint. Treatment comparisons will be made for each post-


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
Protocol Version and Date: Version 4, 28-Jan-2021 
Page 7 of 93
 
 
Confidential 
 
 
baseline scheduled visit utilizing an appropriate analysis 
window scheme.  
Treatment group comparisons for categorical efficacy 
endpoints (IGA Response, EASI-50, -75, and -90) that are 
conducted over time will employ a logistic regression model 
fit at each scheduled visit separately, where appropriate. The 
logistic regression model will include treatment group as a 
factor and the baseline value and/or baseline severity of AD 
as a covariate. Model-based point estimates for the treatment 
proportions will be provided as well as model-based 
differences and corresponding 9590% confidence intervals 
and 1-sided p-values. 
Study Schematic 
Figure 1 - Study Schematic 
Revised: 
Figure 1 
Study Schematic 
 
 
Section 4.1.2 – Treatment 
Period 
Sentence 1 
Revised: 
A total of approximately 4250 patients who meet all the entry 
criteria will be randomized on Day 1 via an interactive voice/web 
response system (IXRS) to ATI-1777 or vehicle treatment in a 1:1 
ratio. 
Section 9.3 – Sample Size 
Revised: 
A total of approximately 4250 patients will be enrolled in 
order to achieve 34 patients who complete the study. Data 
from 34 patients is estimated to provide 9095.6% power to 
detect a statistically significant difference between the 
Randomization 
N = ~4250 
ATI-1777 
N = ~2125 
4 weeks 
Vehicle 
N = ~2125 
4 weeks 
Screening 
Up to 30 days 
Follow-up 
2 weeks after last dose of study medication 


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
Protocol Version and Date: Version 4, 28-Jan-2021 
Page 8 of 93
 
 
Confidential 
 
 
treatment groups in the primary endpoint (percent change 
from baseline in EASI scores). This power calculation is 
based upon a 1-sided treatment contrast within a 1-way 
ANOVA model and assumes group means of 65% and 20% 
for ATI-1777 and vehicle, respectively. The group means 
were based upon slightly more conservative estimates than 
were observed in a Phase 2 study of topical ruxolitinib in AD 
(Kim et al 2020b). The variance for the percent change from 
baseline in EASI was assumed to be 38.3%. This variance 
assumption was based upon data observed in a pilot AD study 
for the topical compound ATI-502 (ATI-502-AD-201). 
Section 9.4.5 – Treatment 
Period 
Revised: 
All efficacy summaries will be conducted on both the FAS 
and PP populations. All p-values for efficacy will be based on 
a 1-sided hypothesis test of the superiority of ATI-1777 to 
vehicle. 
The primary efficacy analysis will be the treatment 
comparison between ATI-1777 and vehicle for the percent 
change from baseline in EASI scores at Week 4 based on the 
FAS. This treatment comparison will be made within the 
context of a Mixed Model Repeated Measures analysis where 
the EASI scores over time are treated as repeated measures 
within a given patient. Treatment group, time (study visit), 
and treatment by time interaction will enter the model as 
categorical factors, baseline EASI score and/or baseline 
severity of AD will be included as a continuous covariate and 
patient ID will enter the model as a random effect. Treatment 
group model-based means and model-based differences in 
treatment groups will be provided along with corresponding 
9590% confidence intervals and 1-sided p-values.  
Treatment comparisons between ATI-1777 and vehicle for 
each of the continuous efficacy endpoints that are conducted 
over time (change in IGA, BSA, and PP-NRS) will be 
analyzed using a similar model as described for the primary 
endpoint. Treatment comparisons will be made for each post-
baseline scheduled visit utilizing an appropriate analysis 
window scheme.  
Treatment group comparisons for categorical efficacy 
endpoints (IGA Response, EASI-50, EASI-75, and EASI-90) 
that are conducted over time will employ a logistic regression 
model fit at each scheduled visit separately, where 
appropriate. The logistic regression model will include 
treatment group as a factor and the baseline value and/or 
baseline severity of AD as a covariate. Model-based point 
estimates for the treatment proportions will be provided as 


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
Protocol Version and Date: Version 4, 28-Jan-2021 
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well as model-based differences and corresponding 9590% 
confidence intervals and 1-sided p-values. 
Section 9.4.9 – Handling of 
Missing Values 
Paragraph 2, Sentence 1 
Revised: 
For the primary efficacy analysis and all continuous analyses 
based on the FAS population, missing data will be imputed 
using last observation carried forward (LOCF). 
 
 


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
Protocol Version and Date: Version 4, 28-Jan-2021 
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PROTOCOL SUMMARY 
Protocol number: ATI-1777-AD-201 
Protocol title: A Phase 2a, Multicenter, Randomized, Double-blind, Vehicle-controlled, Parallel-group 
Study to Determine the Safety, Tolerability, Pharmacokinetics, and Efficacy of ATI-1777 in Adult 
Patients with Moderate or Severe Atopic Dermatitis 
Sponsor: Aclaris Therapeutics, Inc. 
Study phase: Phase 2a 
Study sites: It is planned to recruit approximately 15 sites in the United States (US). 
Objectives:  
Primary: 
The primary objective of this study is to assess the preliminary clinical efficacy of ATI-1777 topical 
solution in adult patients with moderate or severe atopic dermatitis (AD). 
Secondary: 
The secondary objective of this study is to assess the safety, tolerability, and pharmacokinetics (PK) of 
ATI-1777 topical solution twice daily for 4 weeks in adult patients with moderate or severe AD. 
Study design:  
This is a first-in-human, randomized, double-blind, parallel-group, vehicle-controlled study to evaluate 
the efficacy, safety, tolerability, and PK of ATI-1777 solution following twice-daily applications to 
target areas of patients with moderate or severe AD. All AD lesions in protocol allowed areas should be 
treated. All AD lesions in protocol allowed areas should be treated. 
Patients will undergo screening evaluations to determine eligibility up to 30 days prior to randomization. 
Patients who meet all the entry criteria will be randomized on Day 1 to active or vehicle treatment. 
Patients will apply study drug (ATI-1777 topical solution 2.0% w/w or vehicle) twice daily for 4 weeks 
with weekly study visits and will return 2 weeks after the last dose of study medication for a 
Post-treatment Follow-up (PTFU) Visit. Adverse event (AE) collection, physical examinations, clinical 
disease assessments (Eczema Area and Severity Index [EASI], Investigator’s Global Assessment [IGA], 
AD body surface area [BSA], Peak Pruritus Numerical Rating Scale [PP-NRS]), vital sign assessments, 
PK evaluations, and clinical laboratory evaluations will be performed as detailed in the Schedule of 
Events. 
Study duration: Patients will undergo up to 30 days of screening, followed by 4 weeks of treatment and 
2 weeks of PTFU. 
The start of the study will be the date on which the first patient provides informed consent, and the end 
of the study will be the date of the last patient’s last assessment. 
Planned number of patients: It is planned to enroll approximately 50 patients. Patients will be 
randomized (1:1 to ATI-1777 Topical Solution 2.0% w/w or vehicle) to achieve approximately 34 
evaluable patients having a non-missing Week 4 EASI assessment. 
Target population: Patients aged between 18 and 65 years (inclusive) with moderate or severe AD 
Inclusion Criteria: 
Patients must meet the following criteria to be eligible for participation in the study:  
1. Able to comprehend and willing to sign the IRB-approved informed consent form (ICF) prior to 
administration of study-related procedures.  
2. Male patients or non-pregnant, non-nursing female patients 18 to 65 years old, inclusive, at the 
time of informed consent. 


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
Protocol Version and Date: Version 4, 28-Jan-2021 
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3. Pregnancy and Contraception: 
• 
Women of childbearing potential (WOCBP), must have a negative serum pregnancy test at 
the Screening Visit, a negative urine pregnancy test immediately prior to the first 
application of study medication on Day 1, and a negative urine pregnancy test at each study 
visit thereafter. 
• 
Sexually active heterosexual women must agree to use the following throughout the 
screening period and for 30 days after last study drug application. WOCBP who are not 
sexually active at Baseline and become sexually active during the study must agree to 
follow the birth control measures listed below. 
o 
Agree to use 2 forms of highly effective contraception, including 1 physical barrier 
(condom or diaphragm) plus another highly effective method, such as adequate 
hormonal method (e.g., contraceptive implants, injectables, oral contraceptives) or 
nonhormonal methods (e.g., intrauterine device) or male partner who is surgically 
sterile (vasectomy). 
• 
Male patients with partners of childbearing potential may be enrolled if they are: 
o 
Documented to be surgically sterile (vasectomy), or 
o 
Using 2 adequate forms of highly effective contraception, 1 of which should be a 
physical barrier until 90 days after the last administration of study medication. 
4. Have a diagnosis of AD fulfilling the specified diagnostic criteria of Hanifin and Rajka (Hanifin 
and Rajka 1980). 
5. Have at least a 6-month history of AD prior to the Screening Visit, and no significant AD flares 
for the 4 weeks prior to the Screening Visit.  
6. Have at least 1 lesion that measures at least 3 cm2 at the Screening Visit and on Day 1 prior to 
the first dose of study medication. This lesion must be representative of the patient’s disease 
state, but not located on the hands, feet, or genitalia. 
7. Have a stable diagnosis of moderate or severe (IGA score 3 or 4) AD at the Screening Visit.  
8. Have AD affecting 3% to 20% BSA (not including head [neck, scalp, face], palms of hands, 
soles of feet, groin, and genitalia) at the Screening Visit. 
9. Willing to refrain from washing area of treatment or swimming for 6 hours after each study 
medication application.  
10. Willing to refrain from excessive sun exposure (e.g., sunbathing and/or tanning salon visits) and 
to minimize sun exposure (e.g., wear sun protective clothing, hat) as much as possible. 
11. Willing to refrain from use of moisturizers, emollients, and sunscreen on AD study treatment 
areas for duration of protocol therapy. 
12. Willing to refrain from participating in strenuous exercise that would cause profuse sweating 
for a period of 6 hours after each study medication application. 
13. Willing to return to the clinic, follow all study instructions, attend all study visits, and complete 
study procedures.  
14. In good general health and free of any known disease state or physical condition that, in the 
investigator’s opinion, might impair evaluation of the patient or that might expose the patient to 
an unacceptable risk by study participation. 
15. Willing and capable of taking appropriate coronavirus disease 2019 (COVID-19) risk 
mitigation precautions (e.g., wearing a mask in public, adhering to social distancing, etc.) as 
recommended or required by local, state, or federal guidelines during participation in the study. 
Exclusion Criteria: 
Patients with any of the following are excluded from the study: 


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
Protocol Version and Date: Version 4, 28-Jan-2021 
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1. Unstable course of AD (spontaneously improving or rapidly deteriorating) based on the patient 
history or as determined by the investigator during the Screening Period. 
2. Refractory AD (i.e., AD that required frequent hospitalizations and/or frequent intravenous 
treatment for skin infections within the year before the Screening Visit). 
3. AD of a severity (EASI >48) that the patient is not a candidate for a vehicle-controlled study. 
4. Any signs or symptoms associated with AD therapy (e.g., history of anaphylaxis, 
hypersensitivity reactions, skin atrophy, striae, pigmentary changes) that, in the investigator’s 
opinion, might impair evaluation of the AD or which exposes the patient to unacceptable risk 
by study participation.  
5. Concomitant skin disease or clinically infected AD or presence of other skin disease in the area 
to be dosed that may interfere with study assessments.  
6. Use of any of the following treatments within the indicated washout period prior to Day 1:  
• 
Phototherapy (ultraviolet A, ultraviolet B, or psoralen and ultraviolet A therapy) within 4 
weeks prior to Day 1. 
• 
Systemic biologic immunosuppressant or immunomodulatory therapy (e.g., etanercept, 
alefacept, infliximab, dupilumab) within 12 weeks (or 5 half-lives of the product, 
whichever is longer) prior to Day 1. 
• 
Non-biologic immunosuppressants (e.g., methotrexate, retinoids, calcineurin inhibitors, 
cyclosporine, hydroxycarbamide [hydroxyurea], azathioprine) within 4 weeks prior to 
Day 1. 
• 
Janus kinase (JAK) inhibitors (systemic and topical) within 4 weeks prior to Day 1. 
• 
Systemic corticosteroids within 2 weeks prior to Day 1 (intranasal, inhaled, and topical 
ocular corticosteroids are allowed). 
• 
Cytostatic agents within 4 weeks prior to Day 1.  
• 
Crisaborole within 2 weeks prior to Day 1.  
• 
Systemic antibiotics within 30 days prior to Day 1. 
• 
Topical treatments for AD (corticosteroids, calcineurin inhibitors, topical H1 and H2 
antihistamines, topical antimicrobials, and other medicated topical agents) within 2 weeks 
prior to Day 1.  
• 
Live attenuated vaccine treatment within 12 weeks prior to Day 1. 
• 
Other investigational product within 30 days or 5 half-lives (whichever is longer) prior to 
Day 1. 
7. Previous failure to respond to prior therapy with JAK inhibitors (systemic or topical), as 
determined by the investigator. 
8. Current use of an oral H1 antihistamine (e.g., diphenhydramine, terfenadine) UNLESS the 
patient is on a stable dose for at least 14 days prior to the Screening Visit. 
9. Medical marijuana unless the patient is on a stable dose for at least 14 days prior to the 
Screening Visit. 
10. Clinically significant laboratory abnormalities at the Screening Visit that, in the opinion of the 
investigator, could affect interpretation of study data or the safety of the patient’s participation 
in the study.  
11. Clinical laboratory values: 
• 
White blood cell count <2×109/L 
• 
Absolute neutrophil count (ANC) <1800/µL  
• 
Platelet count <130,000/µL 
• 
Hemoglobin <8g/dL 
• 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2× the upper limit 
of normal 


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
Protocol Version and Date: Version 4, 28-Jan-2021 
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• 
Lymphocyte count <0.5×109/L 
12. Investigator-assessed history of, or current physical findings of, severe, progressive, or 
uncontrolled immunologic, hepatic, gastrointestinal, pulmonary, cardiovascular, genitourinary 
(renal), hematological, neurologic or cerebral disorders, infectious disease or coagulation 
disorders that, as determined by the investigator, could affect the safety of the patient’s 
participation in the study or would preclude participation in and completion of study 
assessments.  
13. History of, current, or suspected systemic or cutaneous malignancy and/or lymphoproliferative 
disease within the last 5 years, other than patients with a history of adequately treated and well 
healed and completely cleared nonmelanoma skin cancers (i.e., basal or squamous cell 
carcinoma) or cervical carcinoma in situ treated successfully at least 1 year prior to the 
Screening Visit 1 with no evidence of disease.  
14. Evidence of active, chronic, or latent infections at the time of enrollment or a systemic infection 
including but not limited to a history of treated infection (e.g., pneumonia, septicemia) within 3 
months prior to Day 1. 
15. Patient has a known active or history of incompletely treated or untreated active tuberculosis. 
Patients with a history of active tuberculosis must have documented adequate treatment verified 
by the investigator. Patients who demonstrate evidence of latent tuberculosis infection (positive 
QuantiFERON® Tuberculosis Gold Test) will only be allowed to participate in the study if there 
is documented evidence of a completed adequate treatment course for latent tuberculosis and if 
active tuberculosis is excluded per the investigator’s judgment. 
16. History of a serious local skin infection (e.g., cellulitis, abscess) within 5 years of the Screening 
Visit. 
17. Positive serological test for human immunodeficiency virus (HIV) (antibody), hepatitis C virus 
(antibody), hepatitis B surface antigen, or hepatitis B core antigen antibody. 
18. Known significant exposure (close contact [<6 feet] for ≥15 minutes) to an individual with a 
confirmed diagnosis of coronavirus disease 2019 (COVID-19) at any time during the Screening 
Period. 
19. Herpes zoster or cytomegalovirus infection that resolved less than 2 months prior to the 
Screening Visit. Patients with a history of frequent outbreaks of herpes simplex virus (defined 
as 4 or more outbreaks a year). 
20. Clinically significant electrocardiogram (ECG) findings such as, but not limited to, baseline 
mean QTcF >450 msec for males or >470 msec for females (use of the ECG algorithm is 
acceptable for this purpose). 
21. Known allergy to any of the inactive ingredients in the study drug. 
22. Female patients who are pregnant, nursing, or planning to become pregnant during the study. 
23. Legal incapacity or limited legal capacity. 
24. Major surgery within 3 months of the Screening Visit. 
25. Any other condition that precludes adequate understanding, cooperation, and compliance with 
study procedures or any condition that could pose a risk to the patient’s safety, as per the 
investigator’s judgment. 
26. Use of potent inhibitors of cytochrome P450 3A4 such as (but not limited to) clarithromycin, 
erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal, and 
grapefruit. 
Test product: 
ATI-1777 topical solution 2.0% w/w applied to areas with AD. 


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
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Control Product: 
Topical vehicle solution containing no ATI-1777. 
Endpoints: 
Primary 
Percent change from baseline in EASI score at Week 4 
Secondary 
• 
Percent change from baseline in EASI score at each study visit 
• 
Proportion of patients achieving an IGA score of 0 to 1 combined with an improvement of 2 or 
more points from baseline within 4 weeks of the start of treatment 
• 
Proportions of patients who achieve 50%, 75%, and 90% improvement in EASI score 
(EASI-50, EASI-75, and EASI-90, respectively) within 4 weeks of the start of treatment 
• 
Change from baseline in IGA score at each study visit 
• 
Change from baseline in BSA at each study visit 
• 
Change from baseline in PP-NRS score over time 
Safety 
• 
Incidence of treatment-emergent AEs (TEAEs) and SAEs 
• 
Laboratory values 
• 
Vital signs 
• 
Physical examination results 
• 
12-lead ECG 
Pharmacokinetics 
A sparse sampling approach will be employed because it is not anticipated that clinically relevant plasma 
concentrations will be observed. A total of 8 PK samples will be collected from each patient.  
One sample will be collected before study medication application, and 1 sample will be collected 
approximately 2 hours after application on each of Days 1, 8, and 15. 
Samples for Day 28 will be collected from 3 subgroups of patients within each of the specified time 
windows as follows: 
• 
Subgroup 1: One sample predose and one sample at 0.5 to 2.5 hours post application 
• 
Subgroup 2: One sample at 2.5 to 5 hours post application and one sample at least 2 hours later 
• 
Subgroup 3: One sample at 5 to 8 hours post application and one sample at least 2 hours later 
(prior to the subsequent application) 
Statistical methods: Details of all statistical summaries will be provided in the study-specific statistical 
analysis plan (SAP). 
Determination of sample size: 
Data from 34 patients provides 95.6% power to detect a statistically significant difference between the 
treatment groups in the primary endpoint (percent change from baseline in EASI scores). This power 
calculation is based upon a 1-sided treatment contrast within a 1-way ANOVA model and assumes group 
means of 65% and 20% for ATI-1777 and vehicle, respectively. The group means were based upon 
slightly more conservative estimates than were observed in a Phase 2 study of topical ruxolitinib in AD. 
The variance for the percent change from baseline in EASI was assumed to be 38.3%. This variance 
assumption was based upon data observed in a pilot AD study for the topical compound ATI-502 (ATI-
502-AD-201). 
Analysis populations: 
• 
Full Analysis Set (FAS): All patients who have been randomized and administered at least one 
dose of study medication. The efficacy analyses will be conducted on the FAS population as 
randomized; the safety analyses and summaries will be conducted on the FAS as treated.  


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
Protocol Version and Date: Version 4, 28-Jan-2021 
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• 
Per-Protocol (PP) Population: All patients who have non-missing Week 4 EASI scores 
recorded. The PP population will be analyzed as treated. 
• 
PK Population: All patients who receive at least 1 dose of study medication and provide at least 
1 plasma concentration value. 
Analysis methods: 
All data will be presented by treatment group. Descriptive statistics (number of observations, mean, 
standard deviation, median, minimum, and maximum) will be provided for continuous variables, and 
counts and percentages will be presented for categorical variables. Baseline is defined as the last 
non-missing measurement before or on the date of first administration of study medication. 
Efficacy Analyses: 
All efficacy summaries will be conducted on both the FAS and PP populations. All p-values for efficacy 
will be based on a 1-sided hypothesis test of the superiority of ATI-1777 to vehicle. 
The primary efficacy analysis will be the treatment comparison between ATI-1777 and vehicle for the 
percent change from baseline in EASI scores at Week 4. This treatment comparison will be made within 
the context of a Mixed Model Repeated Measures analysis where the EASI scores over time are treated 
as repeated measures within a given patient. Treatment group, time (study visit), and treatment by time 
interaction will enter the model as categorical factors, baseline EASI score and/or baseline severity of 
AD will be included as a continuous covariate, and patient ID will enter the model as a random effect. 
Treatment group model-based means and model-based differences in treatment groups will be provided 
along with corresponding 90% confidence intervals and 1-sided p-values.  
Treatment comparisons between ATI-1777 and vehicle for each of the continuous efficacy endpoints that 
are conducted over time (Change in IGA, BSA, and PP-NRS) will be analyzed using a similar model as 
described for the primary endpoint. Treatment comparisons will be made for each post-baseline 
scheduled visit utilizing an appropriate analysis window scheme.  
Treatment group comparisons for categorical efficacy endpoints (IGA Response, EASI-50, -75, and -90) 
that are conducted over time will employ a logistic regression model fit at each scheduled visit 
separately, where appropriate. The logistic regression model will include treatment group as a factor and 
the baseline value and/or baseline severity of AD as a covariate. Model-based point estimates for the 
treatment proportions will be provided as well as model-based differences and corresponding 90% 
confidence intervals and 1-sided p-values. 
Safety Analyses: 
The FAS will be used for the analysis of safety data (AEs, clinical laboratory values, vital signs, physical 
examination results, and ECGs). AEs will be coded with the Medical Dictionary for Regulatory 
Activities (MedDRA). TEAEs are defined as AEs with onset dates on or after the date of first 
administration of study medication and before the end of the study, or that exist prior to the first dose 
and worsen with dosing. TEAEs will be presented by system organ class and preferred term in frequency 
tables. Patients with multiple AEs will be counted only once within each preferred term and system 
organ class. Key patient information for patients with an AE with an outcome of death, patients with 
SAEs, and patients with an AE leading to discontinuation of study medication will be listed.  
Laboratory data (hematology, serum chemistry, coagulation, and urinalysis) will be converted to 
Système International units for reporting and processing purposes. Absolute values and changes from 
baseline will be presented descriptively. Laboratory data outside study-specific reference ranges will be 
listed. Vital signs and ECG parameters will be presented descriptively.  
Plasma Drug Concentrations  
Plasma concentrations of ATI-1777 will be summarized by nominal time point and day. 
Protocol version and date: Version 4, 28-Jan-2021 
 


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STUDY SCHEMATIC 
Figure 1 
Study Schematic 
 
 
Randomization 
N = ~50 
ATI-1777 
N = ~25 
4 weeks 
Vehicle 
N = ~25 
4 weeks 
Screening 
Up to 30 days 
Follow-up 
2 weeks after last dose of study medication 


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SCHEDULE OF EVENTS 
Table 1 
Schedule of Events 
Study Period 
Screening 
Treatment Period 
PTFU 
Study Day 
 
-30 to -1 
 
Day 1 
Day 8 
±3 days 
Day 15 
±3 days 
Day 28/ET 
±2 days 
Day 42 
±3 days 
Informed Consent1 
X 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical history, including AD 
history 
X 
X 
 
 
 
 
Full physical examination2 
X 
 
 
 
 
 
Brief physical examination2 
 
X 
 
 
X 
 
SARS-Cov-2 nasopharyngeal test 
 
X 
 
 
 
 
ECG3 
X 
 
 
X 
X 
 
Vital signs4 
X 
X 
X 
X 
X 
X 
Serum pregnancy test5 
X 
 
 
 
 
 
Urine pregnancy test 
 
X 
X 
X 
X 
 
Clinical chemistry, hematology, 
urinalysis6 
X 
X 
X 
X 
X 
 
Virology (Hepatitis B and C, 
HIV) 
X 
 
 
 
 
 
QuantiFERON® Tuberculosis 
Gold Test 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
PK sample7 
 
X 
X 
X 
X 
 
Fitzpatrick skin type assessment 
X 
 
 
 
 
 
EASI8 
X 
X 
X 
X 
X 
 
IGA8 
X 
X 
X 
X 
X 
 
BSA8 
X 
X 
X 
X 
X 
 
PP-NRS8 
 
X 
X 
X 
X 
 
Photography 
X 
X 
X 
X 
X 
 
Dispense study drug and patient 
diary 
 
X 
X 
X 
 
 
Study drug instruction, first 
administration, and observation 
 
X 
 
 
 
 
Study drug administration 
(by patient)9 
 
X 
X 
X 
X 
 
Collection of study drug, patient 
diary review, including 
medication compliance  
 
 
X 
X 
X 
 
AE assessment10 
X 
X 
X 
X 
X 
X 
Prior and concomitant medication 
review 
X 
X 
X 
X 
X 
X 


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AD = atopic dermatitis; AE = adverse event; BSA = body surface area; EASI = Eczema Area and Severity 
Index; ECG = electrocardiogram; ET = Early Termination; HIV = human immunodeficiency virus; 
ICF = informed consent form; IGA = Investigator’s Global Assessment; PK = pharmacokinetic; 
PP-NRS = Peak Pruritus Numerical Rating Scale; PTFU = Post-treatment Follow-up; SAE = serious 
adverse event; SARS-Cov-2 = severe acute respiratory syndrome coronavirus 2; WOCBP = women of 
child bearing potential 
1. A written, signed ICF must be obtained from each patient prior to performing any study-related 
procedure. 
2. A full examination will be performed at the Screening Visit. A full examination will include general 
appearance, skin, head, eyes, ears, nose, throat, neck, thyroid, chest/lungs, heart, abdomen, lymph 
nodes, and extremities. A brief examination will be performed at the Day 1 and Day28/ET Visits and 
any unscheduled visits and will include symptom-focused assessments. 
3. Triplicate 12-lead ECGs will be obtained as outlined in Section 6.3.4. 
4. Vital signs will be measured in a semi-supine position after 5 minutes of rest and will include 
temperature, systolic and diastolic blood pressure, pulse, and respiratory rate. Height will be measured 
and recorded at the Screening Visit, and weight will be measured and recorded at each study visit. 
5. Serum pregnancy test at the Screening Visit, urine pregnancy test at all other specified time points; for 
WOCBP only. 
6. On dosing day(s), sampling for the analysis of clinical laboratory parameters will be performed before 
the administration of study medication. 
7. PK samples will be drawn as outlined in Section 6.4. 
8. IGA and BSA assessed at the Screening Visit to ensure inclusion criteria are met. EASI, IGA, BSA, 
and PP-NRS assessed prior to study medication application on Day 1 to establish baseline and at study 
visits and end of the study (or ET) to document severity and extent of AD following study medication. 
The patient will complete the PP-NRS in their diary each morning before applying study medication 
during the Treatment Period. 
9. Study medication will be applied at the site on study visit days, except Day 28 for PK subgroups 2 and 
3. On Day 28, study medication will be applied at home to accommodate the timing of PK sample 
collection for PK subgroups 2 and 3. 
10. Nonserious AEs will be collected after the patient’s first application of study drug and continue until 
the patient’s last visit. SAEs will be collected from the time the patient signs the ICF until the patient’s 
last visit. 
 
 


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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ...................................................................... 1 
PROTOCOL SIGNATURE PAGE – SPONSOR ............................................. 2 
PROTOCOL SIGNATURE PAGE – INVESTIGATOR ................................. 3 
SERIOUS ADVERSE EVENT CONTACT INFORMATION ........................ 5 
SUMMARY OF CHANGES ............................................................................... 6 
PROTOCOL SUMMARY ................................................................................. 10 
STUDY SCHEMATIC ....................................................................................... 16 
SCHEDULE OF EVENTS ................................................................................ 17 
TABLE OF CONTENTS ................................................................................... 19 
LIST OF TABLES .............................................................................................. 22 
LIST OF FIGURES ............................................................................................ 22 
LIST OF ABBREVIATIONS ............................................................................ 23 
1 
INTRODUCTION AND RATIONALE .................................................... 25 
1.1 
Background ............................................................................................. 25 
1.1.1 
Atopic Dermatitis ............................................................................. 25 
1.1.2 
Current Treatments ......................................................................... 25 
1.1.3 
Janus Kinase Inhibitors for Treatment of Atopic Dermatitis ...... 26 
1.1.4 
ATI-1777 ............................................................................................ 27 
1.1.5 
Nonclinical Studies ........................................................................... 27 
1.2 
Study Rationale ....................................................................................... 28 
1.3 
Benefit/Risk Assessment ........................................................................ 28 
1.3.1 
Potential Benefits .............................................................................. 29 
1.3.2 
Potential Risks .................................................................................. 29 
1.3.2.1 
Infections ..................................................................................... 29 
1.3.2.2 
Viral Reactivation ....................................................................... 29 
1.3.2.3 
Malignancies ............................................................................... 29 
1.3.2.4 
Thrombosis .................................................................................. 30 
1.3.2.5 
Cytopenias ................................................................................... 30 
1.3.2.6 
Liver Enzyme Elevations ........................................................... 30 
1.3.2.7 
Lipid Parameters ........................................................................ 30 
1.3.3 
Benefits and Risks Conclusion ........................................................ 30 
2 
STUDY OBJECTIVES ............................................................................... 31 
2.1 
Primary Objective .................................................................................. 31 
2.2 
Secondary Objectives ............................................................................. 31 
3 
STUDY ENDPOINTS ................................................................................. 32 
3.1 
Primary Endpoint ................................................................................... 32 
3.2 
Secondary Endpoints ............................................................................. 32 
3.3 
Pharmacokinetic Endpoints .................................................................. 32 
3.4 
Safety Endpoints ..................................................................................... 32 
4 
STUDY PLAN ............................................................................................. 33 
4.1 
Overall Study Design and Plan ............................................................. 33 
4.1.1 
Screening Period ............................................................................... 33 
4.1.2 
Treatment Period ............................................................................. 33 


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4.1.3 
Follow-up Period .............................................................................. 34 
4.1.4 
Sentinel Dosing ................................................................................. 34 
4.2 
Unscheduled Visits ................................................................................. 35 
4.3 
Discussion of Study Design .................................................................... 35 
4.4 
Stopping Rules ........................................................................................ 35 
4.4.1 
Individual Patient Stopping Rules .................................................. 35 
4.4.2 
Study Stopping Rules ....................................................................... 36 
4.5 
End of Study ............................................................................................ 36 
5 
STUDY POPULATION .............................................................................. 37 
5.1 
Inclusion Criteria ................................................................................... 37 
5.2 
Exclusion Criteria ................................................................................... 38 
5.3 
Screen Failures ....................................................................................... 40 
5.3.1 
Retesting During Screening ............................................................. 41 
5.3.2 
Rescreening ....................................................................................... 41 
5.4 
Premature Discontinuation ................................................................... 41 
5.4.1 
Premature Discontinuation of Study Medication .......................... 41 
5.4.2 
Premature Discontinuation from the Study ................................... 43 
5.4.3 
Lost to Follow-up .............................................................................. 43 
6 
DESCRIPTION OF STUDY ASSESSMENTS ........................................ 45 
6.1 
Demographics and Other Screening Assessments ............................... 45 
6.1.1 
Medical History ................................................................................ 45 
6.1.2 
Demographics ................................................................................... 45 
6.1.3 
Tuberculosis Test .............................................................................. 45 
6.1.4 
SARS-CoV-2 Testing and Monitoring ............................................ 45 
6.1.5 
Fitzpatrick Skin Type Assessment .................................................. 46 
6.1.6 
Lesion Photography ......................................................................... 46 
6.2 
Efficacy Assessments .............................................................................. 47 
6.2.1 
Eczema Area and Severity Index .................................................... 47 
6.2.1.1 
Extent ........................................................................................... 47 
6.2.1.2 
Severity ........................................................................................ 47 
6.2.1.3 
Score Calculation ........................................................................ 47 
6.2.2 
Investigator’s Global Assessment ................................................... 48 
6.2.3 
Body Surface Area ............................................................................ 49 
6.2.4 
Peak Pruritus Numerical Rating Scale ........................................... 49 
6.3 
Safety Assessments ................................................................................. 49 
6.3.1 
Adverse Events ................................................................................. 49 
6.3.2 
Clinical Laboratory Evaluations ..................................................... 49 
6.3.2.1 
Potential Drug-induced Liver Injury ....................................... 51 
6.3.3 
Pregnancy .......................................................................................... 51 
6.3.4 
12-lead Electrocardiogram .............................................................. 52 
6.3.5 
Vital Signs ......................................................................................... 53 
6.3.6 
Physical Examination ....................................................................... 53 
6.4 
Pharmacokinetics ................................................................................... 53 
7 
TREATMENTS ........................................................................................... 55 
7.1 
Investigational Product(s) ...................................................................... 55 


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7.1.1 
Description of Study Medications ................................................... 55 
7.1.2 
Preparation, Handling, and Storage ............................................... 55 
7.1.3 
Packaging, Labeling, and Shipment ............................................... 55 
7.2 
Blinding ................................................................................................... 56 
7.3 
Method of Assigning Treatment ........................................................... 56 
7.4 
Dose and Administration ....................................................................... 57 
7.4.1 
Identification of Target Treatment Areas ...................................... 57 
7.4.2 
Dose Modification ............................................................................. 58 
7.4.3 
Intervention After the End of the Study ........................................ 58 
7.5 
Precautions and/or Lifestyle Considerations ....................................... 59 
7.6 
Prior and Concomitant Medications .................................................... 59 
7.6.1 
Prior Medications ............................................................................. 59 
7.6.2 
Concomitant Medication ................................................................. 59 
7.7 
Overdose .................................................................................................. 60 
7.8 
Compliance .............................................................................................. 60 
7.9 
Accountability ......................................................................................... 61 
8 
ADVERSE EVENTS ................................................................................... 62 
8.1 
Definitions ............................................................................................... 62 
8.1.1 
Adverse Events ................................................................................. 62 
8.1.2 
Serious Adverse Events .................................................................... 62 
8.1.3 
Suspected Unexpected Serious Adverse Reactions........................ 63 
8.1.4 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments ....................................................................................... 63 
8.1.5 
Adverse Events of Special Interest .................................................. 63 
8.2 
Assessment of Adverse Events ............................................................... 64 
8.2.1 
Severity .............................................................................................. 64 
8.2.2 
Causality ............................................................................................ 64 
8.3 
Documenting and Reporting Adverse Events ...................................... 65 
8.4 
Reporting of Serious Adverse Events ................................................... 66 
8.5 
Adverse Event and Serious Adverse Event Follow-up ........................ 66 
8.6 
Safety Reporting Oversight ................................................................... 66 
9 
STATISTICS ............................................................................................... 68 
9.1 
General Procedures ................................................................................ 68 
9.2 
Analysis Populations .............................................................................. 68 
9.3 
Sample Size ............................................................................................. 68 
9.4 
Statistical Methods ................................................................................. 69 
9.4.1 
Primary Endpoint ............................................................................. 69 
9.4.2 
Secondary Endpoints ....................................................................... 69 
9.4.3 
Pharmacokinetic Endpoint .............................................................. 69 
9.4.4 
Safety Endpoints ............................................................................... 69 
9.4.5 
Analysis of Efficacy .......................................................................... 69 
9.4.6 
Analysis of Safety .............................................................................. 70 
9.4.7 
Demographic and Baseline Characteristics ................................... 71 
9.4.8 
Pharmacokinetic Endpoints ............................................................ 71 
9.4.9 
Handling of Missing Values ............................................................. 71 


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10 ETHICS AND RESPONSIBILITIES ....................................................... 72 
10.1 
Good Clinical Practice ........................................................................... 72 
10.2 
Institutional Review Board/Independent Ethics Committee.............. 72 
10.3 
Informed Consent ................................................................................... 72 
10.4 
Financing and Insurance ....................................................................... 74 
10.4.1 
Contractual and Financial Details .................................................. 74 
10.4.2 
Insurance, Indemnity, and Compensation ..................................... 74 
10.4.3 
Financial Disclosure ......................................................................... 74 
11 RECORDS MANAGEMENT .................................................................... 75 
11.1 
Source Documentation ........................................................................... 76 
11.2 
Case Report Form Completion and Data Management ..................... 76 
11.3 
Study Files and Record Retention ........................................................ 77 
12 AUDITING AND MONITORING ............................................................ 78 
12.1 
Risk and Quality Tolerance Limits ....................................................... 78 
12.2 
Protocol Adherence and Deviations ...................................................... 78 
13 AMENDMENTS ......................................................................................... 80 
14 STUDY REPORT AND PUBLICATIONS .............................................. 81 
15 STUDY START AND TERMINATION ................................................... 82 
16 CONFIDENTIALITY ................................................................................. 83 
17 REFERENCES ............................................................................................ 84 
18 APPENDICES ............................................................................................. 87 
LIST OF TABLES 
Table 1 
Schedule of Events .................................................................................. 17 
Table 2 
Extent of Atopic Dermatitis in Each Body Region .............................. 47 
Table 3 
EASI Score Calculation ......................................................................... 48 
Table 4 
IGA Scoring ............................................................................................ 48 
Table 5 
Study Medication Interruption Criteria .............................................. 58 
LIST OF FIGURES 
Figure 1 
Study Schematic ..................................................................................... 16 


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LIST OF ABBREVIATIONS 
AD 
atopic dermatitis 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BSA 
body surface area 
CFR 
Code of Federal Regulations 
Cmax 
maximum plasma concentration 
COVID-19 
coronavirus disease 2019 
CPK 
creatine phosphokinase 
CSR 
clinical study report 
eCRF 
electronic case report form 
EASI 
Eczema Area and Severity Index 
ECG 
electrocardiogram 
ET 
Early Termination 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyltransferase 
HDL-C 
high-density lipoprotein cholesterol 
IB 
Investigator’s Brochure 
IC50 
50% inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IGA 
Investigator’s Global Assessment 
LDH 
lactate dehydrogenase 
LDL-C 
low-density lipoprotein cholesterol 
IL 
interleukin 


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INR 
international normalized ratio 
IRB 
institutional review board 
IXRS 
interactive voice/web response system 
JAK 
Janus kinase 
HIV 
human immunodeficiency virus 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
no-observed-adverse-effect level 
PK 
pharmacokinetic(s) 
PTFU 
Post-treatment Follow-up 
PP 
per-protocol 
PP-NRS 
Peak Pruritus Numerical Rating Scale 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
STAT 
signal transducer and activator of transcription 
TC 
total cholesterol 
TG 
triglycerides 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WBC 
white blood cell 
WOCBP 
women of childbearing potential 


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1 INTRODUCTION AND RATIONALE 
1.1 
Background 
1.1.1 
Atopic Dermatitis 
AD is a chronic, relapsing pruritic inflammatory skin disease involving inflammation 
and skin barrier defects in relation to environmental stimuli (Hanifin et al 2001; Rajka 
and Langeland 2020; Tanei et al 2020). It is currently estimated that 10% to 30% of 
children and 0.3% to 14% of adults in developed countries are affected by the disorder 
(Kim et al 2020a; Montillo et al 2019; Napolitano et al 2020). AD has been typically 
categorized into infantile (age <2 years), childhood (age 2 to 12 years), and 
adolescent/adult (>12 years, but not over middle age) types according to patient age and 
characteristics of typical skin lesions; most recently, a newly defined subgroup of 
elderly patients (≥60 years) was added into the classification system (Tanei et al 2020). 
The highest prevalence of AD (i.e., 95% of the cases) is in children aged under 5 years , 
but overall, 60% of the AD cases are reported in children aged under one year (Souta et 
al 2019). No matter what age, the disorder results in significant morbidity and adversely 
affects quality of life. Intense itching characteristic of the disease often leads to skin 
trauma and significant sleep disturbances (Kapur et al 2018). 
1.1.2 
Current Treatments 
Current pharmacological approaches for treatment of AD aim to reduce inflammation, 
eradicate infections induced by bacteria or other parasites, reduce pruritic symptoms, 
and prevent eczema propagation (Souta et al 2019). Behavioral management to reduce 
exposure with antigen sources from pollens, mite dust, traffic or tobacco smoke, volatile 
organic compounds, and animal fur is recommended. Frequent bathing to remove 
surface allergens and use of moisturizers is also an integral part of managing AD and 
can reduce disease severity.  
Food and Drug Administration (FDA)-approved treatments for AD include 
corticosteroids (topical and systemic), calcineurin inhibitors (topical), a 
phosphodiesterase-4 (PDE-4) inhibitor (topical), and dupilumab (systemic), a humanized 
monoclonal antibody that blocks signaling of interleukin (IL)-4/IL-13.  
Corticosteroids are available for treatment of AD by various routes of administration. 
Topical corticosteroids are the most commonly used medications and are first-line in 
pharmacologic treatment of AD for those individuals who have failed to respond to good 
skin care and regular use of emollients alone. Systemic steroids for treatment of AD are 
not recommended by the American Academy of Dermatology. Although corticosteroid 
use may result in rapid disease improvement, skin lesions commonly recur with worse 
severity on discontinuation. In addition, corticosteroids carry the risk of hypothalamic 
pituitary- adrenal axis suppression, with the potential for glucocorticosteroid 
insufficiency.  


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Two non-steroid topical treatment options include calcineurin inhibitors and a PDE-4 
inhibitor. The FDA-approved calcineurin inhibitors include tacrolimus 0.1% ointment, 
tacrolimus 0.03% ointment, and pimecrolimus 1% cream. These treatments are 
considered second-line agents for the management of AD flares. They are intended for 
short-term use and non-continuous chronic treatment of mild to moderate AD in non-
immunocompromised adults and children 2 years of age and older who have failed to 
respond adequately to other topical prescription treatments, or when those treatments are 
not advisable. The PDE-4 inhibitor, crisaborole 2% ointment, is approved for mild to 
moderate AD.  
Dupilumab, a fully humanized monoclonal antibody against the shared alpha subunit of 
IL-4 and IL-13 receptors, is considered first-line systemic treatment for moderate or 
severe AD in adults. Phototherapy may also be an option for patients who are candidates 
for systemic therapy. However, phototherapy may require frequent in-office visits (e.g., 
several times a week). Risks from phototherapy may vary according to the type of 
phototherapy and may include actinic damage, sunburn-like reactions (erythema, 
tenderness, pruritus), skin cancer (nonmelanoma and melanoma), and cataracts.  
Additional to the FDA-approved treatments specific for AD, systemic 
immunosuppressants (e.g., azathioprine, ciclosporin, methotrexate, and mycophenolate 
mofetil), antihistamines, and antimicrobials are used in common practice. 
Although there are FDA-approved products for the treatment of AD, there is a role for 
additional efficacious drug products with acceptable safety profiles. 
1.1.3 
Janus Kinase Inhibitors for Treatment of Atopic Dermatitis 
Lesional skin from patients with AD contains elevated levels of proinflammatory 
cytokines and cellular infiltrates of CD4+ T cells that propagate disease pathophysiology 
(Howell et al 2019; Rodriques and Torres 2020). The cytokine microenvironment in AD 
appears complex, with patients presenting with different cytokine signatures at different 
stages of the disease (Solimani et al 2019). The Janus kinase (JAK) family of signal 
transducers presents itself as an advantageous treatment target since a variety of 
cytokines exert their biological effects through the JAK–signal transducer and activator 
of transcription (STAT) pathway. The JAK family comprises 4 cytoplasmic tyrosine 
kinases: JAK1, JAK2, JAK3, and TYK2; there are 7 STAT proteins: STAT 1, 2, 3, 4, 
5a, 5b, and 6. The JAK-STAT signaling molecules interact downstream of numerous 
cytokines involved in the autoimmune and inflammatory responses. AD is driven 
particularly by cytokines such as IL-4, IL-13, IL-15, and interferon gamma. All of these 
cytokines are largely regulated by JAK1 and JAK3. As such, inhibitors of these 2 JAK 
kinases, in particular, could be valuable in controlling the associated inflammation found 
in AD. JAK inhibitors also have the potential to restore skin barrier function through 
effect on filaggrin expression (Amano et al 2015). 
The efficacy of orally administered JAK inhibitors, such as baricitinib (JAK1/2; 
Guttman-Yassky et al 2019), upadacitinib (JAK1; Guttman-Yassky et al 2020) and 
abrocitinib (JAK1; Gooderham et al 2019), and topical administration of tofacitinib 


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(JAK1/3; Bissonnette et al 2016) in Phase 2 clinical trials in AD provides proof of 
concept for this approach. Although clinical studies have confirmed the potential for 
both oral and topical treatment of AD with JAK inhibitors (Alves de Medeiros et al 
2016; Bissonnette et al 2016; Eyerich and Novak 2013; Levy et al 2015), none are 
currently approved by the FDA. However, further adding to proof of concept, topical 
delgocitinib (Corectim®), a pan-JAK inhibitor, was recently approved in Japan for 
treatment of adult patients with AD (Dhillon 2020). 
1.1.4 
ATI-1777 
ATI-1777 is a potent inhibitor of both JAK1 and JAK3 enzymes and has shown 
pharmacological activity in a porcine model of dermal inflammation following topical 
administration. This new chemical entity competes with adenosine triphosphate at its 
binding site within the kinase domain, therefore, inhibiting phosphorylation of and the 
activation of JAKs, recruitment of STATs, and downstream effects on gene expression. 
Topical delivery of JAK inhibitors, limiting systemic circulation, may be the best option 
for treatment of AD since oral administration of JAK inhibitors (e.g., tofacitinib and 
ruxolitinib) can result in significant side effect liabilities. ATI-1777 was designed to act 
locally in the skin and to be metabolically labile, thereby resulting in short-lived 
circulating drug levels – an approach aimed to provide efficacy and minimize the risks 
of systemic toxicity. Approval of topical JAK inhibitors with selective profiles will add 
to the nonsteroidal options for treatment of AD. Aclaris Therapeutics, Inc. is developing 
ATI-1777 topical solution as a treatment for AD. ATI-1777 is a potent, selective, 
reversible adenosine triphosphate–competitive inhibitor of JAK 1/3. 
1.1.5 
Nonclinical Studies 
The nonclinical development program for ATI-1777 included dermal penetration, 
pharmacokinetic (PK), and toxicity studies following topical application, i.e., the 
intended route of administration. The intravenous PK of ATI-1777 was characterized by 
a mono-exponential pattern of elimination with a mean elimination half-life of <1 hour. 
Consistent with its rapid clearance and short half-lives in vivo, metabolism of ATI-1777 
in vitro was rapid in liver microsomes from various nonclinical species and human (half-
life for loss of parent compound was ≤30 minutes) and was rapid to moderate in 
hepatocytes from these same species (half-life for loss of parent compound ranged from 
13.5 to 54.6 minutes). Oral bioavailability of ATI-1777 was low. Oral dose escalation 
studies confirmed increased systemic exposure with increasing dose, and generally 
higher exposure in female than male rats. Importantly, systemic exposure to ATI-1777 
was negligible following topical application to the dermis of minipigs such that plasma 
levels in humans are expected to be similarly negligible and also significantly lower than 
the concentration needed to inhibit JAK 1/3 in human whole blood (~45 ng/mL). Details 
on the systemic (intravenous and oral) PK and absorption, distribution, and metabolism 
profile of ATI-1777 can be found in the Investigator’s Brochure (IB). 
Seven-day and 28-day repeat-dose oral toxicity studies in rats demonstrated that 
ATI-1777 was well tolerated at levels up to 600 mg/kg/day and 300 mg/kg/day, 


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respectively. The oral no-observed-adverse-effect levels (NOAELs) were considered to 
be equal to or greater than the maximum doses administered in each study. 
Following once daily topical administration of ATI-1777 for 28 or 29 days at doses up 
to 160 mg/day in male and female minipigs, no ATI-1777-related effects were noted. 
Thus, the NOAEL was considered to be 160 mg/day. This dose level corresponded to 
mean maximum plasma concentration (Cmax) and area under the plasma 
concentration-time curve (AUC) values of 3.77 ng/mL and 23.5 ng•h/mL, respectively, 
in males and 1.99 ng/mL and 10.7 ng•h/mL, respectively, in females on Day 28 of the 
dosing phase and dermal ATI-1777 concentrations of 9150 to 75200 ng/g in abraded 
skin biopsies and 13,100 to 99,800 ng/g in non-abraded skin biopsies at the completion 
of dosing. 
ATI-1777 did not demonstrate phototoxicity or ocular toxicity, nor was it a contact 
allergen. 
ATI-1777 was not genotoxic based on the in vitro bacterial reverse mutagenicity (Ames) 
and in vivo micronuclei formation assays. Carcinogenesis and reproductive toxicology 
studies have yet to be conducted.  
For further details regarding the nonclinical safety evaluation of ATI-1777, refer to the 
IB. 
1.2 
Study Rationale 
ATI-1777 is aimed to act locally in the skin and to be metabolically labile, with 
short-lived circulating drug levels that should provide efficacy and minimize the risks of 
systemic toxicity. 
This first-in-human study is being conducted as a preliminary assessment of the efficacy 
and the safety and tolerability of ATI-1777 in adult patients with moderate or severe AD 
and to examine the potential for ATI-1777 systemic exposure. The study seeks to 
demonstrate that efficacy can be achieved, using a tolerated topical concentration of 
ATI-1777 without systemic levels that exceed the 50% inhibitory concentration (IC50) 
for inhibition of JAK 1/3 in human whole blood (i.e., ~45 ng/mL). 
The study is being conducted in the target population because of the potential for 
differences in absorption of ATI-1777 through the skin of patients with AD compared 
with that of healthy volunteers. 
The 2% w/w concentration was chosen based on repeat-dose toxicity and toxicokinetic 
studies in minipigs, which showed a topical NOAEL of ≥160 mg/day. 
1.3 
Benefit/Risk Assessment 
This is a first-in human study and there is no previous clinical experience with 
ATI-1777. More detailed information about the anticipated benefits and risks can be 
found in the IB.  


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1.3.1 
Potential Benefits 
It is anticipated that treatment with ATI-1777 will result in a clinically significant 
improvement in AD. Topical administration of tofacitinib (JAK1/3; Bissonnette et al 
2016) and ruxolitinib (JAK 1/2; Kim et al 2020a) in Phase 2 and most recently 
encouraging Phase 3 efficacy and safety data following topical administration of 
ruxolitinib (Incyte Press Release 2020) in clinical trials in patients with AD provides 
proof of concept for this approach. 
1.3.2 
Potential Risks 
Potential risks are derived from information provided in the product labels for JAK 
inhibitors approved in oral dose forms for indications other than AD. Tofacitinib, 
upadacitinib, and baricitinib are approved for the treatment of rheumatoid arthritis; 
tofacitinib is also approved for the treatment of psoriatic arthritis and ulcerative colitis; 
and ruxolitinib is approved for the treatment of myelofibrosis and polycythemia vera. 
ATI-1777 is designed to be metabolically labile with limited systemic exposure to 
minimize these systemic toxicities. There were no ATI-1777-related dermal or systemic 
effects observed following repeated daily dermal applications to minipigs for to 28 days, 
where little or no quantifiable systemic exposure was observed. Effects observed after 
repeated oral administration of ATI-1777 to rats, which achieved substantial and dose-
related systemic exposure to ATI-1777, were considered to represent a spectrum of 
clinical effects known to be associated with oral JAK inhibitors. 
1.3.2.1 
Infections 
Serious infections due to bacterial, mycobacterial, invasive fungal, viral, or other 
opportunistic pathogens have been reported with orally administered JAK1 and JAK3 
inhibitors. Patients with evidence of active, chronic, or latent infections or history of 
serious local skin infections or tuberculosis at the Screening Visit will be excluded from 
this study. Infections will be monitored during the study and will be reported as AEs. 
1.3.2.2 
Viral Reactivation 
Viral reactivation and herpes zoster have been observed in clinical studies with 
tofacitinib and upadacitinib. Patients who screen positive for HIV (antibody), hepatitis B 
or C, patients with herpes zoster or cytomegalovirus infections that resolved less than 
2 months prior to the Screening Visit, and patients with a history of frequent outbreaks 
(defined as 4 or more outbreaks a year) of herpes simplex virus will be excluded from 
this study. Viral infections and activations will be monitored during the study and will 
be reported as AEs. 
1.3.2.3 
Malignancies 
Malignancies were observed in clinical studies with baricitinib, tofacitinib, upadacitinib, 
and ruxolitinib. Patients with a history of, or current or suspected systemic or cutaneous 
malignancy and/or lymphoproliferative disease within the 5 years prior to the study will 


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be excluded from the study. Malignancies will be monitored during the study and will be 
reported as AEs. 
1.3.2.4 
Thrombosis 
Thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial 
thrombosis, some fatal, have occurred in patients treated with baricitinib and 
upadacitinib. Patients with symptoms of thrombosis will be monitored during the study 
and thromboses will be reported as AEs. 
1.3.2.5 
Cytopenias 
Cytopenias (lymphopenia, neutropenia, anemia, and thrombocytopenia) have been 
reported after chronic oral dosing with commercially available JAK1/JAK2 and 
pan-JAK inhibitors such as ruxolitinib, upadacitinib, and tofacitinib. Treatment with 
ATI-1777 should be avoided in patients with cytopenias. Patients with laboratory values 
indicative of cytopenias will be excluded from the study. Cytopenias will be monitored 
during the study and reported as AEs.  
1.3.2.6 
Liver Enzyme Elevations 
Liver enzyme elevations were observed in patients receiving oral JAK1/JAK3 inhibitors. 
Patients with elevated liver enzymes AST or ALT ≥2 × the upper limit of normal 
[ULN]) at the Screening Visit will be excluded from study participation. Routine 
monitoring of liver parameters will be conducted throughout the study.  
1.3.2.7 
Lipid Parameters 
Treatment with JAK1/JAK3 inhibitors has been associated with increases in lipid 
parameters including total cholesterol (TC), low-density lipoprotein cholesterol 
(LDL-C), and high-density lipoprotein cholesterol (HDL-C). Lipid parameters will be 
evaluated throughout the study. 
1.3.3 
Benefits and Risks Conclusion 
Considering the measures taken to minimize risk to patients participating in this study, 
the potential risks identified in association with ATI-1777 are justified by the anticipated 
benefits that may be afforded to patients with AD. 


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2 STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to assess the preliminary clinical efficacy of 
ATI-1777 topical solution in adult patients with moderate or severe AD. 
2.2 
Secondary Objectives 
The secondary objectives of this study are to assess the safety, tolerability, and PK of 
ATI-1777 topical solution twice daily for 4 weeks in adult patients with moderate or 
severe AD. 


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3 STUDY ENDPOINTS 
3.1 
Primary Endpoint 
The primary endpoint is percent change from baseline in EASI score at Week 4. 
3.2 
Secondary Endpoints 
The secondary endpoints are: 
• Percent change from baseline in EASI score at each study visit 
• Proportion of patients achieving an IGA score of 0 to 1 combined with an 
improvement of 2 or more points from baseline within 4 weeks of the start of 
treatment 
• Proportions of patients who achieve 50%, 75%, and 90% improvement in EASI 
score (EASI-50, EASI-75, and EASI-90, respectively) within 4 weeks of the start 
of treatment 
• Change from baseline in IGA score at each study visit 
• Change from baseline in AD BSA at each study visit 
• Change from baseline in PP-NRS score over time 
3.3 
Pharmacokinetic Endpoints 
The PK endpoint is ATI-1777 concentration in plasma samples obtained using a sparse 
sampling approach. 
3.4 
Safety Endpoints 
The safety endpoints are: 
• Incidence of TEAEs and SAEs, including incidence of adverse events of special 
interest (AESIs) (e.g., application site reactions) 
• Laboratory values 
• Vital signs 
• Physical examination results 
• 12-lead ECG results 


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4 STUDY PLAN 
4.1 
Overall Study Design and Plan 
This is a first-in-human, randomized, double-blind, parallel-group, multicenter, 
vehicle-controlled study to evaluate the efficacy, safety, tolerability, and PK of 
ATI-1777 solution following twice-daily applications to target areas of male and female 
patients, aged 18 to 65 years, inclusive, with moderate or severe AD. All AD lesions in 
protocol allowed areas should be treated. The study will be conducted at approximately 
15 sites in the (US). 
The study will consist of a Screening Period of up to 30 days, a 4-week Treatment 
Period, and a 2-week follow-up period. The maximum total duration of the study for 
patients remaining in the study until their final follow-up assessment will be 73 days. 
A study schematic is provided in Figure 1 and a Schedule of Events is provided in 
Table 1. 
4.1.1 
Screening Period 
The investigator will obtain a signed ICF from the patient before any study procedures 
are performed. For further details regarding the informed consent process, see Section 
10.3. Patients will undergo screening evaluations within 30 days of Day 1 to determine 
study eligibility (see Section 5). All the results of the screening evaluations should be 
available at the time that patient eligibility is reconfirmed prior to dosing. 
The investigator will maintain a screening log to record details of all participants 
screened and to confirm eligibility or record reasons for screening failure, as applicable. 
Certain procedures conducted as part of the participant’s routine clinical management 
and obtained before signing of informed consent may be utilized for screening purposes 
provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Events (Table 1). 
At the end of the Screening Period, participants meeting all inclusion and no exclusion 
criteria will enter the Treatment Period. 
4.1.2 
Treatment Period 
A total of approximately 50 patients who meet all the entry criteria will be randomized 
on Day 1 via an interactive voice/web response system (IXRS) to ATI-1777 or vehicle 
treatment in a 1:1 ratio. Patients will be stratified at randomization by severity of AD 
(moderate versus severe). The study is randomized and double-blinded with regard to 
ATI-1777 and vehicle in order to prevent bias in treatment allocation and in the 
assessment of treatment effect. The investigator, site personnel, the sponsor, and their 
representatives involved in monitoring and conducting the study, and the patients will be 
blinded to the study medication administered. See Section 7.3 for further details on the 


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method of assigning patients to the treatment groups, and Section 7.2 for details on 
access to the treatment codes in the event of emergency unblinding. 
During the Treatment Period, patients will apply study drug (ATI-1777 topical solution 
2.0% w/w or vehicle) twice daily for 28 days to target areas affected by AD. Patients 
will be trained by site personnel on how to appropriately apply the study medication. 
See Section 7.4 for further details on the dose and administration of ATI-1777 and 
vehicle.  
On Day 1 of the study, patients will apply drug in the clinic. The application site will be 
assessed for serious or severe local AEs prior to discharge from the clinic. Subjects will 
be informed to contact the site if a severe or serious event occurs. Subjects will be asked 
to pay particular attention to any events in the first 24 hours after drug administration. 
During treatment, patients will attend weekly study visits. At the study visits, AE 
collection, physical examinations, clinical disease assessments (EASI, IGA, BSA, and 
PP-NRS), vital sign assessments, PK evaluations, and clinical laboratory evaluations 
will be performed as detailed in the Schedule of Events (Table 1). Patients will complete 
a daily diary recording their dose administration and PP-NRS itch score during the 
study. 
For all study participants, blood samples will be collected for PK analysis according to 
the sparse sampling approach described in Section 6.4. 
Participants who discontinue study medication earlier than Day 28 will have an Early 
Termination (ET) Visit at the time of study medication discontinuation and will return 
for a PTFU Visit, 2 weeks (±3 days) after the Day 28/ET Visit (see Table 1). 
4.1.3 
Follow-up Period 
Participants will return 2 weeks (± 3 days) after the Day 28/ET Visit for a PTFU Visit 
(see Table 1). 
4.1.4 
Sentinel Dosing 
A sentinel dosing strategy will be employed. A minimum of 4 and a maximum of 8 
patients will be initially enrolled in the study. Study enrollment will then be paused until 
the initial 4 to 8 patients have completed their Day 8 Visit and safety data from these 
patients has been reviewed by the sponsor and the ProPharma safety physician to 
determine whether the study should continue or be stopped. If the safety data from the 
first 4 to 8 patients indicate that it is safe to continue the study, enrollment will be 
resumed. 
The first 4 to 8 patients will continue in the study according to the Schedule of Events in 
Table 1 while the review of their safety data is ongoing and will continue in the study 
after enrollment resumes. 


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4.2 
Unscheduled Visits 
If a patient experiences an AE at any time during the study, they may attend an 
unscheduled visit in consultation with the investigator for evaluation and possible 
treatment of the event. Assessments may be collected at the discretion of the 
investigator. In the event of a concern with an AE/SAE, an unscheduled visit can be 
conducted and the following assessments may be performed as needed: vital signs, 
ECG, physical examination, laboratory assessments, PK samples, EASI, IGA, BSA, PP-
NRS, and photography. If it is determined during an unscheduled visit that a patient will 
discontinue the study, all assessments for Day 28/ET (see Table 1) should be completed. 
4.3 
Discussion of Study Design 
The efficacy parameters being evaluated (EASI, BSA, IGA, and PP-NRS) are widely 
used and well-recognized indicators of the disease state of AD. A randomized, 
double-blind, vehicle-controlled design is being employed to mitigate bias in the 
collection and analysis of efficacy data. 
Although this is a first-in-human study, the study is being conducted in the target 
population because of the potential for differences in absorption of ATI-1777 through 
the skin of patients with AD compared with that of healthy volunteers. 
Plasma samples will be collected to preliminarily assess PK using a sparse sampling 
approach. As ATI-1777 is a topical medication and the molecule is metabolically labile, 
it is expected to have only minimal or no systemic exposure. 
The 2% w/w concentration was chosen based on nonclinical toxicity and PK studies in 
repeat-dose rat and minipig models, which showed a NOAEL of 300 mg/kg/day. 
4.4 
Stopping Rules 
4.4.1 
Individual Patient Stopping Rules 
A patient will stop treatment with investigational agent if one or combination of the 
following occurs during the study: 
• An infection which meets the criteria as a study medication-related SAE 
• A deep venous thrombosis and/or pulmonary embolism 
• Lymphoma 
• Hy’s law (see Section 6.3.2.1)  
Treatment with study medication should be temporarily interrupted in the event of 
severe AEs considered related to study medication, or in the event of one or more of the 
abnormal laboratory values in Table 5. 


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4.4.2 
Study Stopping Rules 
The sponsor and ProPharma safety physician will meet regularly (every 4 weeks) and 
assess the ongoing safety of the study. Attention will be paid to the number of severe 
AEs and SAEs, with particular focus paid to the number of patients who meet individual 
patient stopping rules. PK data will be used in the assessment: events associated with 
high plasma levels will be considered of high significance. 
If the study is stopped, a restart will not occur without agreement of the IRB and the 
sponsor’s medical monitor. 
4.5 
End of Study 
A patient is considered to have completed the study if he/she has completed all study 
visits. 
The end of the study is defined as the date of the last visit or last procedure of the last 
patient in the study. 


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5 STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
Patients must meet the following criteria to be eligible for participation in the study:  
1. Able to comprehend and willing to sign the IRB-approved ICF prior to 
administration of study-related procedures. 
2. Male patients or non-pregnant, non-nursing female patients 18 to 65 years old, 
inclusive, at the time of informed consent. 
3. Pregnancy and Contraception: 
• WOCBP (see Section 6.3.3), must have a negative serum pregnancy test at the 
Screening Visit, a negative urine pregnancy test immediately prior to the first 
application of study medication on Day 1, and a negative urine pregnancy test at 
each study visit thereafter. 
• Sexually active heterosexual women must agree to use the following throughout 
the screening period and for 30 days after last study drug application. WOCBP 
who are not sexually active at Baseline and become sexually active during the 
study must agree to follow the birth control measures listed below. 
o Agree to use 2 forms of highly effective contraception, including 1 physical 
barrier (condom or diaphragm) plus another highly effective method, such as 
adequate hormonal method (e.g., contraceptive implants, injectables, oral 
contraceptives) or nonhormonal methods (e.g., intrauterine device) or male 
partner who is surgically sterile (vasectomy). 
• Male patients with partners of childbearing potential may be enrolled if they are: 
o Documented to be surgically sterile (vasectomy), or 
o Using 2 adequate forms of highly effective contraception, 1 of which should 
be a physical barrier until 90 days after the last administration of study 
medication. 
4. Have a diagnosis of AD fulfilling the specified diagnostic criteria of Hanifin and 
Rajka (Hanifin and Rajka 1980). 
5. Have at least a 6-month history of AD prior to the Screening Visit, and no significant 
AD flares for the 4 weeks prior to the Screening Visit.  
6. Have at least 1 lesion that measures at least 3 cm2 at the Screening Visit and on 
Day 1 prior to the first dose of study medication. This lesion must be representative 
of the patient’s disease state, but not located on the hands, feet, or genitalia. 
7. Have a stable diagnosis of moderate or severe (IGA score 3 or 4) AD at the 
Screening Visit.  
8. Have AD affecting 3% to 20% BSA (not including head [neck, scalp, face], palms of 
hands, soles of feet, groin, and genitalia) at the Screening Visit. 


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9. Willing to refrain from washing area of treatment or swimming for 6 hours after 
each study medication application.  
10. Willing to refrain from excessive sun exposure (e.g., sunbathing and/or tanning salon 
visits) and to minimize sun exposure (e.g., wear sun protective clothing, hat) as 
much as possible. 
11. Willing to refrain from use of moisturizers, emollients, and sunscreen on AD study 
treatment areas for duration of protocol therapy. 
12. Willing to refrain from participating in strenuous exercise that would cause profuse 
sweating for a period of 6 hours after each study medication application. 
13. Willing to return to the clinic, follow all study instructions, attend all study visits, 
and complete study procedures.  
14. In good general health and free of any known disease state or physical condition 
that, in the investigator’s opinion, might impair evaluation of the patient or that 
might expose the patient to an unacceptable risk by study participation. 
15. Willing and capable of taking appropriate coronavirus disease 2019 (COVID-19) 
risk mitigation precautions (e.g., wearing a mask in public, adhering to social 
distancing, etc.) as recommended or required by local, state, or federal guidelines 
during participation in the study. 
5.2 
Exclusion Criteria 
Patients with any of the following are excluded from the study: 
1. Unstable course of AD (spontaneously improving or rapidly deteriorating) based on 
the patient history or as determined by the investigator during the Screening Period. 
2. Refractory AD (i.e., AD that required frequent hospitalizations and/or frequent 
intravenous treatment for skin infections within the year before the Screening Visit). 
3. AD of a severity (EASI >48) that the patient is not a candidate for a 
vehicle-controlled study. 
4. Any signs or symptoms associated with AD therapy (e.g., history of anaphylaxis, 
hypersensitivity reactions, skin atrophy, striae, pigmentary changes) that, in the 
investigator’s opinion, might impair evaluation of the AD or that exposes the patient 
to unacceptable risk by study participation.  
5. Concomitant skin disease or clinically infected AD or presence of other skin disease 
in the area to be dosed that may interfere with study assessments.  
6. Use of any of the following treatments within the indicated washout period prior to 
Day 1: 
• Phototherapy (ultraviolet A, ultraviolet B, or psoralen and ultraviolet A therapy) 
within 4 weeks prior to Day 1. 
• Systemic biologic immunosuppressant or immunomodulatory therapy (e.g., 
etanercept, alefacept, infliximab, dupilumab) within 12 weeks (or 5 half-lives of 
the product, whichever is longer) prior to Day 1. 


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• Non-biologic immunosuppressants (e.g., methotrexate, retinoids, calcineurin 
inhibitors, cyclosporine, hydroxycarbamide [hydroxyurea], azathioprine) within 
4 weeks prior to Day 1. 
• JAK inhibitors (systemic and topical) within 4 weeks prior to Day1. 
• Systemic corticosteroids within 2 weeks prior to Day 1 (intranasal, inhaled, and 
topical ocular corticosteroids are allowed). 
• Cytostatic agents within 4 weeks prior to Day 1.  
• Crisaborole within 2 weeks prior to Day 1.  
• Systemic antibiotics within 30 days prior to Day 1. 
• Topical treatments for AD (corticosteroids, calcineurin inhibitors, topical H1 and 
H2 antihistamines, topical antimicrobials, and other medicated topical agents) 
within 2 weeks prior to Day 1.  
• Live attenuated vaccine treatment within 12 weeks prior to Day 1. 
• Other investigational product within 30 days or 5 half-lives (whichever is longer) 
prior to Day 1. 
7. Previous failure to respond to prior therapy with JAK inhibitors (systemic or 
topical), as determined by the investigator. 
8. Current use of an oral H1 antihistamine (e.g., diphenhydramine, terfenadine) 
UNLESS the patient is on a stable dose for at least 14 days prior to the Screening 
Visit. 
9. Medical marijuana unless the patient is on a stable dose for at least 14 days prior to 
the Screening Visit. 
10. Clinically significant laboratory abnormalities at the Screening Visit that, in the 
opinion of the investigator, could affect interpretation of study data or the safety of 
the patient’s participation in the study.  
11. Clinical laboratory values: 
• White blood cell (WBC) count <2×109/L 
• ANC <1800/µL  
• Platelet count <130,000/µL 
• Hemoglobin <8g/dL 
• AST or ALT >2×ULN 
• Lymphocyte count <0.5×109/L 
12. Investigator-assessed history of, or current physical findings of, severe, progressive 
or uncontrolled immunologic, hepatic, gastrointestinal, pulmonary, cardiovascular, 
genitourinary (renal), hematological, neurologic or cerebral disorders, infectious 
disease or coagulation disorders that, as determined by the investigator, could affect 
the safety of the patient’s participation in the study or would preclude participation 
in and completion of study assessments. 
13. History of, current, or suspected systemic or cutaneous malignancy and/or 
lymphoproliferative disease within the last 5 years, other than patients with a history 
of adequately treated and well healed and completely cleared nonmelanoma skin 


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cancers (i.e., basal or squamous cell carcinoma) or cervical carcinoma in situ treated 
successfully at least 1 year prior to the Screening Visit 1 with no evidence of disease. 
14. Evidence of active, chronic, or latent infections at the time of enrollment or a 
systemic infection including but not limited to a history of treated infection (e.g., 
pneumonia, septicemia) within 3 months prior to Day1. 
15. Patient has a known active or history of incompletely treated or untreated active 
tuberculosis. Patients with a history of active tuberculosis must have documented 
adequate treatment verified by the investigator. Patients who demonstrate evidence 
of latent tuberculosis infection (positive QuantiFERON® Tuberculosis Gold Test) 
will only be allowed to participate in the study if there is documented evidence of a 
completed adequate treatment course for latent tuberculosis and if active tuberculosis 
is excluded per the investigator’s judgment. 
16. History of a serious local skin infection (e.g., cellulitis, abscess) within 5 years of the 
Screening Visit. 
17. Positive serological test for HIV (antibody), hepatitis C virus (antibody), hepatitis B 
surface antigen, or hepatitis B core antigen antibody. 
18. Known significant exposure (close contact [<6 feet] for ≥15 minutes) to an 
individual with a confirmed diagnosis of COVID-19 at any time during the 
Screening Period. 
19. Herpes zoster or cytomegalovirus infection that resolved less than 2 months prior to 
the Screening Visit. Patients with a history of frequent outbreaks of herpes simplex 
virus (defined as 4 or more outbreaks a year). 
20. Clinically significant ECG findings such as, but not limited to, baseline mean 
QTcF >450 msec for males or >470 msec for females (use of the ECG algorithm is 
acceptable for this purpose). 
21. Known allergy to any of the inactive ingredients in the study drug. 
22. Female patients who are pregnant, nursing, or planning to become pregnant during 
the study. 
23. Legal incapacity or limited legal capacity. 
24. Major surgery within 3 months of the Screening Visit. 
25. Any other condition that precludes adequate understanding, cooperation, and 
compliance with study procedures or any condition that could pose a risk to the 
patient’s safety, as per the investigator’s judgment. 
26. Use of potent inhibitors of cytochrome P450 3A4 such as (but not limited to) 
clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, 
verapamil, goldenseal, and grapefruit. 
5.3 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but 
who do not meet 1 or more criterion required for participation and are not subsequently 


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entered in the study. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure patients, to meet the Consolidated Standards of 
Reporting Trials publishing requirements, and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any SAE. 
5.3.1 
Retesting During Screening 
Laboratory parameters and/or assessments that are included in the screening procedures 
(Table 1) may be repeated during the Screening Period in consultation with the 
sponsor’s medical monitor. Retesting will be allowed when the significance of a 
laboratory result is unclear and the retest will help interpretation and decision making 
for entry to the study. Retesting will not be undertaken when the laboratory results 
clearly indicate clinically significant disease that could impact study interpretation or the 
safety of a study subject during participation. 
The most current result prior to randomization is the value by which study inclusion will 
be assessed, as it represents the participant’s most current clinical state. 
5.3.2 
Rescreening 
This study will permit 1 rescreening of a participant who has failed 1 or more inclusion 
or exclusion criteria. Consultation with the medical monitor may be needed to identify 
whether rescreening is clinically relevant. If rescreened, the participant must sign a new 
ICF and the same Patient Number will be assigned. 
For participants who are rescreened, consult with the medical monitor to confirm which 
parameters and/or assessments that were collected as part of the original Screening 
Period procedures may be utilized. 
5.4 
Premature Discontinuation 
5.4.1 
Premature Discontinuation of Study Medication 
Patients should be permanently discontinued from study medication in the event of any 
of the following:  
• The patient experiences significant worsening of AD such that additional therapy for 
the treatment of AD is required 
• Confirmed, active infection with the SARS-CoV-2 virus 
• Infection requiring parenteral antimicrobial therapy or hospitalization  
• Symptomatic herpes zoster 
• Malignancy – except for nonmelanoma skin cancer not in or near the treatment area  
• Anaphylactic or severe allergic reaction  
• WBC count: <1 × 109/L or second occurrence of <2 × 109/L – in each case, value 
should be confirmed by retesting before treatment discontinuation 


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• ANC: <0.5 × 109/L or second occurrence of <1 × 109/L – in each case, value should 
be confirmed by retesting before treatment discontinuation 
• Lymphocyte count: <0.3 x 109/L or second occurrence of <0.5 × 109/L – in each 
case, value should be confirmed by retesting before treatment discontinuation 
• Platelet count: <50 × 109/L or second occurrence of <75 × 109/L – in each case, 
value should be confirmed by retesting before treatment discontinuation  
• Hemoglobin: <6.5 g/dL or second occurrence of <8 g/dL – in each case, value 
should be confirmed by retesting before treatment discontinuation  
• AST or ALT:  
o 5×ULN persisting for 2 weeks of study medication interruption or second event 
of >5×ULN  
o >3×ULN and (total bilirubin >2×ULN or international normalized ratio [INR] of 
>1.5) 
o 3×ULN with total bilirubin >2×ULN or symptoms of hepatocellular injury 
[fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash 
and/or eosinophilia (>5%)]. 
• Any patient who develops any of the following ECG findings during the active 
treatment phase will be instructed to stop study medication and will be withdrawn 
from the study:  
o Clinically significant rhythm disturbance other than sinus rhythm or ectopic 
supraventricular rhythm (ectopic atrial rhythm).  
o Clinically significant conduction disturbance including PR >240 msec, 
pre-excitation (delta wave and PR <120 msec), second degree or higher 
atrioventricular block.  
o New finding of QRS >120 ms (if not present at the Screening Visit. For example, 
patients with Right Bundle Branch Block at screening would not need to be 
withdrawn from the study if their subsequent ECGs remained unchanged).  
o Evidence of QT-interval prolongation, defined as an increase in the QTcF 
interval >60 ms from Visit 1.  
o Acute signs of ischemia or infarction.  
o Any ECG abnormality that may, in the opinion of the investigator, represent a 
new medical issue of concern. 
In addition, patients should discontinue study medication if any of the following occurs: 
1. The patient withdraws his/her consent to participate in the study. 
2. The patient develops an illness that would interfere with his/her continued 
participation in the study. 
3. The patient is noncompliant with study procedures or medication, in the opinion 
of the investigator. 
4. The patient is confirmed to be pregnant. 
5. The sponsor or regulatory agency requests withdrawal of the patient. 


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If a patient is prematurely discontinued from study medication, the patient may remain 
in the study. The patient should complete the assessments outlined for each study visit; 
see Table 1. The patient should also attend the PTFU Visit. 
Every effort will be made to ensure that patients who prematurely discontinue study 
medication complete the study. 
Patients who discontinue study medication prematurely will not be replaced. 
Patients are permitted to temporarily discontinue and restart study medication.  
5.4.2 
Premature Discontinuation from the Study 
Participation in the study is strictly voluntary. A patient has the right to withdraw from 
the study at any time for any reason, without any reprisal. 
At the time of premature study discontinuation, the investigator should make every 
effort to ensure the patient completes the assessments indicated at the Day 28/ET Visit 
and completes the PTFU Visit approximately 14 days after the ET Visit; see Table 1. 
The only exception to this requirement is when consent is withdrawn for all study 
procedures or the participant loses the ability to consent freely (e.g., is imprisoned or 
involuntarily incarcerated for the treatment of either a psychiatric or physical illness). 
If a patient withdraws consent to participate in the study, the study monitor/sponsor will 
be informed immediately. If there is a medical reason for withdrawal, the patient should 
remain under the supervision of the investigator until satisfactory health has returned. 
If the patient withdraws consent for disclosure of further information, the sponsor may 
retain and continue to use any collected data before such a withdrawal of consent. If a 
patient withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
Although a patient is not obliged to give his/her reason(s) for withdrawing prematurely 
from a study, the investigator should make a reasonable effort to ascertain the reason(s), 
while fully respecting the patient's rights. 
Patients who prematurely discontinue from the study cannot subsequently rejoin the 
study. 
For details on the discontinuation of study sites or the study as a whole, see Section 15. 
5.4.3 
Lost to Follow-up 
A patient will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 


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The following actions must be taken if a patient fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon 
as possible, counsel the patient on the importance of maintaining the assigned visit 
schedule, and ascertain whether or not the patient wishes to and/or should continue 
in the study. 
• Before a patient is deemed lost to follow-up, the investigator (or designee) must 
make every effort to regain contact with the patient (where possible, 2 telephone 
calls and a certified letter to the patient’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the patient’s 
source record. 


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6 DESCRIPTION OF STUDY ASSESSMENTS 
Refer to Table 1 for the schedule of assessments. 
6.1 
Demographics and Other Screening Assessments 
Safety assessments that are also part of the screening assessments are described in 
Section 6.3. 
6.1.1 
Medical History 
Medical history, including any ongoing illnesses, will be recorded in the eCRF, with the 
start date and stop date (if applicable) of the illness/condition. Medical history will be 
collected at the Screening Visit and updated, if necessary, on Day 1 prior to the first 
administration of study medication. 
6.1.2 
Demographics 
Demographic data, including year of birth/age, sex, race, and ethnicity will be recorded 
in the eCRF. 
6.1.3 
Tuberculosis Test 
An interferon gamma release assay/QuantiFERON Tuberculosis Gold Test for 
active/latent tuberculosis will be performed at the Screening Visit. The test will be 
provided by the central laboratory. 
Patients who demonstrate evidence of latent tuberculosis infection (positive 
QuantiFERON Tuberculosis Gold Test) will only be allowed to participate in the study 
if there is documented evidence of a completed adequate treatment course for latent 
tuberculosis and if active tuberculosis is excluded per the investigator’s judgment. 
In case of indeterminate results, the test may be repeated once. 
6.1.4 
SARS-CoV-2 Testing and Monitoring 
At Day 1, all patients entering the treatment phase of the study must have a 
nasopharyngeal (preferred) or oropharyngeal swab collected prior to the first dose of 
study medication to test for the presence of the SARS-CoV-2 virus. The sample will be 
sent to the study’s central lab for analysis by reverse transcription polymerase chain 
reaction with results reported as either ‘Detected’ or ‘Not detected’ for SARS-CoV-2 
viral particles. If central laboratory testing cannot be performed at the time of Day 1 
(i.e., lab supplies are not yet available) and the study site is able to perform equivalent 
testing locally, they may choose to do so, as long as the test results are available in the 
patient’s research chart for sponsor review. Patients should not initiate study medication 


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treatment in the absence of central laboratory or locally equivalent testing being 
performed. 
Patients will be allowed to dose with study medication in the interval between sample 
collection at Day 1 and result reporting as long as there is no clinical suspicion of 
COVID-19 infection or recent significant exposure (close contact [<6 feet] for ≥15 
minutes) of the patient to an individual with a confirmed, active infection. 
If the patient’s results are positive for SARS-CoV-2 following sample collection at 
Day 1, the patient will be notified immediately upon receipt of the results and treatment 
with study medication will be permanently discontinued. The patient will be advised to 
begin self-isolation and self-monitoring procedures according to any applicable local, 
state, and/or federal health recommendations. Referral to an appropriate health care 
provider for management of the patient’s COVID-19 diagnosis should also be made. 
The patient should be seen for the PTFU Visit (see Table 1) only at such time that the 
investigator assesses the risk for incidental transmission from viral shedding to be 
minimized. The patient’s COVID-19 diagnosis will be reported as medical history 
unless the patient’s clinical course progresses such that criterion for SAE reporting is 
met (see Section 8.3), in which case, all applicable safety reporting procedures will be 
followed by the site. 
Sites will also have the option to perform an unscheduled test for the SARS-CoV-2 virus 
at any time during the treatment phase of the study should a patient’s clinical 
presentation necessitate it in the investigator’s opinion. The same notification and 
referral procedures, as outlined in the preceding paragraphs, should be followed by the 
site. However, it is expected that any COVID-19 diagnosis made from a sample 
collected after the initiation of study be reported as an AE per the requirements of 
Section 8 of this protocol. 
6.1.5 
Fitzpatrick Skin Type Assessment 
Patients’ skin type will be classified according to Fitzpatrick skin type at the Screening 
Visit as follows: 
• Type I: Pale white skin, blue/green eyes, blond/red hair. Always sunburns, does 
not tan. 
• Type II: Fair skin, blue eyes. Burns easily, tans poorly. 
• Type III: Darker white skin. Tans after initial burn. 
• Type IV: Light brown skin. Burns minimally, tans easily. 
• Type V: Brown skin. Rarely burns, tans darkly easily. 
• Type VI: Dark brown or black skin. Never burns, always tans darkly. 
6.1.6 
Lesion Photography 
Photographs of representative lesions will be taken at each study visit. Sites will be 
required to submit the patient’s baseline photographs to Canfield Scientific’s database. 


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Canfield Scientific will supply all investigational sites with study-specific camera 
equipment to photograph each patient’s identified target AD treatment areas (up to 2 
target locations). Sites will be supplied with color stickers to identify each target area. 
Details regarding the use of the equipment and how to upload the photographs to the 
Canfield database will be supplied to the sites in the Photography Manual. 
6.2 
Efficacy Assessments 
6.2.1 
Eczema Area and Severity Index 
The EASI (Hanifin et al 2001; Rullo et al 2008) assesses the extent and severity of AD. 
This study will employ a modified EASI that excludes evaluation of the head (neck, 
scalp, face), palms of hands, soles of feet, groin, and genitalia. The modified EASI will 
evaluate AD in each of 3 body regions (trunk [excluding groin and genitalia], upper 
extremities [excluding palms of hands], and lower extremities [excluding soles of feet]). 
The EASI scoring system uses a defined process to grade the severity of the signs of AD 
and the extent affected. If possible, the same individual should conduct the extent and 
severity evaluations at each visit. 
6.2.1.1 
Extent 
Each respective body region will be given a score between 0 and 6 based on the 
percentage involvement in that region according to Table 2. Precise measurements are 
not required. 
Table 2 
Extent of Atopic Dermatitis in Each Body Region 
% Involvement 
0% 
1% to 9% 
10-29% 
30-49% 
50-69% 
70-89% 
90-100% 
Region Score 
0 
1 
2 
3 
4 
5 
6 
 
6.2.1.2 
Severity 
For each respective body region, the severity of each of 4 signs (erythema, 
edema/papulation, excoriation, lichenification) will be graded by the investigator or 
qualified designee on a 0- to 3-point scale ([0] none, [1] mild, [2] moderate, [3] severe) 
in AD-affected areas. Half scores are allowed. The average severity across AD-affected 
areas in each body region will be used as the score for that region. 
6.2.1.3 
Score Calculation 
The investigator or qualified designee will enter the extent and severity values into the 
eCRF. The final EASI score will then be calculated by an electronic data capture system 
as described in Table 3. 


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Table 3 
EASI Score Calculation 
Body 
Region 
Erythema 
Edema/ 
papulation 
Excoriation 
Lichenification 
Area 
Score 
Multiplier 
Score 
Trunk 
( 
+ 
+ 
+ 
) 
× 
× 0.3 
 
Upper 
extremity 
( 
+ 
+ 
+ 
) 
× 
× 0.2 
 
Lower 
extremity 
( 
+ 
+ 
+ 
) 
× 
× 0.4 
 
Final EASI score is the sum of the 3 region scores: 
 
 
EASI = Eczema Area and Severity Index 
6.2.2 
Investigator’s Global Assessment 
The IGA is the investigator’s assessment of the overall appearance of the lesions at a 
particular point in time. At every study visit, the investigator will assess the IGA using 
the scale in Table 4 and report the one score that best describes the overall appearance of 
the lesions. It is not necessary that all characteristics under Morphological Description 
be present. In indeterminate cases, please use extent to differentiate between scores. 
For example: 
• Patient with marked erythema (deep or bright red), marked papulation, and/or 
marked lichenification that is limited in extent, will be considered “3 – Moderate”. 
The investigator or qualified designee will enter the score into the eCRF. Whenever 
possible, the same individual should conduct the evaluation at each visit. 
Table 4 
IGA Scoring 
Score 
Morphological Description 
0 - Clear 
No inflammatory signs of atopic dermatitis (no erythema, no 
induration/papulation, no lichenification, no oozing/crusting). Post-inflammatory 
hyperpigmentation and/or hypopigmentation may be present. 
1 - Almost clear 
Barely perceptible erythema, barely perceptible induration/papulation, and/or 
minimal lichenification. No oozing or crusting. 
2 - Mild 
Slight but definite erythema (pink), slight but definite induration/papulation, 
and/or slight but definite lichenification. No oozing or crusting. 
3 - Moderate 
Clearly perceptible erythema (dull red), clearly perceptible induration/papulation, 
and/or clearly perceptible lichenification. Oozing and crusting may be present. 
4 - Severe 
Marked erythema (deep or bright red), marked induration/papulation, and/or 
marked lichenification. Disease is widespread in extent. Oozing or crusting may 
be present. 
IGA = Investigator’s Global Assessment 
 


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6.2.3 
Body Surface Area 
The total percentage of the patient’s AD-affected BSA will be estimated by the 
investigator or designee using the handprint method, which estimates that the area of a 
patient’s full handprint (fingers and thumbs together) constitutes 1% of their total BSA.  
The BSA should be calculated for the EASI score using Regional Percentage Estimates 
as described in the study training video. 
Whenever possible, the same evaluator should perform the estimation at each study visit. 
If new areas of AD develop while the patient is on the study, these new areas will not be 
assessed. 
6.2.4 
Peak Pruritus Numerical Rating Scale 
The PP-NRS (Yosipovitch et al 2019) is a single patient‐reported item designed to 
measure peak pruritus, or ‘worst’ itch, over the previous 24 hours based on the following 
question: ‘On a scale of 0 to 10, with 0 being “no itch” and 10 being “worst itch 
imaginable,” how would you rate your itch at the worst moment during the previous 
24 hours?’. 
Prior to study medication application on Day 1, the study coordinator should show the 
PP-NRS scale to the patient, explain the scale and ask the patient to indicate which 
integer best describes the worst pruritus the subject experienced for their AD over the 
previous 24 hours. 
The patient will complete this assessment and record in their diary each morning before 
applying study medication during the Treatment Period. 
The patient will report the diary rating to site staff at each visit, who will enter it into the 
patient’s source documents and eCRF. 
6.3 
Safety Assessments 
6.3.1 
Adverse Events 
AEs will be followed, recorded, and reported in line with the procedures described in 
Section 8. 
6.3.2 
Clinical Laboratory Evaluations 
All laboratory samples will be processed and shipped to the central laboratory, as 
described in the Laboratory Manual. The central laboratory will analyze the samples or 
send them to reference laboratory(ies) for analysis, as indicated in the manual. Refer to 
the central Laboratory Manual for the maximum total volume of blood to be collected 
per patient throughout the study. 


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Non-fasting blood and urine samples will be collected at the times indicated in Table 1. 
On dosing day(s) sampling for the analysis of clinical laboratory parameters will be 
performed before the administration of study medication. 
The following parameters will be assessed: 
Hematology: hemoglobin, hematocrit, red blood cell (RBC) count, RBC morphology, 
platelets, total WBC count, differential WBC count, lymphocyte count, and ANC 
Biochemistry: albumin, alkaline phosphatase, ALT, amylase, AST, blood urea nitrogen, 
bicarbonate, calcium, chloride, creatine phosphokinase (CPK), creatinine, phosphorus, 
gamma glutamyltransferase (GGT), glucose, lactate dehydrogenase (LDH), lipase, 
LDL-C, HDL-C, potassium, sodium, total and direct bilirubin, TC, and triglycerides 
(TG) 
Urinalysis: pH, specific gravity, creatinine, glucose, bilirubin, blood, and protein 
Screening serology tests will be performed to assess HIV (antibody), hepatitis C 
(antibody), hepatitis B surface antigen, or hepatitis B core antigen antibody. For 
hepatitis B, the following tests will be done at the Screening Visit and patients with a 
positive result for either hepatitis B surface antigen and or hepatitis B core antigen 
antibody will be excluded from the study. 
Serum (β-human chorionic gonadotrophin) pregnancy testing will be performed at the 
Screening Visit, and urine pregnancy tests will be performed at the other study visits in 
the Treatment Period.  
Refer to the Laboratory Manual for details regarding the collection, processing, and 
shipping of the blood and urine samples. 
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
eCRF. Whenever possible, the underlying cause for clinically relevant laboratory value 
should be recorded as an AE, rather than the laboratory value itself. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those that are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the patient’s condition. 
All laboratory tests with values considered clinically significantly abnormal during the 
patient’s participation in the study or within 2 weeks after the last dose of study 
medication should be repeated until the values return to normal, or baseline, or are no 
longer considered clinically significant by the investigator or medical monitor. 
If such values do not return to normal/baseline within a period of time judged reasonable 
by the investigator, then the etiology should be identified, and the sponsor notified. 


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6.3.2.1 
Potential Drug-induced Liver Injury 
Hy’s Law cases have the following 3 components:  
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 
≥3-fold elevations above the ULN of ALT or AST than the placebo  
2. Among study patients showing such aminotransferase elevations, often with 
aminotransferases much greater than 3×ULN, one or more also shows elevation of 
serum total bilirubin to >2×ULN or INR >1.5, without initial findings of cholestasis 
(elevated ALP)  
3. No other reason can be found to explain the combination of increased 
aminotransferase and total bilirubin, such as viral hepatitis A, B, or C; evidence for 
biliary obstruction; acute alcoholic hepatitis (recent drinking and AST >2×ALT are 
supportive); recent history of severe hypotension or congestive heart failure; other 
underlying viral disease; pre-existing or acute liver disease; or another drug 
(including non-prescription products such as herbal supplements) capable of causing 
the observed injury  
During the study, the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a patient meets 
potential drug-induced liver injury criteria at any point during the study.  
In the event that a patient shows laboratory results of:  
• AST or ALT: >5×ULN persisting for 2 weeks after study medication interruption or 
second occurrence of >5×ULN  
• ≥ 3×ULN and (total bilirubin ≥2×ULN or INR >1.5)  
• ≥ 3×ULN with appearance of fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash and/or eosinophilia (>5%)  
Please refer to Appendix 4 for further information. 
6.3.3 
Pregnancy 
WOCBP includes any female who has experienced menarche and who has not 
undergone successful surgical sterilization (e.g., hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy) or is not postmenopausal. Postmenopausal is defined as 
≥12 months with no menses without an alternative medical cause. WOCBP must have a 
negative serum pregnancy test at screening and a negative urine pregnancy test on Day 1 
prior to randomization. 
Serum (β-human chorionic gonadotrophin) or urine pregnancy tests will be performed 
for WOCBP at the Screening Visit. Urine pregnancy tests will be performed at each 
study visit. 


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Serum pregnancy test results must be negative and must be available before Day 1. A 
pregnancy test must be performed at each study visit, and the result must be negative for 
the patient to continue to be eligible. If the test result is positive, the patient must be 
excluded from the study (if at the Screening Visit) or discontinued from the study (if at 
subsequent study visits). The serum pregnancy tests will be analyzed by the central 
laboratory; urine pregnancy tests will be analyzed locally. 
Male patients will be required to inform the investigator if their partner becomes 
pregnant during the study.  
The investigator should inform the sponsor within 24 hours of learning of the pregnancy 
or partner pregnancy by completing and submitting a pregnancy report form to the 
ProPharma Group, as shown in SERIOUS ADVERSE EVENT CONTACT 
INFORMATION. 
If a patient becomes pregnant, she will not receive any further study medication. The 
investigator will record pregnancy information on the appropriate form and submit it to 
the sponsor within 24 hours of learning of the partner’s pregnancy. Any pregnant patient 
or pregnant partner of a male patient and the fetus will be closely followed up 
throughout the duration of the pregnancy to determine the outcome (including 
spontaneous miscarriage, elective termination, normal birth, or congenital abnormality). 
The investigator will ask the patient to provide informed consent to record information 
on the health of the baby. Information on the status of the mother and child will be 
forwarded to the sponsor. Generally, follow-up will be required for no longer than 6 to 8 
weeks beyond the estimated delivery date. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for 
the procedure. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE. Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal 
death, stillbirth, congenital abnormalities, ectopic pregnancy) will be considered SAEs. 
6.3.4 
12-lead Electrocardiogram 
Triplicate 12-lead ECGs will be obtained as outlined in Table 1 using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals. At each time point at which triplicate ECG are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession, but no more than 
2 minutes apart. The full set of triplicates should be completed in less than 4 minutes. 
The ECG tracing should include the date and time of the assessment and the signature of 
the person who made the interpretation; the tracing will be archived at the study site. 


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6.3.5 
Vital Signs 
Vital signs will be measured in a semi-supine position after 5 minutes of rest and will 
include temperature, systolic and diastolic blood pressure, pulse, and respiratory rate. 
6.3.6 
Physical Examination 
Physical examinations will be performed by a Doctor of Medicine (MD) or equivalent, 
or someone who is authorized to perform the examinations by training and has been 
delegated this task by the investigator.  
A full examination will be performed at the Screening Visit. A full examination will 
include general appearance, skin, head, eyes, ears, nose, throat, neck, thyroid, 
chest/lungs, heart, abdomen, lymph nodes, and extremities.  
An abbreviated examination will be performed at the Day 1 and Day28/ET Visits and 
will include symptom-focused assessments. An abbreviated examination does not 
preclude examination of any of the other body systems as clinically indicated. Every 
effort should be made to ensure the same evaluator will complete the examination for 
each participant at all visits throughout the study. Documentation of who performed the 
examination is to be recorded in the patient source documentation. 
Height will be measured and recorded at the Screening Visit, and weight will be 
measured and recorded at each study visit. The patient should be dressed in light 
clothing, without shoes. 
6.4 
Pharmacokinetics 
The PK of ATI-1777 will be preliminarily evaluated by measurement of ATI-1777 
concentrations in plasma samples obtained using a sparse sampling schedule. A sparse 
sampling approach is being employed because it is not anticipated that clinically relevant 
plasma concentrations will be observed. 
Actual time of PK sample collection, the time of last application of study medication, and 
the volume of study medication applied in the last study medication application must be 
collected in the eCRF.  
A total of 8 PK samples will be collected from each patient.  
One sample will be collected before study medication application and 1 sample will be 
collected approximately 2 hours after application on each of Days 1, 8, and 15. 
Samples for Day 28 will be collected from 3 subgroups of patients within each of the 
specified time windows as follows: 
• Subgroup 1: One sample predose and one sample at 0.5 to 2.5 hours post 
application 


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• Subgroup 2: One sample at 2.5 to 5 hours post application and one sample at least 2 
hours later 
• Subgroup 3: One sample at 5 to 8 hours post application and one sample at least 2 
hours later (prior to the subsequent application) 
The IXRS system will be used to randomly assign patients to subgroups. 
The plasma samples will be analyzed for ATI-1777 using a validated assay. Samples will 
be used to evaluate the PK of ATI-1777. Each plasma sample will be divided into 
2 aliquots (1 each for PK and a backup). 
Detailed instructions for the PK blood collection, labeling, processing, storage, and 
shipping will be provided to the site in the Laboratory Manual. 


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7 TREATMENTS 
7.1 
Investigational Product(s) 
7.1.1 
Description of Study Medications 
 
Test Product 
 
Name: 
ATI-1777 
Dose(s):  
Up to 8 mL 2% w/w topical solution applied to affected 
skin areas 
Mode of administration: 
Topical application to AD-affected skin areas 
Manufacturer: 
Drug Substance: 
GVK Biosciences Pvt. Ltd 
Hyderabad, India 
 
Drug Product: 
Tergus Pharma 
Durham, North Carolina, USA 
 
Vehicle 
 
Substance: 
Topical vehicle solution identical in appearance to 
ATI-1777 
Dose(s):  
Up to 8 mL topical solution applied to affected skin areas 
Mode of administration: 
Topical application to AD-affected skin areas 
Manufacturer: 
Tergus Pharma 
Durham, North Carolina, USA 
7.1.2 
Preparation, Handling, and Storage 
The investigator (or designee) is responsible for the safe and proper storage of study 
medication at the site. ATI-1777 topical solution and vehicle topical solution will be 
stored under controlled conditions according to the storage requirements described on 
the label(s). ATI-1777 topical solution and vehicle topical solution should be stored at 
room temperature 15°C – 25°C (59°F – 77°F), with excursions permitted up to 30°C 
(86°F). The investigator (or designee) will instruct the patients to store the study 
medication in accordance to the instructions on the label. 
7.1.3 
Packaging, Labeling, and Shipment 
ATI-1777 topical solution and vehicle topical solution will be packaged and labeled in 
accordance with all applicable regulatory requirements and Good Manufacturing 
Practice guidelines. 


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Fifty mL of ATI-1777 topical solution or vehicle topical solution will be provided in 
60-mL amber glass bottles with 1-mL droppers metered to 0.25 mL. 
ATI-1777 topical solution and vehicle topical solution will be shipped and stored under 
controlled conditions according to the storage requirements. 
Refer to the Pharmacy Manual for full details for packaging, labeling, and shipment of 
the study medication. 
7.2 
Blinding 
The study is double-blinded; therefore, the sponsor, investigators, study personnel, and 
the study patients will remain blinded to treatment allocation. 
ATI-1777 and vehicle will be coded and labeled in a manner that protects blinding. The 
IXRS will permit rapid identification of the product (in case of medical emergencies), 
that does not permit detectable breaking of the blind. 
Breaking of the blind is only allowed in the case of an emergency, when knowledge of 
the study medication is essential for the clinical management of the patient. The 
investigator must make every effort to contact the sponsor’s medical monitor prior to 
breaking the blind and must contact the sponsor within 1 business day after the event, 
without revealing to the sponsor (or designee) the results of the code break, except to the 
ProPharma Group safety team. Patients whose treatment assignments are unblinded will 
not receive any further study medication. 
Emergency unblinding will be organized through the IXRS. The investigator must 
record the date of unblinding and the reason. All breaks of the blind must be adequately 
documented in the patient’s source documentation. 
If an SAE is reported, the designated global patient safety representative may unblind 
the treatment assignment for the individual patient through IXRS in order to meet 
regulatory reporting requirements. 
7.3 
Method of Assigning Treatment 
Each patient will be assigned a unique Patient Number, which will be obtained from the 
IXRS following the patient providing informed consent. The investigator will keep a 
record (the screening log) of patients who enter screening. 
Randomization will be performed via a centralized IXRS. On Day 1, eligible patients 
will be assigned to ATI-1777 or vehicle in a 1:1 ratio. Patients will be allocated to 
treatment according to the randomization code. 
If a patient withdraws from study participation, his/her unique identification number(s) 
cannot be re-used for another patient. 


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Patients will be stratified at randomization by severity of AD (moderate versus severe). 
7.4 
Dose and Administration 
Patients will be instructed to apply a thin film of study medication, twice daily, once in 
the morning and approximately 8 to 12 hours later, to the identified target AD areas. 
Study medication should be applied using the metered dropper to drop study medication 
onto the skin and gently rubbing in over the target area. No more than a total of 8 mL of 
study medication should be applied to all combined target areas at a given 
administration session. Study medication should be applied to clean dry skin. The 
patient must wash her/his hands thoroughly before and after each study medication 
administration. 
Investigational site staff will dispense study medication to the patient on Day 1. 
Subsequent study medication dispensing will be determined by the site based on the 
amount used between visits. Study medication bottles will be weighed by the site staff at 
the time of dispensing and when the bottles are returned. Patients are to return used and 
unused study medication bottles at each study visit so that the bottles can be weighed. 
Sites can re-dispense partially used bottles of study medication. 
Patients will be trained by site staff on the appropriate application of study medication 
before the first application on Day 1, and the first application will be supervised by site 
staff. Patients may be retrained after Day 1 if site staff determines that it is necessary. 
Throughout the study, patients will record the amount applied in a patient diary. 
Additional details on the application of study medication are in Appendix 2 and the 
Pharmacy Manual. 
7.4.1 
Identification of Target Treatment Areas 
On Day 1, the investigator will identify a target treatment area(s) that meets all inclusion 
criteria (e.g., a diagnosis of AD based on the criteria of Hanifin and Rajka (Hanifin and 
Rajka 1980; Appendix 3), BSA between 3% and 20%, inclusive, and an IGA score of 3 
or 4). The target treatment area cannot include the head (neck, scalp, face), palms of 
hands, soles of feet, groin, or genitalia. The investigator will record the identified target 
treatment area(s) on the body map in the patient’s source documents and give to the 
patient to take home for reference. Up to 2 target treatment areas will be photographed at 
each specified protocol time point (see Table 1). Sites will use colored stickers to mark 
the treatment areas prior to the photographs being taken. 
Patients will continue treatment of all target areas identified on Day 1, even if the 
lesion(s) have cleared. If new areas of AD develop while the patient is on study, study 
medication may be applied to these areas. New areas should be treated at the first sign of 
disease and continue until the Day 28 visit. New areas of treatment will be recorded in 
the source notes at the time the patient begins treating them with study medication. 


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7.4.2 
Dose Modification 
Study medication dosing for individual patients will be allowed to be paused and 
restarted if it is deemed to be in the best interest of the patient’s safety due to AE. 
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the medical monitor based on the clinical evaluation of the patient. 
All treatment interruptions and the reason for the interruption should be recorded in the 
eCRF. 
Treatment with ATI-1777 should be temporarily interrupted in the event of severe AEs 
considered related to ATI-1777, or in the event of one or more of the abnormal 
laboratory values in Table 5.  
Table 5 
Study Medication Interruption Criteria 
Laboratory Test 
Hold Study Medication if:  
Resume Study Medication if:  
WBC count  
<2×109/L  
≥2.5×109/L  
ANC 
<1×109/L  
≥1.5×109/L  
Lymphocyte count  
<0.5×109/L  
≥0.75×109/L  
Platelet count  
<75×109/L  
≥100×109/L 
Hemoglobin 
8 g/dL or a decrease >2g/dL  
≥10 g/dL  
AST or ALT 
>3×ULN  
<2×ULN or within 20% of baseline 
values  
Serum creatinine 
>2×ULN  
<1.5×ULN or within 10% of 
baseline value  
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; 
ULN = upper limit of normal range; WBC = white blood cell 
 
If a patient has one or more of the abnormal laboratory values noted in Table 5, the 
investigator or designee upon receipt and review of the central laboratory report should 
instruct the patient to hold study medication applications. The investigator or designee 
should ask the patient about symptoms, concomitant illnesses and medications and 
repeat the test(s) as soon as possible. The medical monitor must be notified of dose 
interruptions due to AEs or laboratory abnormalities noted in Table 5. 
If the retest confirms the abnormal laboratory value, then the study medication should 
continue to be held followed by repeat testing once a week or sooner at the discretion of 
the investigator. The patient should be followed until the laboratory abnormality(s) 
returns to normal or to baseline values. 
7.4.3 
Intervention After the End of the Study 
There is no intervention planned for patients after the end of the study. 


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7.5 
Precautions and/or Lifestyle Considerations 
Prior to the application of the study medication, the identified AD treatment area(s) 
should be washed and cleaned using the patient’s routine cleansing products. The area 
should be dried completely prior to the application of the study medication. Patients 
must not wash the treatment area, go swimming, or perform physical exercise that may 
cause profuse sweating for a period of 6 hours after applying the study medication. 
While on study, patients should continue to use their routine cleansing and cosmetic 
products. 
Patients may not use a non-therapeutic, bland emollient, moisturizers, or sunscreens on 
areas being treated with study medication for the duration of the study. Moisturizers, 
emollients, and sunscreens may be used on areas not being treated with study 
medication. Patients must take special precautions to try and limit sun exposure to all 
identified treatment areas by wearing protective clothing and applying sunscreen to 
areas not being treated with study medication. 
7.6 
Prior and Concomitant Medications 
All medications (including vaccines, over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) taken from 3 months before the Screening Visit 
until the end of the follow-up period will be recorded in the appropriate section of the 
eCRF. The following details must be recorded in the eCRF: 
• Medication name, ideally the generic name 
• Reason for use 
• Start and end date of administration 
• The dose and frequency of administration 
The medical monitor should be contacted if there are any questions regarding prior or 
concomitant medication or procedures. 
7.6.1 
Prior Medications 
Prior medications are defined as medications taken prior to the first dose of study 
medication and discontinued before the first dose of study medication. Prior medication 
information will be collected at the Screening Visit and updated, if necessary, on Day1 
prior to the first administration of study medication. 
See Section 15 for details of medication that is permitted or prohibited according to the 
inclusion and exclusion criteria. 
7.6.2 
Concomitant Medication 
Concomitant medications are defined as any medication taken after the first dose of 
study medication until the Day 42/PTFU Visit. 


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Concomitant medications (e.g., prescription, over-the-counter, or herbal) should be 
administered during the study only if they are prescribed for treatment of specific 
clinical events. 
Use of any of the following treatments is prohibited during the study:  
• Phototherapy (ultraviolet A, ultraviolet B, or psoralen and ultraviolet A therapy).  
• Systemic biologic immunosuppressant or immunomodulatory therapy (e.g., 
etanercept, alefacept, infliximab, dupilumab).  
• Non-biologic immunosuppressants (e.g., methotrexate, retinoids, calcineurin 
inhibitors, cyclosporine, hydroxycarbamide [hydroxyurea], azathioprine). 
• JAK inhibitors (systemic and topical). 
• Systemic or topical corticosteroids (intranasal, inhaled, and topical ocular 
corticosteroids are allowed if used to treat other medical conditions). 
• Cytostatic agents. 
• Crisaborole.  
• Systemic antibiotics.  
• Topical treatments for AD (corticosteroids, calcineurin inhibitors, topical H1 and 
H2 antihistamines, topical antimicrobials, and other medicated topical agents).  
• Live attenuated vaccine treatment. 
• Other investigational products. 
• Use of potent inhibitors of cytochrome P450 3A4 such as (but not limited to) 
clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, 
verapamil, goldenseal, and grapefruit. 
7.7 
Overdose 
It is not anticipated that ATI-1777 will be systemically absorbed, and dosing will vary 
between patients. Treatment of suspected overdose with ATI-1777 should consist of 
clinically appropriate supportive measures. 
7.8 
Compliance 
Site staff will train patients in the correct application of the study medication to each 
patient and will check that each patient is following the instructions properly. Any 
deviation from the correct use of the study medication will be recorded in the eCRF. 
Study staff will counsel the patients, as required to make sure patients are compliant 
with study medication applications. 
The volume of each study medication applied in each application will be recorded in a 
patient diary, which will be reviewed at each study visit. The investigator or designee 
will be responsible for monitoring patient compliance through diary review, questioning 
the patient, documenting missed doses, if any, weighing the bottle before dispensing and 
after return, and performing a visual inspection of the quantity in the study medication 
bottles (used and unused). A record of the study medication dispensed to and returned by 
each patient will be maintained and reconciled with study medication and compliance 


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records at the site. The study medication start and stop dates, including dates for study 
medication delays and/or dose reductions, will also be recorded in the eCRF. 
7.9 
Accountability 
The study medication must not be used for any purpose other than that defined in this 
protocol. All supplies of study medication will be accounted for in accordance with 
GCP. 
The pharmacist or (designee) should maintain accurate records of all study medication 
supplies received during the study. These records should include the dates and amounts 
of study medication that were received at the site, dispensed, and destroyed or returned 
to the sponsor (or designee). The records should include dates, quantities, batch/serial 
numbers, expiration dates (if applicable), and the unique code numbers assigned to the 
study medication and study patients. If errors or damage in the study medication 
shipments occur, the investigator should contact the sponsor (or its designee) 
immediately. Copies of the study medication accountability records will be provided by 
each investigator for inclusion in the trial master file. The study monitor will 
periodically check the supplies of study medication held by the investigator or 
pharmacist to verify accountability of the study medication used. 
Investigators will maintain records that document adequately that the patients were 
provided the medication specified by the protocol and reconcile all study medication 
received from the sponsor (or designee). 
After the end of the study, all unused study medication and all medication containers 
should be destroyed at the study center or returned to the sponsor (or designee) for 
destruction. In either instance, complete documentation will be returned to the sponsor. 
The study medication resupply will be managed by the IXRS. 


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8 ADVERSE EVENTS 
8.1 
Definitions 
8.1.1 
Adverse Events 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
TEAEs are defined as AEs with an onset date on or after the first administration of study 
medication and before the date of last administration of study medication + 14 days. 
8.1.2 
Serious Adverse Events 
An SAE is any event that meets any of the following criteria: 
• Results in death. 
• Is life-threatening. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event that may not result in death, be life-threatening, or 
require hospitalization. The event will be considered an SAE when, based upon 
appropriate medical and scientific judgment, the event may jeopardize the patient 
and may require medical or surgical intervention to prevent one of the outcomes 
listed above. Examples of such events include intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse. 
Definition of Terms 
Life-threatening: an AE is life-threatening if the patient was at immediate risk of death 
from the event as it occurred, i.e., it does not include a reaction that, if it had occurred in 
a more severe form, might have caused death. For example, drug-induced hepatitis that 
resolved without evidence of hepatic failure would not be considered life-threatening 
even though drug-induced hepatitis can be fatal. It does not include an AE or suspected 
adverse reaction that, had it occurred in a more severe form, might have caused death. 
Hospitalization: AEs requiring hospitalization should be considered SAEs. 
Hospitalization for elective surgery, or for procedures planned prior to the patient 
providing informed consent, or routine clinical procedures that are not the result of an 


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AE (e.g., elective surgery for a pre-existing condition that has not worsened) need not be 
considered AEs or SAEs. If anything untoward is reported during the procedure, that 
occurrence must be reported as an AE, either 'serious' or 'nonserious' according to the 
usual criteria. 
In general, hospitalization signifies that the patient has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician's office or outpatient 
setting. When in doubt as to whether hospitalization occurred or was necessary, the AE 
should be considered serious. 
Disability/incapacity: an AE is incapacitating or disabling if the experience results in a 
substantial and/or permanent disruption of the patient’s ability to carry out normal life 
functions. 
8.1.3 
Suspected Unexpected Serious Adverse Reactions 
A suspected unexpected serious adverse reaction is defined as any AE for which there is 
a reasonable possibility that the study medication caused the AE (where ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the study 
medication and the AE), the AE is not listed in the IB or is not listed at the specificity or 
severity that has been observed, and the AE meets at least one of the criteria for 
seriousness (see Section 8.1.2). 
8.1.4 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
Laboratory abnormalities without clinical significance should not be recorded as AEs or 
SAEs. However, laboratory abnormalities (e.g., clinical chemistry, hematology, and 
urinalysis abnormalities) that require medical or surgical intervention or lead to study 
medication interruption, modification, or discontinuation must be recorded as an AE or 
SAE, as applicable. In addition, laboratory or other abnormal assessments (e.g., in 
ECGs, X-rays, or vital signs) that are associated with signs and/or symptoms must be 
recorded as an AE or SAE if they meet the definition of an AE or SAE as described in 
Sections 8.1.1 and 8.1.2. Whenever possible, the underlying cause for clinically relevant 
laboratory value (e.g., anemia) should be recorded as an AE, rather than the laboratory 
value itself (e.g., decreased hemoglobin). 
For specific information on handling of clinical laboratory abnormalities, see 
Section 6.3.2. 
8.1.5 
Adverse Events of Special Interest 
The AESIs for this study are TEAEs of: 
• Application site AEs 
• Serious infections 


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• Malignancies 
• Thrombosis 
• Cytopenias 
• Liver enzyme elevation AEs (e.g., ALT, AST, bilirubin, GGT, LDH) 
• Increased lipid parameter AEs (e.g., TC, LDL-C, HDL-C, TG) 
An AESI should be reported by the investigative site using the relevant page of the 
eCRF. The documentation and processing of AESIs is further detailed in the investigator 
site file. 
8.2 
Assessment of Adverse Events 
8.2.1 
Severity 
Severity grading for every AE is to be performed by the investigator based on his/her 
best medical judgment as follows: 
• Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
• Moderate: minimal, local, or noninvasive intervention indicated; limited 
age-appropriate instrumental activities of daily living 
• Severe: medically significant; disabling; or limiting self-care activities of daily living 
The terms serious and severe are not synonymous. The general term “severe” is often 
used to describe the intensity (severity) of a specific event; the event itself, however, 
may be of relatively minor medical significance (such as a “severe” headache). This is 
NOT the same as serious, which is usually associated with events that pose a threat to a 
patient’s life or ability to function (see Section 8.1.2). A severe AE (classified as 
“severe” or “life-threatening”) does not necessarily need to be considered serious. For 
example, a WBC count of 1000/mm3 to less than 2000/mm3 is considered severe but 
may not be considered serious. Seriousness (not intensity) serves as a guide for defining 
regulatory reporting obligations. 
8.2.2 
Causality 
Investigators are required to systematically assess the causal relationship between the 
AEs and SAEs and the exposure to the study medication using the following definitions: 
Related: 
• The AE follows a reasonable temporal sequence to study medication administration, 
and it cannot be reasonably explained by the patient’s clinical state or other factors 
(e.g., disease under study, concurrent diseases, or concomitant medications). 


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• The AE follows a reasonable temporal sequence to study medication administration, 
and it is a known reaction to the drug under study or a related chemical group or is 
predicted by known pharmacology. 
Not Related: 
• The AE does not follow a reasonable sequence from study medication 
administration, or it can be reasonably explained by the patient’s clinical state or 
other factors (e.g., disease under study, concurrent diseases, and concomitant 
medications). 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
8.3 
Documenting and Reporting Adverse Events 
Reporting of SAEs will begin when the patient has provided informed consent. 
Nonserious events that occur between receipt of informed consent and the first study 
medication application will be added to the patient’s medical history. Reporting of 
nonserious AEs will begin with the first application of study medication. Nonserious 
events that occur between receipt of informed consent and the first study medication 
application will be added to the patient’s medical history. Reporting of all AEs will 
continue through the PTFU Visit or 14 days after last administration of study 
medication, whichever is later. 
Occurrence of AEs may be volunteered spontaneously by the patient; discovered as a 
result of general, nonleading verbal questioning by the study staff; or determined by 
physical examination or other safety assessments. All AEs will be monitored and 
recorded in the eCRF throughout the entire study. 
For all AEs, the investigator must pursue and obtain adequate information (a description 
of the event, severity, time of occurrence [including whether the AE onset was before, 
during, or after the study medication application], duration, and any action, e.g., 
treatment/follow-up tests). The outcome of the event should be provided along with the 
investigator’s assessment of the relationship to the study medication. The investigator 
must also assess whether the event meets the criteria for classification as an SAE. 
It is the investigator’s responsibility to review all documentation (e.g., hospital notes, 
laboratory reports, and diagnostic reports) related to an AE. Wherever possible, the 
investigator’s diagnosis, not the individual signs and symptoms, will be documented as 
the AE. 
Investigators are not obligated to actively seek AEs or SAEs after the patient’s 
conclusion of study participation. However, if the investigator learns of any SAE, 
including death, at any time after a patient has been discharged from the study, and 


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he/she considers the event to be reasonably related to the study medication or study 
participation, the investigator must promptly notify the sponsor. 
8.4 
Reporting of Serious Adverse Events 
For SAEs with an onset inside the reporting period (i.e., onset after provision of 
informed consent and up to the PTFU Visit or 14 days after the last application of study 
medication administration (for SAEs), whichever is later) and SAEs considered related 
to study medication that occur after this reporting period (e.g., during poststudy follow-
up), the investigator must immediately (no later than 24 hours after becoming aware of 
the event) inform the ProPharma Group of the SAE utilizing the safety report form (see 
SERIOUS ADVERSE EVENT CONTACT INFORMATION). 
The investigator is obliged to respond to any request for follow-up information (e.g., 
additional information, event outcome, final evaluation, or other records where needed) 
or to any question the sponsor (or designee) may have concerning the SAE within the 
same timelines as those noted above for initial reports. This is necessary to ensure 
prompt assessment of the event by the sponsor (or designee) and, as applicable, to allow 
the sponsor to meet strict regulatory timelines associated with expedited reporting 
obligations for events of this nature. 
8.5 
Adverse Event and Serious Adverse Event Follow-up 
During the study (and after the End-of-Study Visit), all AEs and SAEs should be 
followed proactively by the investigator until the event resolves or the condition 
stabilizes to a level acceptable to the investigator, until the event is otherwise explained, 
or until the patient is lost to follow-up. At the time the patient’s study participation ends, 
all ongoing AEs and SAEs should be evaluated for resolution. New or updated 
information will be recorded in the originally completed eCRF and the investigator will 
submit any updated SAE information to the sponsor within 24 hours of receipt of the 
information. 
8.6 
Safety Reporting Oversight 
In accordance with ICH GCP and 21 CFR312.32, the sponsor (or designee) will inform 
investigators of “findings that could affect adversely the safety of patients, impact the 
conduct of the trial, or alter the IRB’s approval/favorable opinion to continue the trial.” 
The sponsor has a legal responsibility to notify the FDA about the safety of a study 
medication under clinical investigation. The sponsor will comply with US regulatory 
requirements relating to safety reporting to the regulatory authority, IRB, and 
investigators. To support compliance with these requirements, the investigator must 
provide requested information in a timely manner. 
An investigator who receives an investigator safety report describing SAEs or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will file 


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it along with the IB and will notify the IRB, if appropriate, according to local 
requirements. 


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9 STATISTICS 
9.1 
General Procedures 
All personnel involved with the analysis of the study will remain blinded until database 
lock and identification of protocol deviations. Analyses will be performed using SAS® 
(SAS Institute, Cary, NC, US) by the sponsor or its representatives. 
Details of all statistical summaries will be provided in the study-specific SAP. The SAP 
will be approved prior to any lock of the study database and unblinding of the study 
data. The SAP will provide a detailed description of the statistical methods and expand 
on the details provided in the protocol. 
Patients will be stratified at randomization according to their baseline disease severity 
(moderate versus severe). 
All data will be presented by treatment group. Descriptive statistics (number of 
observations, mean, standard deviation [SD], median, minimum, and maximum) will be 
provided for continuous variables, and counts and percentages will be presented for 
categorical variables. 
Baseline is defined as the last non-missing measurement before or on the date of first 
administration of study medication. 
9.2 
Analysis Populations 
FAS: All patients who have been administered at least one dose of study medication. 
The FAS will be used for both the efficacy and safety analyses. The efficacy analyses 
will be conducted on the FAS population as randomized, and the safety analyses and 
summaries will be conducted on the FAS as treated. 
PP Population: All patients who have non-missing Week 4 EASI scores recorded. The 
PP population will be analyzed as treated. Important protocol deviations that could 
affect the primary endpoint will be defined and agreed upon before unblinding. 
PK Population: All patients who receive at least 1 dose of study medication and provide 
at least 1 plasma concentration value. 
9.3 
Sample Size 
A total of approximately 50 patients will be enrolled in order to achieve 34 patients who 
complete the study. Data from 34 patients is estimated to provide 95.6% power to detect 
a statistically significant difference between the treatment groups in the primary 
endpoint (percent change from baseline in EASI scores). This power calculation is based 
upon a 1-sided treatment contrast within a 1-way ANOVA model and assumes group 
means of 65% and 20% for ATI-1777 and vehicle, respectively. The group means were 


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based upon slightly more conservative estimates than were observed in a Phase 2 study 
of topical ruxolitinib in AD (Kim et al 2020b). The variance for the percent change from 
baseline in EASI was assumed to be 38.3%. This variance assumption was based upon 
data observed in a pilot AD study for the topical compound ATI-502 
(ATI-502-AD-201). 
9.4 
Statistical Methods 
9.4.1 
Primary Endpoint 
The primary endpoint is the percent change from baseline in EASI score at Week 4. 
9.4.2 
Secondary Endpoints 
The secondary endpoints are: 
• Percent change from baseline in EASI score at each study visit 
• Proportion of patients achieving an IGA score of 0 to 1 combined with an 
improvement of 2 or more points from baseline within 4 weeks of the start of 
treatment 
• Proportions of patients who achieve EASI-50, EASI-75, and EASI-90 within 4 
weeks of the start of treatment 
• Change from baseline in IGA score at each study visit 
• Change from baseline in BSA at each study visit 
• Change from baseline in PP-NRS score over time 
9.4.3 
Pharmacokinetic Endpoint 
The PK endpoint is the concentration of ATI-1777 in plasma samples obtained using a 
sparse sampling approach. 
9.4.4 
Safety Endpoints 
The safety endpoints are: 
• Incidence of TEAEs and SAEs 
• Laboratory values 
• Vital signs 
• Physical examination results 
• 12-lead ECG results 
9.4.5 
Analysis of Efficacy 
All efficacy summaries will be conducted on both the FAS and PP populations. All 
p-values for efficacy will be based on a 1-sided hypothesis test of the superiority of 
ATI-1777 to vehicle. 


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The primary efficacy analysis will be the treatment comparison between ATI-1777 and 
vehicle for the percent change from baseline in EASI scores at Week 4 based on the 
FAS. This treatment comparison will be made within the context of a Mixed Model 
Repeated Measures analysis where the EASI scores over time are treated as repeated 
measures within a given patient. Treatment group, time (study visit), and treatment by 
time interaction will enter the model as categorical factors, baseline EASI score and/or 
baseline severity of AD will be included as a continuous covariate and patient ID will 
enter the model as a random effect. Treatment group model-based means and model-
based differences in treatment groups will be provided along with corresponding 90% 
confidence intervals and 1-sided p-values.  
Treatment comparisons between ATI-1777 and vehicle for each of the continuous 
efficacy endpoints that are conducted over time (change in IGA, BSA, and PP-NRS) 
will be analyzed using a similar model as described for the primary endpoint. Treatment 
comparisons will be made for each post-baseline scheduled visit utilizing an appropriate 
analysis window scheme.  
Treatment group comparisons for categorical efficacy endpoints (IGA Response, 
EASI-50, EASI-75, and EASI-90) that are conducted over time will employ a logistic 
regression model fit at each scheduled visit separately, where appropriate. The logistic 
regression model will include treatment group as a factor and the baseline value and/or 
baseline severity of AD as a covariate. Model-based point estimates for the treatment 
proportions will be provided as well as model-based differences and corresponding 90% 
confidence intervals and 1-sided p-values. 
9.4.6 
Analysis of Safety 
The FAS will be used for the analysis of safety data (AEs, clinical laboratory, vital 
signs, physical examination results, and ECGs). 
AEs will be coded with MedDRA. TEAEs are defined as AEs with onset dates on or 
after the date of first administration of study medication through the end of the study, or 
that exist prior to the first dose and worsen with dosing. TEAEs will be presented by 
system organ class and preferred term in frequency tables. Patients with multiple AEs 
will be counted only once within each preferred term and system organ class. Key 
patient information for patients with an AE with an outcome of death, patients with 
SAEs, and patients with an AE leading to discontinuation of study medication will be 
listed. 
Laboratory data (hematology, serum chemistry, and urinalysis) will be converted to 
Système International units for reporting and processing purposes. Absolute values and 
changes from baseline will be presented descriptively. Laboratory data outside 
study-specific reference ranges will be listed. 
Vital signs and ECG parameters will be presented descriptively. 


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9.4.7 
Demographic and Baseline Characteristics 
Demographic characteristics (including age, sex, ethnicity, and race) and baseline 
characteristics (including height, weight, and disease characteristics) will be presented 
descriptively. 
9.4.8 
Pharmacokinetic Endpoints 
Individual and mean plasma concentrations at each sampling time point for ATI-1777 
will be listed and summarized in a tabular form including means, geometric means, 
ranges, standard deviations, and coefficients of variation. Mean concentrations will be 
plotted versus nominal time on linear and semilogarithmic scales. 
9.4.9 
Handling of Missing Values 
Patients who discontinue study medication will be asked to come to each visit for the 
scheduled assessments up to the end of the study. 
For the primary efficacy analysis and all continuous analyses based on the FAS 
population, missing data will be imputed using last observation carried forward (LOCF). 
Missing data will not be imputed for continuous efficacy analyses that are based on the 
PP population. For responder-type categorical endpoints (such as EASI-50, EASI-75, 
and EASI-90), missing data will be treated as a non-response. Specific details regarding 
the imputation of missing data and intercurrent events will be described further in the 
SAP. 
Patients who prematurely discontinue the study will be evaluated based on the data 
collected at each visit attended. Data collected during the ET Visit will be used as an 
end-of-study assessment for these patients. If the ET Visit was performed >1 day after 
the last dose was administered, then the previous visit will be used as the end-of-study 
assessment. 


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10 ETHICS AND RESPONSIBILITIES 
10.1 
Good Clinical Practice 
This study will be conducted in accordance with the Note for Guidance on GCP ICH 
Harmonised Tripartite Guideline E6 (R1)/Integrated Addendum E6 (R2); US FDA Code 
of Federal Regulations (CFR; Title 21 Parts 50, 56, 312), the general guidelines 
indicated in the Declaration of Helsinki; and all applicable regulatory requirements. 
10.2 
Institutional Review Board/Independent Ethics Committee 
Before initiating a study, the investigator/institution must have written and dated 
approval/favorable opinion from the IRBs for the study protocol/amendment(s), written 
ICF, any ICF updates, patient recruitment procedures (e.g., advertisements), and any 
written information to be provided to patients and a statement from the IRBs that these 
comply with GCP requirements (if applicable). A current copy of the IB should be 
included as part of the written application to the IRB. 
The IRB approval(s) must identify the protocol version as well as the documents 
reviewed. Any amendments to the protocol will require IRB approval before the 
implementation of the changes made to the study, except for changes necessary to 
eliminate an immediate hazard to the study patients. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB 
• Notifying the IRB of SAEs or other significant safety findings, including adverse 
drug reactions that are both serious and unexpected, as required by IRB procedures 
• Providing oversight of the conduct of the study at the site and adherence to the 
requirements of all applicable regulations 
• Promptly reporting deviations from, or changes to, the protocol to eliminate 
immediate hazards to the study patients 
10.3 
Informed Consent 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s) and should adhere to GCP and to the ethical 
principles that have their origin in the Declaration of Helsinki. Prior to the beginning of 
the study, the investigator should have the IRB's written approval/favorable opinion of 
the written ICF and any other written information to be provided to patients. 
• The investigator or his/her representative will explain the purpose and nature of the 
study as well as possible adverse effects to the patient or his/her legally acceptable 
representative and answer all questions regarding the study. 


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• Patients must be informed that their participation is voluntary, and consent can be 
withdrawn at any point. 
• Patients or their legally acceptable representative will be required to sign a statement 
of informed consent that meets the requirements of US FDA CFR Title 21 Part 50, 
local regulations, ICH guidelines, Health Insurance Portability and Accountability 
Act requirements, and the IRB or study site. 
• Prior to a patient’s participation in the study, the written ICF should be signed and 
personally dated by the patient or by the patient's legally acceptable representative, 
and by the person who conducted the informed consent discussion. 
• The medical record must include a statement that written informed consent was 
obtained before the patient was enrolled in the study and the date the written consent 
was obtained. 
• The original copy of the signed ICF will be retained at the study site. 
• A copy of the ICF and any other written information must be provided to the patient 
or the patient’s legally acceptable representative. 
• If the ICF is revised, the revised ICF must have received the IRB's 
approval/favorable opinion in advance of its use. Patients must be informed of the 
changes to the ICF and must re-consent to the most current version during their 
participation in the study. The patient or the patient’s legally acceptable 
representative should be informed in a timely manner if new information becomes 
available that may be relevant to the patient’s willingness to continue participation in 
the study. The communication of this information should be documented. 
Patients who are rescreened are required to sign a new ICF. 
If a patient is unable to read or if a legally acceptable representative is unable to read, an 
impartial witness should be present during the entire informed consent discussion. The 
witness should sign and personally date the ICF after: 
• The written ICF and any other written information to be provided to patients is read 
and explained to the patient or the patient’s legally acceptable representative 
• The patient or the patient’s legally acceptable representative has orally consented to 
the patient’s participation in the study 
• The patient or the patient’s legally acceptable representative has signed and 
personally dated the ICF, if they are capable of doing so 
By signing the ICF, the witness attests that the information in the ICF and any other 
written information was accurately explained to, and apparently understood by, the 
patient or the patient's legally acceptable representative, and that informed consent was 
freely given by the patient or the patient’s legally acceptable representative. 


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10.4 
Financing and Insurance 
10.4.1 
Contractual and Financial Details 
The investigator (and/or, as appropriate, the hospital administrative representative) and 
the sponsor will sign a clinical study agreement prior to the start of the study, outlining 
overall sponsor and investigator responsibilities in relation to the study. The contract 
should describe whether costs for pharmacy, laboratory, and other protocol-required 
services are being paid directly or indirectly. 
10.4.2 
Insurance, Indemnity, and Compensation 
Aclaris Therapeutics, Inc. will maintain an appropriate clinical study insurance policy. 
10.4.3 
Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 


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11 RECORDS MANAGEMENT 
All clinical study information should be recorded, handled, and stored in a way that 
allows its accurate reporting, interpretation, and verification. This principle applies to all 
records referenced in this protocol, irrespective of the type of media used. 
An eCRF will be used to store and transmit patient information. The eCRF must be 
reviewed and electronically signed and dated by the investigator. The investigator is 
responsible for verifying that the data entries are accurate and correct by signing the 
eCRF. 
Access to the eCRF will be strictly password protected and limited to personnel directly 
participating in the study. Data should be entered into the eCRF completely by 
authorized site personnel (e.g., investigators and the study coordinator). The eCRF must 
be completed as soon as possible after any patient evaluation or communication. If data 
are to be changed due to erroneous input or other reason, an electronic audit trail will 
track these changes. The eCRFs and computers that store them must be accessible to 
study monitors and other regulatory auditors. 
During each study visit, a physician participating in the study will maintain progress 
notes in the patient’s medical records to document all significant observations. At a 
minimum, these notes are to contain: 
• The date of the visit and the corresponding day or visit in the study schedule 
• General condition and status remarks by the patient, including any significant 
medical findings. The severity, frequency, duration, and resolution of any reported 
AE, and the investigator's assessment as to whether or not the reported AE is related 
to study medication 
• Changes (including dosages) in concomitant medications/therapies (including 
medical foods) or procedures 
• A general reference to the procedures completed 
• The signature or initials of all physicians making an entry in the medical record 
(progress notes) 
In addition, any contact with the patient via telephone or other means that provides 
significant clinical information is to also be documented in the medical record (progress 
notes), as described above. 
Information from the medical records (progress notes) and other source documents is to 
be promptly entered into the appropriate section of the eCRF. 
Changes to information in the medical record (progress notes) and other source 
documents are to be initialed and dated on the day the change is made by the 
investigator (or designee). If the reason for the change is not apparent, a brief 


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explanation for the change is to be written adjacent to the change. Changes to the eCRF 
will be electronically tracked. 
The PRA data management department will write a data management plan, which will 
be finalized prior to performing any data validation. 
11.1 
Source Documentation 
Source documents contain the results of original observations and activities of a clinical 
investigation. They are the original records in which raw data are first recorded. Source 
documents include, but are not limited to, medical records (progress notes), ECG and 
computer printouts, screening logs, completed scales, quality of life questionnaires, and 
recorded data from automated instruments. 
The investigator/site personnel should maintain adequate and accurate source documents 
and study records that include all pertinent observations on each of the site’s study 
patients. Source data should be attributable, legible, contemporaneous, original, 
accurate, and complete. Changes to source data should be traceable, should not obscure 
the original entry, and should be explained if necessary (e.g., via an audit trail). 
All source documents from this study are to be maintained by the investigator and made 
available for inspection by authorized personnel. The investigator will provide direct 
access to source documents/data for study-related monitoring, audits, IRB review, and 
regulatory inspections. The sponsor should verify that each patient has consented, in 
writing, to direct access to his/her original medical records for study-related monitoring, 
audit, IRB review, and regulatory inspection. 
11.2 
Case Report Form Completion and Data Management 
An eCRF will be used to store and transmit patient information. The file structure and 
format for the eCRF will be provided by the sponsor or its representative and should be 
handled in accordance with the instructions provided. 
The eCRF must be reviewed and electronically signed and dated by the investigator. 
Access to the eCRF will be strictly password protected and limited to personnel directly 
participating in the study. Data should be entered into the eCRF completely by 
authorized site personnel (e.g., investigators and the study coordinator). The eCRF must 
be completed as soon as possible after any patient evaluation or communication. If data 
are to be changed due to erroneous input or other reason, an electronic audit trail will 
track the changes. The eCRFs and computers that store them must be accessible to study 
monitors and other regulatory auditors. Changes to the eCRF will be electronically 
tracked. 


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Data will be entered/loaded into a validated electronic database using a clinical data 
management system. Computerized data cleaning checks will be used in addition to 
manual review to check for discrepancies and to ensure consistency of the data. 
11.3 
Study Files and Record Retention 
All data derived from the study will remain the property of the sponsor. The sponsor 
assumes accountability for actions delegated to other individuals, e.g., the CRO. 
Records must be retained in accordance with the current ICH guidelines on GCP. All 
essential study documents, including records of patients, source documents, eCRFs, and 
the study medication inventory, must be kept on file. 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region, or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of ATI-1777. However, essential 
documents may be retained for a longer period if required by the applicable regulatory 
requirements or by agreement with the sponsor. The sponsor is responsible for 
informing the investigator when these documents need no longer be retained. 
The investigator is not to dispose of any records relevant to this study without written 
permission from the sponsor and is to provide the sponsor the opportunity to collect such 
records. The investigator shall take responsibility for maintaining adequate and accurate 
hard copy source documents of all observations and data generated during this study. 
Such documentation is patient to inspection by the sponsor, its representatives, and 
regulatory authorities. 
If an investigator moves, withdraws from a study, or retires, the responsibility for 
maintaining the records may be transferred to another person who will accept 
responsibility. Notice of transfer must be made to and agreed by the sponsor. 


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12 AUDITING AND MONITORING 
Sponsor-assigned monitors will conduct regular site visits to the investigational facilities 
for the purpose of monitoring various aspects of the study, such as assessing patient 
enrollment, compliance with protocol procedures, completeness and accuracy of data 
entered into the eCRFs, verification of eCRF data against original source documents, 
and occurrence of AEs. The investigator must agree to sponsor-authorized personnel 
having direct access to the clinical (or associated) files and clinical study supplies 
(dispensing and storage areas) to ensure compliance with applicable regulations, and the 
investigator will assist with the sponsor’s monitoring activities. 
Quality control will occur at each stage of data handling to ensure that all data are 
reliable and have been processed correctly. The sponsor should ensure oversight of any 
study-related duties and functions carried out on its behalf, including study-related 
duties and functions that are subcontracted to another party by the sponsor’s contracted 
CRO(s). 
The eCRFs should be completed in a timely manner and on an ongoing basis to allow 
regular review by the study monitor. 
Details describing the strategy, responsibilities, and requirements of the study 
monitoring are provided in the Study Monitoring Plan. 
The purpose of an audit is to assess whether ethics, regulatory, and quality requirements 
are being fulfilled. The sponsor or its representative may conduct audits at the 
investigative sites including, but not limited to, drug supply, presence of required 
documents, the informed consent process, and comparison of eCRFs with source 
documents. Government regulatory authorities may also inspect the investigator during 
or after the study. The investigator (or designee) should contact the sponsor/CRO 
immediately if this occurs. All medical records (progress notes) must be available for 
audit. The investigator must agree to participate with audits conducted at a convenient 
time in a reasonable manner. 
12.1 
Risk and Quality Tolerance Limits 
The sponsor will review risk control measures outlined in the study-specific monitoring 
plan periodically to ascertain whether the implemented clinical quality management 
activities remain effective and relevant. The clinical quality management approach and 
any important deviations from the predefined quality tolerance limits and remedial 
actions adopted will be described in the clinical study report (CSR). 
12.2 
Protocol Adherence and Deviations 
The investigator and site personnel should conduct the study in compliance with the 
protocol and should use continuous vigilance to identify and report protocol deviations. 


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A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol that may be on the part of the investigator, site 
personnel, or the patient. 
Important protocol deviations are a subset of protocol deviations that may significantly 
impact the completeness, accuracy, and/or reliability of the study data or that may 
significantly affect a patient's rights, safety, or well-being. For example, important 
protocol deviations may include enrolling patients in violation of key eligibility criteria 
designed to ensure a specific patient population or failing to collect data necessary to 
interpret primary endpoints, as this may compromise the scientific value of the study. 
The investigator should not implement any deviation from the protocol without 
agreement from the sponsor and prior review and approval from the IRB of an 
amendment, except where necessary to eliminate an immediate hazard to a study patient, 
or when the change involves only logistical or administrative aspects of the study, such 
as a change in a monitor or telephone number. 
In the event of an important protocol deviation, the investigator will discuss the 
deviation with the sponsor’s medical monitor and will come to an agreement as to 
whether the patient should be withdrawn from the study due to the important protocol 
deviation. 


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13 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study patients, 
may be made only by the sponsor. A protocol change intended to eliminate an apparent 
immediate hazard to patients should be implemented immediately. 
Any permanent change to the protocol must be handled as a protocol amendment. The 
written amendment must be submitted to the IRB, and the investigator must await 
approval before implementing the changes. The sponsor will submit protocol 
amendments to the appropriate regulatory authorities for approval. 
The current version of the ICF will require similar modification if the IRB, investigator, 
and/or sponsor, judge the amendment to the protocol to substantially change the study 
design and/or increase the potential risk to the patient and/or impact the patient's 
involvement as a study patient. In such cases, the ICF will be renewed for enrolled 
patients before their continued participation in the study. 


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14 STUDY REPORT AND PUBLICATIONS 
This study will be registered on ClinicalTrials.gov in accordance with applicable laws or 
publication policy and may also be registered on other publicly accessible websites, as 
necessary. 
The sponsor is responsible for preparing and providing the appropriate regulatory 
authorities with the CSR according to the applicable regulatory requirements. The 
sponsor should ensure that the CSR meets the standards of the ICH Guideline for 
Structure and Content of CSR (ICH E3). 
The publication policy of the sponsor is discussed in the investigator's clinical research 
agreement. 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. 
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual site 
data. In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 


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15 STUDY START AND TERMINATION 
The study start date is the date on which the first patient provides informed consent. 
The end of the study is defined as the last patient’s last assessment. 
This study may be terminated prematurely in whole or in part due to a change in the 
benefit/risk profile for ATI-1777 such that continuation of the study would not be 
justified on medical or ethical grounds. This determination may be made by the study 
investigators in conjunction with the sponsor, or by the IRB or the US FDA. The 
sponsor may also elect to terminate the study if enrollment is sufficiently slow to prevent 
the completion of the study in an acceptable timeframe, or if ATI-1777 development is 
discontinued. Both the sponsor and the investigator reserve the right to terminate the 
study or the participation in the study at an investigator’s site at any time. In terminating 
the study, the sponsor and the investigator will assure that adequate consideration is 
given to the protection of the patients’ interests. 
If the study is prematurely terminated or suspended for any reason, the 
sponsor/investigator/site personnel should promptly inform the study patients and should 
assure appropriate therapy and follow-up for the patients. Where required by the 
applicable regulatory requirements, the IRB should be informed promptly and be 
provided with a detailed written explanation of the termination or suspension. 
If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the site personnel. The investigator/site 
personnel should promptly inform the sponsor and the IRB. The investigator/site 
personnel should also provide the sponsor and the IRB a detailed written explanation of 
the termination or suspension. 


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16 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written 
consent is gained from the sponsor. However, authorized regulatory officials, IRB 
personnel, and the sponsor and its authorized representatives are allowed full access to 
the records. 
All study patients must be informed that their personal study-related data will be used by 
the sponsor in accordance with local data protection law. The patients must be informed 
that their medical records may be examined by auditors or other authorized personnel 
appointed by the sponsor, by appropriate IRB members, and by inspectors from 
regulatory authorities. 
Identification of patients and eCRFs shall be by unique patient identification numbers 
(such as randomization number) only. All personal identifiers according to applicable 
regulations (e.g., name, telephone number) must be redacted permanently by the site 
personnel and replaced with the patient’s unique identification number in all records and 
data before transfer to the sponsor (or designee). 
All personal details will be treated as confidential by the investigator and staff at PRA. 


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symposium. 05 April 2020. https://investor.incyte.com/news-releases/news-release-
details/incyte-announces-positive-topline-results-phase-3-true-ad 


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
Protocol Version and Date: Version 4, 28-Jan-2021 
Page 85 of 93
 
 
Confidential 
 
James LP, Letzig L, Simpson PM, et al. 2009. Pharmacokinetics of acetaminophen-
adduct in adults with acetaminophen overdose and acute liver failure. Drug Metab 
Dispos. 2019; 37:1779-84. 
Kapur S, Watson W, Carr S. Atopic dermatitis. Allergy Asthma Clin Immunol 2018; 14 
(Suppl 2):52. https://doi.org/10.1186/s13223-018-0281-6. 
Kim BS, Howel MD, Sun K, Papp K, Nasir A, Kuligowski ME. Treatment of atopic 
dermatitis with ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream. J 
Allergy Clin Immunol. 2020a; 145:572-82. 
Kim BS, Sun K, Papp K, et al. Effects of ruxolitinib cream on pruritus and quality of life 
in atopic dermatitis: Results from a phase 2, randomized, dose-ranging, vehicle-and 
active-controlled study. J Am Acad Dermatol. 2020b Feb 11. pii; S0190-
9622(20)30213-9. doi: 10.1016/j.jaad.2020.02.009. [Epub ahead of print] 
Levy LL, Urban J, King BA. Treatment of recalcitrant atopic dermatitis with the oral 
Janus kinase inhibitor tofacitinib citrate. J Am Acad Dermatol. 2015; 73(3):395-9. 
Montillo AM, Gómez-García F, Gómez-Arias PJ, et al. Scoping review on the use of 
drugs targeting JAK/ STAT pathway in atopic dermatitis, vitiligo, and alopecia areata. 
Dermatol Ther (Heidelb). 2019; 9:655–83. 
Napolitano M, Fabbrocini G, Cinelli E, et al. Profile of baricitinib and its potential in the 
treatment of moderate to severe atopic dermatitis: A short review on the emerging 
clinical evidence. J Asthma Allergy. 2020; 13 89–94. 
Rajka G, Langeland T. Grading of the severity of atopic dermatitis. J Am Acad 
Dermatol. 2020; S0190-9622(20); 30213-9. 
Rodriques MA, Torres T. JAK/STAT inhibitors for treatment of atopic dermatitis. J 
Dermatolog Treat. 2020:31(1); 33-40. 
Rullo VEV, Segato A, Kirsh A, Sole D. Severity scoring of atopic dermatitis: a 
comparison of two scoring systems. Allergol Immunopathol. 2008; 36(4):201-11. 
Solimani F, Meier K, Ghoreschi K. Emerging topical and systemic JAK inhibitors in 
dermatology. Front. Immunol. 10:2847. doi: 10.3389/fimmu.2019.0284.7. 
Souta EB, Dias-Ferreira J, Oliveira J, et al. Trends in atopic dermatitis—From standard 
pharmacotherapy to novel drug delivery systems. Int J Mol Sci. 2019; 20, 5659; 
doi:10.3390/ijms20225659. 
Tanei R. Atopic dermatitis in older adults: A review of treatment options. Drugs & 
Aging. 2020; 37:149–60. 


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
Protocol Version and Date: Version 4, 28-Jan-2021 
Page 86 of 93
 
 
Confidential 
 
Yosipovitch G, Reaney M, Mastey V, et al. Peak pruritus numerical rating scale: 
psychometric validation and responder definition for assessing itch in 
moderate-to-severe atopic dermatitis. Br J Dermatol. 2019; 181(4):761-769. 


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
Protocol Version and Date: Version 4, 28-Jan-2021 
Page 87 of 93
 
 
Confidential 
 
18 APPENDICES 
APPENDIX 1 – STUDY ADMINISTRATIVE STRUCTURE 
Sponsor: 
Aclaris Therapeutics, Inc. 
640 Lee Road 
Suite 200 
Wayne, Pennsylvania 19087 
USA 
Phone: 
 
Sponsor’s medical 
expert: 
 
Aclaris Therapeutics, Inc. 
640 Lee Road 
Suite 200 
Wayne, Pennsylvania 19087 
USA 
Phone: 
 
Sponsor’s project 
manager: 
 
Aclaris Therapeutics, Inc. 
640 Lee Road 
Suite 200 
Wayne, Pennsylvania 19087 
USA 
Phone: 
 
Contract research 
organization’s project 
manager: 
 
PRA Health Sciences, Inc. 
4130 Park Lake Avenue 
Suite 400 
Raleigh, North Carolina 27612 
USA 
Phone: 
 
Medical monitor: 
 
Aclaris Therapeutics, Inc. 
640 Lee Road 
Suite 200 
Wayne, Pennsylvania 19087 
USA 
Phone: 
 
 
Pharmacovigilance: 
ProPharma Group 
2635 University Avenue West, Suite 195 
St Paul, MN 55114 
USA 
FAX: 
  
Email: 
 


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
Protocol Version and Date: Version 4, 28-Jan-2021 
Page 88 of 93
 
 
Confidential 
 
CRO: 
PRA Health Sciences, Inc. 
4130 Park Lake Avenue 
Suite 400 
Raleigh, North Carolina 27612 
USA 
Phone: 
 
Central laboratory: 
ACM Global Laboratories 
160 Elmgrove Park 
Rochester, New York 14624 
USA 
Phone: 
 
ATI-1777 manufacturer: 
Drug Substance: 
GVK Biosciences Pvt. Ltd 
Plot No. 28 A 
IDA Nacharam 
Hyderabad – 500076, India 
 
Drug Product: 
Tergus Pharma 
2810 Meridian Parkway 
Suite 120 
Durham, NC 27713  
USA 
ATI-1777 distributor: 
Xerimis, Inc. 
102 Executive Drive 
Moorestown, NJ 08057 
USA 
A log of the name and title of the investigators who are responsible for conducting the 
study, and the address and telephone numbers of the study sites will be maintained. 
The names and addresses of any other laboratories involved in the study (further to those 
stated above) will be provided in the Laboratory Manual. 


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
Protocol Version and Date: Version 4, 28-Jan-2021 
Page 89 of 93
 
 
Confidential 
 
APPENDIX 2 - PATIENT INSTRUCTIONS 
Preparation and General Instructions:  
1. Reminder to: 
a) Refrain from bathing, swimming and/or participating in strenuous exercise that 
would cause profuse sweating for 6 hours after application of study medication. 
b) Refrain from applying moisturizers, emollients, and sunscreen to AD treatment 
areas for the duration of protocol therapy. Moisturizers, emollients, and 
sunscreens may be applied to non-AD treatment areas. 
c) Refrain from excessive sun exposure (e.g., sunbathing and/or tanning salon 
visits) and minimize sun exposure (e.g., wear sun protective clothing, hat) as 
much as possible. 
2. Gather a clean washcloth and towel, the study medication bottle, and dropper.  
3. Skin should be clean and dry before applying study medication.  
4. Wash your hands with soap and water before and after using this study medication.  
5. Record your ‘worst’ itch over the previous 24 hours on your diary in the morning 
before applying study medication. 
6. Apply a thin layer of study medication to the identified AD target skin area as 
instructed by the study doctor or the study staff. Keep applying study medication to 
the area throughout the study, even if the skin begins to clear. If new areas of AD 
appear, study medication may be applied to these areas.  
7. Avoid study medication contact with the eye.  
8. You will apply study medication twice a day, approximately 8 to 12 hours apart.  
9. Document on your diary whether you completed the morning and/or evening dose 
and total amount of drug (mL) applied at each application timepoint. 
10. Remember to bring your study medication bottles both used and unused to each 
study visit along with your diary.  
Study Medication Application:  
1. Draw up exactly 1 mL of study medication into the dropper. The medication level 
should be at the 1-mL line.  
2. During study medication application, avoid any study medication running into your 
eyes.  
3. Squeeze a few drops of study medication onto the center of the identified target AD 
area and gently rub the study medication into your skin. Keep applying a few drops 
and rubbing into your skin until the entire area is covered with a thin film of study 
medication.  
4. Draw up additional medication 1 mL at a time to cover the entire AD area. No more 
than a total of 8 mL should be used to treat all affected areas. Less than 8 mL may be 
used if a lower amount is sufficient to cover all affected skin areas. 
5. Place the dropper back on the bottle and make sure it is closed tightly.  
6. Document the total amount of mL used at each application timepoint on your diary. 
7. It is important to continue to apply study medication to the target AD areas 
throughout the study, even if the skin begins to clear.  


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
Protocol Version and Date: Version 4, 28-Jan-2021 
Page 90 of 93
 
 
Confidential 
 
8. Wash your hands after using this product to prevent any residue being left on your 
hands.  
9. If you missed a dose or doses, record the missed dose or doses in your diary and tell 
the study staff at your next visit. 
Missed Doses: If you miss a dose of this study medicine, apply it as soon as possible. 
However, if it is almost time for your next dose, skip the missed dose, and go back to 
your regular dosing schedule.  
Storage: Store the medicine in the original glass bottle in the carton provided at room 
temperature, away from heat, moisture, and direct light. Keep from freezing. Keep out of 
the reach of children. 


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
Protocol Version and Date: Version 4, 28-Jan-2021 
Page 91 of 93
 
 
Confidential 
 
APPENDIX 3 - HANIFIN AND RAJKA DIAGNOSTIC CRITERIA 
FOR ATOPIC DERMATITIS (HANIFIN AND RAJKA 
1980) 
Major criteria: Must have 3 or more of the following:  
1. Pruritus  
2. Typical morphology and distribution  
• Flexural lichenification or linearity in adults  
• Facial and extensor involvement in infants and children  
3. Chronic or chronically relapsing dermatitis  
4. Personal or family history of atopy (asthma, allergic rhinitis, AD)  
Minor criteria: Should have 3 or more of:  
1. Xerosis  
2. Ichthyosis, palmar hyperlinearity, or keratosis pilaris  
3. Immediate (Type 1) skin-test reactivity  
4. Raised serum IgE  
5. Early age of onset  
6. Tendency toward cutaneous infections (especially S aureus and herpes simplex) or 
impaired cell-mediated immunity  
7. Tendency toward non-specific hand or foot dermatitis  
8. Nipple eczema  
9. Cheilitis  
10. Recurrent conjunctivitis  
11. Dennie-Morgan infraorbital fold  
12. Keratoconus  
13. Anterior subcapsular cataracts  
14. Orbital darkening  
15. Facial pallor or facial erythema  
16. Pityriasis alba  
17. Anterior neck folds  
18. Itch when sweating  
19. Intolerance to wool and lipid solvents  
20. Perifollicular accentuation  
21. Food intolerance  
22. Course influenced by environmental or emotional factors  
23. White dermographism or delayed blanch  


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
Protocol Version and Date: Version 4, 28-Jan-2021 
Page 92 of 93
 
 
Confidential 
 
APPENDIX 4 - POSSIBLE HY’S LAW LIVER CHEMISTRY 
ACTION AND FOLLOW-UP ASSESSMENTS 
 
Suggested Actions and Follow-up Assessments1  
Actions 
Follow-up Assessments 
• 
Immediately discontinue study medication. 
• 
Report the event to the sponsor or designee 
within 24 hours. 
• 
Complete an SAE data collection tool if the 
event also met the criteria for an SAE.2 
• 
Perform liver chemistry follow-up 
assessments. 
• 
Monitor the participant until liver chemistry 
test abnormalities resolve, stabilize, or return 
to baseline (see MONITORING below). 
• 
Do not restart/rechallenge participant with 
study treatment unless allowed per the 
protocol and sponsor approval is granted. 
• 
If restart/rechallenge is either not allowed per 
the protocol or not granted, permanently 
discontinue study treatment. The participant 
may continue in the study for any protocol-
specified follow-up assessments. 
 
MONITORING:  
If ALT ≥3×ULN AND bilirubin ≥2×ULN or 
INR >1.5:  
• 
Repeat liver chemistry tests (ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow-up assessments within 24 
hours. 
• 
Monitor participant twice weekly until liver 
chemistry test abnormalities resolve, stabilize, 
or return to baseline. 
• 
A specialist or hepatology consultation is 
recommended. 
 
If ALT ≥3×ULN AND bilirubin <2×ULN and 
INR ≤1.5:  
• 
Repeat liver chemistry tests (include ALT, 
AST, alkaline phosphatase, bilirubin) and 
perform liver chemistry follow-up 
assessments within 24 to 72 hours.  
• 
Monitor participants weekly until liver 
chemistry abnormalities resolve, stabilize, or 
return to baseline. 
• 
Viral hepatitis serology3 
• 
Obtain INR and recheck with each liver 
chemistry assessment until the transaminases 
values show downward trend  
• 
Obtain blood sample for ATI-1777 drug 
concentration4 
• 
Serum CPK and lactate dehydrogenase 
• 
Fractionate bilirubin, if total bilirubin 
≥2×ULN 
• 
Obtain complete blood count with 
differential to assess eosinophilia 
• 
Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE eCRF 
• 
Record use of concomitant medications 
(including acetaminophen, herbal remedies, 
and other over-the-counter medications) on 
the concomitant medications eCRF 
 
If ALT ≥3×ULN AND bilirubin ≥2×ULN or 
INR >1.5:  
• 
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative total 
immunoglobulin G or gamma globulins. 
• 
Serum acetaminophen adduct high 
performance liquid chromatography assay 
(quantifies potential acetaminophen 
contribution to liver injury in participants 
with definite or likely acetaminophen use in 
the preceding week [James et al 2019]). 


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-1777-AD-201 
Protocol Version and Date: Version 4, 28-Jan-2021 
Page 93 of 93
 
 
Confidential 
 
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine 
phosphokinase; eCRF = electronic case report form; INR = international normalized ratio; SAE = serious 
adverse event; ULN = upper limit of normal 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin 
fractionation is not immediately available, discontinue study treatment if ALT ≥3×ULN and bilirubin 
≥2×ULN. Additionally, if serum bilirubin fractionation testing is unavailable, record the 
absence/presence of detectable urinary bilirubin on dipstick which is indicative of direct bilirubin 
elevations suggesting liver injury. 
2. All events of ALT ≥3×ULN and bilirubin ≥2×ULN (>35% direct bilirubin) or ALT ≥3×ULN and 
INR >1.5 may indicate severe liver injury (possible ‘Hy’s Law’) and must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis). The INR measurement is not required and 
the stated threshold value will not apply to participants receiving anticoagulants. 
3. Hepatitis A immunoglobulin M antibody; hepatitis B surface antigen and hepatitis B core antibody; 
hepatitis C ribonucleic acid; cytomegalovirus immunoglobulin M antibody; Epstein-Barr viral capsid 
antigen immunoglobulin M antibody (or, if unavailable, heterophile antibody or monospot testing); 
and hepatitis E immunoglobulin M antibody. 
4. Drug concentration sample may not be required for participants known to be receiving placebo or 
non-comparator treatments. Record the date/time of the blood sample draw and the date/time of the 
last dose of study treatment prior to the blood sample draw in the eCRF. If the date or time of the last 
dose is unclear, provide the participant’s best approximation. If the date/time of the last dose cannot 
be approximated, do not obtain a blood sample. Instructions for sample handling and shipping are in 
the reference manual. 
 

SAP_001.pdf: 
,,..., 
1 aclaris .. 
THfRAPEUTICS 
Statistical Analysis Plan (SAP) 
Version Date: 06NOV2020 
Sponsor: Aclaris Therapeutics 
Protocol no: ATl-1777-AD-201 
Statistical Analysis Plan (SAP) 
Protocol Title: 
Protocol Version No./Date: 
CRF Version No./Date: 
SAP Version No./Date: 
1.
Approvals
Sponsor 
Sponsor Name: 
Representative/ Title: 
Signature /Date: 
PRA 
Biostatistician / Title: 
Signature /Date: 
A Phase 2a, Multicenter, Randomized, Double-blind, Vehicle­
controlled, Parallel-group Study to Determine the Safety, 
Tolerability, Pharmacokinetics and Efficacy of A TI-1777 in Adult 
Patients with Moderate or Severe A topic Dermatitis 
V2.0/1 0SEPT2020 
VI .1/27OCT2020 
Vl .0/06NOV2020 
Aclaris Therapeutics 
(NOTE: Electronic Signatures should only be used if all parties have the ability to eSign.)
PRA-OMS-02745 9.0
Strictly Confidential. © 2020. PRA Health S . 
ciences. All nghts reseNed.
Page 1 of 30 
NCT #: NCT04598269


Statistical Analysis Plan (SAP) 
Version Date: 06NOV2020  
 
Sponsor: Aclaris Therapeutics 
 
Protocol no: ATI-1777-AD-201 
PRA-QMS-02745 9.0 
Page 2 of 30 
Strictly Confidential.  © 2020, PRA Health Sciences.  All rights reserved. 
2. 
Change History 
Version/Date 
Change Log 
1.0 
Created as new 
 
 
 
 
 


Statistical Analysis Plan (SAP) 
Version Date: 06NOV2020  
 
Sponsor: Aclaris Therapeutics 
 
Protocol no: ATI-1777-AD-201 
PRA-QMS-02745 9.0 
Page 3 of 30 
Strictly Confidential.  © 2020, PRA Health Sciences.  All rights reserved. 
3. 
Table of Contents 
1. 
Approvals ................................................................................................................................................ 1 
2. 
Change History ........................................................................................................................................ 2 
3. 
Table of Contents ..................................................................................................................................... 3 
4. 
Purpose .................................................................................................................................................... 5 
5. 
Scope ...................................................................................................................................................... 5 
6. 
Introduction ............................................................................................................................................. 5 
6.1. 
Changes from Protocol ................................................................................................................. 5 
7. 
Study Objectives ...................................................................................................................................... 5 
7.1. 
Primary Objectives ...................................................................................................................... 5 
7.2. 
Secondary Objectives ................................................................................................................... 5 
8. 
Study Design ............................................................................................................................................ 5 
8.1. 
Sentinel Dosing ........................................................................................................................... 6 
8.2. 
Stopping Rules ............................................................................................................................ 6 
8.3. 
Sample Size Considerations ........................................................................................................ 10 
8.4. 
Randomization .......................................................................................................................... 10 
9. 
Study Endpoints, Variables and Covariates ............................................................................................... 10 
9.1. 
Endpoints .................................................................................................................................. 10 
9.2. 
Population Sets .......................................................................................................................... 11 
9.2.1. 
Full Analysis Set (FAS) ...................................................................................................... 11 
9.2.2. 
Per-Protocol (PP) Set ......................................................................................................... 11 
9.2.3. 
Pharmacokinetic (PK) Analysis Set ..................................................................................... 11 
9.3. 
Predetermined Covariates and Prognostic Factors ......................................................................... 11 
10. 
Conventions and Derivations ............................................................................................................ 11 
10.1.1. 
Study day and Visit Window .......................................................................................... 11 
10.1.2. 
Baseline ........................................................................................................................ 12 
10.1.3. 
Change from baseline ..................................................................................................... 12 
11. 
Interim Analyses ............................................................................................................................. 13 
12. 
Statistical Methods .......................................................................................................................... 13 
12.1. 
Patient Disposition ..................................................................................................................... 13 
12.1.1. 
Disposition .................................................................................................................... 13 
12.1.2. 
Important Protocol Deviations ........................................................................................ 13 
12.2. 
Demographic and Baseline Characteristics ................................................................................... 14 
12.2.1. 
Demographics ............................................................................................................... 14 
12.2.2. 
Medical History ............................................................................................................. 14 
12.3. 
Treatments ................................................................................................................................ 14 
12.3.1. 
Prior, Concomitant and Prohibited Medications ................................................................ 14 
12.3.2. 
Extent of Study Drug Exposure ....................................................................................... 15 
12.4. 
Efficacy Analyses ...................................................................................................................... 15 
12.4.1. 
Multiplicity ................................................................................................................... 15 
12.4.2. 
Imputation Methods ....................................................................................................... 15 
12.4.3. 
Primary Estimand .......................................................................................................... 15 
12.4.4. 
Secondary Analyses ....................................................................................................... 18 
12.5. 
PK Analyses .............................................................................................................................. 20 
12.6. 
Safety Analyses ......................................................................................................................... 20 
12.6.1. 
Adverse Events .............................................................................................................. 20 
12.6.2. 
Laboratory Data ............................................................................................................. 22 
12.6.3. 
Vital Signs .................................................................................................................... 22 
12.6.4. 
Physical Examinations ................................................................................................... 22 
12.6.5. 
Electrocardiograms ........................................................................................................ 22 
13. 
References ...................................................................................................................................... 23 
14. 
Glossary of Abbreviations ................................................................................................................ 24 
Appendix 1 Possible Hy’s Law Liver Chemistry Action and Follow-up Assessments .......................................... 26 


Statistical Analysis Plan (SAP) 
Version Date: 06NOV2020  
 
Sponsor: Aclaris Therapeutics 
 
Protocol no: ATI-1777-AD-201 
PRA-QMS-02745 9.0 
Page 4 of 30 
Strictly Confidential.  © 2020, PRA Health Sciences.  All rights reserved. 
Appendix 2 Study Medication Interruption Criteria .......................................................................................... 28 
Appendix 3 Adverse Event Start/Stop Date Study Imputation ............................................................................ 29 
Appendix 4 Prior and Concomitant Medication Start/Stop Date Study imputation ............................................... 30 
 
 
 


Statistical Analysis Plan (SAP) 
Version Date: 06NOV2020  
 
Sponsor: Aclaris Therapeutics 
 
Protocol no: ATI-1777-AD-201 
PRA-QMS-02745 9.0 
Page 5 of 30 
Strictly Confidential.  © 2020, PRA Health Sciences.  All rights reserved. 
4. 
Purpose 
The Statistical Analysis Plan (SAP) describes the statistical methods to be used during the reporting and analyses of 
data collected under Aclaris Therapeutics, Inc. (Aclaris) Protocol ATI-1777-AD-201. 
5. 
Scope 
The SAP outlines the following: 
x 
Study Objectives 
x 
Study Design 
x 
Endpoints  
x 
Applicable Study Definitions 
x 
Statistical Methods 
6. 
Introduction 
This SAP should be read in conjunction with the study protocol V2.0, 10SEP2020 and electronic case report form 
(eCRF) V1.1 27OCT 2020. Any further changes to the protocol or eCRF may necessitate updates to the SAP. Changes 
following approval of the first version SAP will be tracked in the SAP Change History. 
Final approval of the SAP by the Aclaris and PRA statisticians will occur prior to database lock and unblinding study 
treatment.  
6.1. 
Changes from Protocol 
The sample size computation was changed from one based upon a two-sided hypothesis test to one based upon a one-
sided hypothesis test in order to match the planned primary analysis. The missing continuous efficacy endpoints will 
be imputed using last observation carry forward (LOCF) for all the continuous efficacy endpoints instead only for the 
primary efficacy endpoint (Protocol Section 9.4.9). Baseline severity of atopic dermatitis (AD) (moderate versus 
severe) was added as a covariate in the models assessing the efficacy parameters. 
7. 
Study Objectives 
7.1. 
Primary Objectives 
The primary objective of this study is to assess the preliminary clinical efficacy of ATI-1777 topical solution in adult 
patients with moderate or severe AD. 
7.2. 
Secondary Objectives 
The secondary objective of this study is to assess the safety, tolerability, and pharmacokinetics (PK) of ATI-1777 
topical solution twice daily for 4 weeks in adult patients with moderate or severe AD. 
8. 
Study Design 
This is a first-in-human, randomized, double-blind, parallel-group, multicenter, vehicle-controlled study to evaluate 
the efficacy, safety, tolerability, and PK of ATI-1777 solution following twice-daily applications to target areas of 
patients with moderate or severe AD. All AD lesions in protocol allowed areas should be treated.  
Patients will undergo screening evaluations to determine eligibility up to 30 days prior to randomization. Patients who 
meet all the inclusion/exclusion criteria will be randomized on Day 1 to active or vehicle treatment. Patients will apply 
study drug (ATI-1777 topical solution 2.0% w/w or vehicle) twice daily for 4 weeks with weekly study visits and will 
return 2 weeks after the last dose of study medication for a Post-treatment Follow-up (PTFU) Visit. Adverse event 
(AE) collection, physical examinations, clinical disease assessments (Eczema Area and Severity Index [EASI], 
Investigator’s Global Assessment [IGA], AD body surface area [BSA], Peak Pruritus Numerical Rating Scale 


Statistical Analysis Plan (SAP) 
Version Date: 06NOV2020  
 
Sponsor: Aclaris Therapeutics 
 
Protocol no: ATI-1777-AD-201 
PRA-QMS-02745 9.0 
Page 6 of 30 
Strictly Confidential.  © 2020, PRA Health Sciences.  All rights reserved. 
[PP-NRS]), vital sign assessments, PK evaluations, ECG assessments, and clinical laboratory evaluations will be 
performed as detailed in the Schedule of Events in Table 1.  
All AD lesions in protocol allowed areas should be treated. The study will be conducted at approximately 15 sites in 
the United States (US).  
The study will consist of a Screening Period of up to 30 days, a 4-week Treatment Period, and a 2-week PTFU period. 
The maximum total duration of the study for patients remaining in the study until their final follow-up assessment will 
be 73 days.  
It is planned to enroll approximately 42 patients. Patients will be randomized (1:1 to ATI-1777 Topical Solution 2.0% 
w/w or vehicle) to achieve approximately 34 evaluable patients having a non-missing Week 4 EASI assessment. 
8.1. 
Sentinel Dosing 
A sentinel dosing strategy will be employed. A minimum of 4 and a maximum of 8 patients will be initially enrolled 
in the study. Study enrollment will then be paused until the initial 4 to 8 patients have completed their Day 8 Visit and 
safety data from these patients has been reviewed by the sponsor and the ProPharma safety physician to determine 
whether the study should continue or be stopped. If the safety data from the first 4 to 8 patients indicate that it is safe 
to continue the study, enrollment will be resumed.  
The first 4 to 8 patients will continue in the study according to the Schedule of Events in Table 1 while the review of 
their safety data is ongoing and will continue in the study after enrollment resumes. 
8.2. 
Stopping Rules 
A patient will stop treatment with investigational agent if one or combination of the following occurs during the study:  
x 
An infection which meets the criteria as a study medication-related serious adverse event (SAE)  
x 
A deep venous thrombosis (DVT) and/or pulmonary embolism (PE) 
x 
Lymphoma  
x 
Hy’s law (Appendix 1)  
Treatment with study medication should be temporarily interrupted in the event of severe AEs considered related to 
study medication, or in the event of one or more of the abnormal laboratory values in Appendix 2. 
The sponsor and ProPharma safety physician will meet regularly (every 4 weeks) and assess the ongoing safety of the 
study. Attention will be paid to the number of severe AEs and SAEs, with particular focus paid to the number of 
patients who meet individual patient stopping rules. PK data will be used in the assessment: events associated with 
high plasma levels will be considered of high significance.  
If the study is stopped, a restart will not occur without agreement of the institutional review board (IRB) and the 
sponsor’s medical monitor. 
The study overview is specified in Figure 1. 
The schedule of study events is specified in Table 1.  
 
 


Statistical Analysis Plan (SAP) 
Version Date: 06NOV2020  
 
Sponsor: Aclaris Therapeutics 
 
Protocol no: ATI-1777-AD-201 
PRA-QMS-02745 9.0 
Page 7 of 30 
Strictly Confidential.  © 2020, PRA Health Sciences.  All rights reserved. 
Figure 1 Study Schematic 
 
 
 
 
Randomization 
N = ~42 
ATI-1777 
N = ~21 
4 weeks 
Vehicle 
N = ~21 
4 weeks 
Screening 
Up to 30 days 
Follow-up 
2 weeks after last dose of study medication 


Statistical Analysis Plan (SAP) 
Version Date: 06NOV2020  
 
Sponsor: Aclaris Therapeutics 
 
Protocol no: ATI-1777-AD-201 
PRA-QMS-02745 9.0 
Page 8 of 30 
Strictly Confidential.  © 2020, PRA Health Sciences.  All rights reserved. 
Table 1 
Schedule of Events 
Study Period 
Screening 
Treatment Period 
PTFU 
Study Day 
 
-30 to -1 
 
Day 1 
Day 8 
±3 days 
Day 15 
±3 days 
Day 28/ET 
±2 days 
Day 42 
±3 days 
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Statistical Analysis Plan (SAP) 
Version Date: 06NOV2020  
 
Sponsor: Aclaris Therapeutics 
 
Protocol no: ATI-1777-AD-201 
PRA-QMS-02745 9.0 
Page 9 of 30 
Strictly Confidential.  © 2020, PRA Health Sciences.  All rights reserved. 
 α  Ǣ  α  Ǣ  α   Ǣ  α     Ǣ

 α Ǣ  α  Ǣ  α   Ǣ 	 α   Ǣ

 α ǯ 
 Ǣ  α Ǣ Ǧ α     Ǣ 	 α
Ǧ 	ǦǢ  α   Ǣ ǦǦʹ α      ʹǢ
 α     
1. 
A written, signed ICF must be obtained from each patient prior to performing any study-related procedure. 
2. 
A full examination will be performed at the Screening Visit. A full examination will include general appearance, skin, head, 
eyes, ears, nose, throat, neck, thyroid, chest/lungs, heart, abdomen, lymph nodes, and extremities. A brief examination will 
be performed at the Day 1 and Day28/ET Visits and any unscheduled visits and will include symptom-focused assessments. 
3. 
Triplicate 12-lead ECGs will be obtained as outlined in Section Error! Reference source not found.. 
4. 
Vital signs will be measured in a semi-supine position after 5 minutes of rest and will include temperature, systolic and 
diastolic blood pressure, pulse, and respiratory rate. Height will be measured and recorded at the Screening Visit, and weight 
will be measured and recorded at each study visit. 
5. 
Serum pregnancy test at the Screening Visit, urine pregnancy test at all other specified time points; for WOCBP only. 
6. 
On dosing day(s), sampling for the analysis of clinical laboratory parameters will be performed before the administration of 
study medication. 
7. 
PK samples will be drawn as outlined in Section Error! Reference source not found.. 
8. 
IGA and BSA assessed at the Screening Visit to ensure inclusion criteria are met. EASI, IGA, BSA, and PP-NRS assessed 
prior to study medication application on Day 1 to establish baseline and at study visits and end of the study (or ET) to 
document severity and extent of AD following study medication. The patient will complete the PP-NRS in their diary each 
morning before applying study medication during the Treatment Period. 
9. 
Study medication will be applied at the site on study visit days, except Day 28 for PK subgroups 2 and 3. On Day 28, study 
medication will be applied at home to accommodate the timing of PK sample collection for PK subgroups 2 and 3. 
10. Nonserious AEs will be collected after the patient’s first application of study drug and continue until the patient’s last visit. 
SAEs will be collected from the time the patient signs the ICF until the patient’s last visit. 
 
 
 


Statistical Analysis Plan (SAP) 
Version Date: 06NOV2020  
 
Sponsor: Aclaris Therapeutics 
 
Protocol no: ATI-1777-AD-201 
PRA-QMS-02745 9.0 
Page 10 of 30 
Strictly Confidential.  © 2020, PRA Health Sciences.  All rights reserved. 
8.3. 
Sample Size Considerations 
A total of approximately 42 patients will be enrolled and randomized in order to achieve 34 patients who complete 
the study. Data from 34 patients provides 95.6% power to detect a statistically significant difference between the 
treatment groups in the primary endpoint (percent change from baseline in EASI scores). This power calculation is 
based upon a 1-sided treatment contrast within 1-way ANOVA model and assumes group means of 65% and 20% for 
ATI-1777 and vehicle, respectively. The group means were based upon slightly more conservative estimates than 
were observed in a Phase 2 study of topical ruxolitinib in AD. (Kim et al 2020b) The variance for the percent change 
from baseline in EASI was assumed to be 38.3%. This variance assumption was based upon data observed in a pilot 
AD study for the topical compound ATI-502 (ATI-502-AD-201). 
8.4. 
Randomization 
At Visit 2, in the morning of Day 1, eligible patients will be randomly assigned in a 1:1 ratio via an interactive 
voice/web response system (IXRS) to ATI-1777 or vehicle treatment. 
Enrolled patients will be allocated a unique patient number in a sequential order by trial site. Following randomization, 
Aclaris will provide all study medication in a packed and labelled kit, and the IXRS will identify the kit number to be 
dispensed to the patient at each relevant visit according to the treatment assigned in the randomization schedule. 
9. 
Study Endpoints, Variables and Covariates 
9.1. 
Endpoints 
The table below lists the endpoints vs objectives for the study. 
Objectives 
Endpoints 
Primary 
Primary endpoint 
The primary objective of this study is to assess the 
preliminary clinical efficacy of ATI-1777 topical 
solution in adult patients with moderate or severe 
AD. 
Percent change from baseline in EASI score at Week 4. 
Secondary 
Secondary efficacy endpoints 
 
x 
Percent change from baseline in EASI score at each study 
visit 
x 
Proportion of patients achieving an IGA score of 0 to 1 
combined with an improvement of 2 or more points from 
baseline within 4 weeks of the start of treatment 
x 
Proportions of patients who achieve 50%, 75%, and 90% 
improvement in EASI score (EASI-50, EASI-75, and 
EASI-90, respectively) within 4 weeks of the start of 
treatment 
x 
Change from baseline in IGA score at each study visit 
x 
Change from baseline in BSA at each study visit 
x 
Change from baseline in PP-NRS score at each study 
visit 
Pharmacokinetic  
Pharmacokinetic endpoints 
The secondary objective of this study is to assess 
the safety, tolerability, and pharmacokinetics (PK) 
of ATI-1777 topical solution twice daily for 4 
The PK endpoint is ATI-1777 concentration in plasma 
samples obtained using a sparse sampling approach. 


Statistical Analysis Plan (SAP) 
Version Date: 06NOV2020  
 
Sponsor: Aclaris Therapeutics 
 
Protocol no: ATI-1777-AD-201 
PRA-QMS-02745 9.0 
Page 11 of 30 
Strictly Confidential.  © 2020, PRA Health Sciences.  All rights reserved. 
weeks in adult patients with moderate or severe 
AD. 
Safety 
Safety endpoints 
The secondary objective of this study is to assess 
the safety, tolerability, and pharmacokinetics (PK) 
of ATI-1777 topical solution twice daily for 4 
weeks in adult patients with moderate or severe 
AD. 
 
x 
Incidence of treatment-emergent adverse event (TEAE)s 
and SAEs, including incidence of adverse event of 
special interest (AESI) (e.g., application site reactions) 
x 
Laboratory values 
x 
Vital signs 
x 
Physical examination results 
x 
12-lead ECG results 
9.2. 
Population Sets 
The following analysis sets are defined in accordance with the International Council for Harmonization (ICH)-E9 
guidance. 
9.2.1. 
Full Analysis Set (FAS) 
All patients who have been randomized and administered at least one dose of study medication. The efficacy analyses 
will be conducted on the FAS population as randomized; the safety analyses and summaries will be conducted on the 
FAS as treated. 
9.2.2. 
Per-Protocol (PP) Set 
The Per-Protocol (PP) set is defined as a subset of the FAS who have non-missing Week 4 EASI scores recorded with 
no major protocol deviations deemed to compromise the assessment of efficacy. Major protocol deviations will be 
identified as a subset of the Important protocol deviations and fully defined prior to unblinding of the trial. The PP 
analysis will only be conducted on efficacy endpoints and patients analyzed according to their actual treatment. 
9.2.3. 
Pharmacokinetic (PK) Analysis Set 
All patients who have received at least 1 dose of active study medication and provided at least 1 plasma concentration 
value will be included in the PK Analysis Set. 
9.3. 
Predetermined Covariates and Prognostic Factors 
The following factors will be adjusted as covariates: 
x 
Baseline severity of AD (moderate vs severe) 
x 
Continuous baseline severity EASI score/BSA score/IGA score 
x 
Baseline BSA (3 to 10 vs greater than 10 to 20) to be used for PK spaghetti plots 
10. 
Conventions and Derivations 
Patients who discontinue study medication will be asked to come to each visit for the scheduled assessments up to the 
end of the study.  
Patients who prematurely discontinue the study will be evaluated based on the data collected at each visit attended. 
Data collected during the ET Visit will be used as an end-of-study assessment for these patients. If the ET Visit was 
performed >1 day after the last dose was administered, then the previous visit will be used as the end-of-study 
assessment. 
10.1.1. 
Study day and Visit Window 
For each patient there will be a baseline period, a four-week treatment period and a two-week post treatment follow 
up period.  


Statistical Analysis Plan (SAP) 
Version Date: 06NOV2020  
 
Sponsor: Aclaris Therapeutics 
 
Protocol no: ATI-1777-AD-201 
PRA-QMS-02745 9.0 
Page 12 of 30 
Strictly Confidential.  © 2020, PRA Health Sciences.  All rights reserved. 
Study day is defined relative to the date of the first dose of study drug. For assessments that occur after this visit date, 
study day is calculated as (assessment date – first dose date + 1). For assessments that occur prior to first dose date, 
study day will be calculated as (assessment date – first dose date). There is no study Day 0. When there are multiple 
observations within a visit window, the value closest to the target day will be analyzed. 
The visit window (Table 2) and PK draw window (Table 3) appear in the table below. 
Table 2 will be used to define the analysis window for safety assessments (vital signs, ECGs, lab assessment) and for 
efficacy assessment of EASI, IGA, BAS, PP-NRS). Plasma concentrations will be summarized according to nominal 
time (no analysis visit windows) and may be plotted according to actual time relative to the time of first dose, as 
appropriate. 
Table 2 Visit Window and Target day 
Visit 
Target Study Day 
Analysis Visit 
Visit Window 
Visit 1 
 
Screening 
< Time of First Dose 
Visit 2 
1 
Day 1 
Time of First Dose < Study Day ≤ Day 3 
Visit 3 
8 
Day 8 
Day 4< Study Day ≤ Day 11 
Visit 4 
15 
Day 15 
Day 12 < Study Day ≤ Day 21 
Visit 5 
28/ET 
Day 28/ET 
Day 22 < Study Day ≤ Day 34 
Visit 6 
42 
Day 42 
Day 35 < Study Day ≤ Day 45 
Table 3 PK Draw Timing 
Visit 
Target Day 
Nominal Time 
Visit 2 
Day 1 
x 
At Predose and 2 hours postdose 
Visit 3 
Day 8 
x 
At Predose and 2 hours postdose  
Visit 4 
Day 15 
x 
At Predose and 2 hours postdose 
Visit 5 
Day 28/ET 
x 
Subgroup 1: One sample predose and one sample at 
0.5 to 2.5 hours post application 
x 
Subgroup 2: One sample at 2.5 to 5 hours post 
application and one sample at least 2 hours later 
x 
Subgroup 3: One sample at 5 to 8 hours post 
application and one sample at least 2 hours later 
(prior to the subsequent application) 
10.1.2. 
Baseline 
Baseline is defined as the last, non-missing measurement, before or on the date of first administration of study 
medication.  
10.1.3. 
Change from baseline 
Change from baseline (CFB) will be calculated as (post-baseline – baseline). CFB will be calculated for patients with 
both a baseline and post-baseline value as applicable.  
Percent CFB will be calculated as (CFB/baseline)*100, where applicable.  
If a baseline value has not been recorded for a parameter, then CFB will not be calculated for that parameter. 


Statistical Analysis Plan (SAP) 
Version Date: 06NOV2020  
 
Sponsor: Aclaris Therapeutics 
 
Protocol no: ATI-1777-AD-201 
PRA-QMS-02745 9.0 
Page 13 of 30 
Strictly Confidential.  © 2020, PRA Health Sciences.  All rights reserved. 
11. 
Interim Analyses 
No interim analysis will be conducted. 
12. 
Statistical Methods 
All analyses will use SAS version 9.4 or higher.  
Categorical variables will be summarized using counts and percentages based on the specified population total. 
Percentages will be rounded to one decimal place, except 100% will be displayed without any decimal places and 
percentages will not be displayed for zero counts.  
Continuous data will be summarized using non-missing observations (n, mean, standard deviation (SD), median, 
Quartile 1, Quartile 3, minimum, and maximum). The median, minimum, and maximum values will be displayed to 
the same level of the precision as the raw value. Mean, median, Q1 and Q3 will be rounded to 1 decimal place greater 
than the precision of the original value. The SD will be rounded to 2 decimal places greater than the precision of the 
original value. Confidence intervals, least square mean (LSM) and standard error (SE) will be provided as appropriate. 
Confidence intervals, LSM will present the same precision as the mean value whereas SEs will present the same 
precision as SD. 
P-values will be rounded to 3 decimal places. P-values less than 0.001 will be presented as “<0.001” and p-values 
greater than 0.999 will be presented as “>0.999.”  
Statistical hypothesis testing will be one-sided and carried out at the 5% level of significance. Testing will be 
performed on the primary endpoint and secondary endpoints as appropriate. No adjustments for multiplicity will be 
made. 
If there is strong collinearity between the baseline EASI score/BSA score/IGA score and the baseline severity of AD 
(moderate versus severe),  the continuous baseline score will be included the efficacy analysis.  
All the listings will be displayed by treatment arm, patient identifier and date of assessment. Age, gender, and race 
will be presented on each listing. 
12.1. 
Patient Disposition 
12.1.1. 
Disposition 
The number of patients screened, randomized, randomized and treated, randomized and not treated, and the number 
of patients in the analysis sets will be summarized for all screened patients.  
The number and percentage of patients will also be summarized for the following patient disposition categories: 
1. Completed study drug treatment PP  
2. Discontinued study drug early and the reason for discontinuation  
3. Completed the study including PTFU 
4. Discontinued from the study early and the reason for discontinuation 
The table will be presented by treatment arm using the FAS.  
All patient’s disposition data will be listed. 
12.1.2. 
Important Protocol Deviations 
As a guideline, important protocol deviations (IPDs) are:  
x 
Non-compliance with study drug  
x 
Pregnancy  
x 
Other deviations that violate inclusion or exclusion criteria  
x 
Outside Study Windows  
Important protocol deviations will be listed. 


Statistical Analysis Plan (SAP) 
Version Date: 06NOV2020  
 
Sponsor: Aclaris Therapeutics 
 
Protocol no: ATI-1777-AD-201 
PRA-QMS-02745 9.0 
Page 14 of 30 
Strictly Confidential.  © 2020, PRA Health Sciences.  All rights reserved. 
12.2. 
Demographic and Baseline Characteristics 
12.2.1. 
Demographics 
Baseline data will be summarized for continuous and categorical variables as applicable. 
The following demographic and baseline characteristics will be summarized for the FAS by treatment arm and overall: 
x 
Sex (female, male) 
x 
Race (White, Black or African American, Asian, American Indian or Alaska Native, Native Hawaiian or 
other Pacific Islander, other) 
x 
Ethnicity (Hispanic or Latino, not Hispanic or Latino) 
x 
Age (years), as continuous variable and Age groups (≥ 18 years to <30 years, ≥ 31 years to <40 years, ≥ 41 
years to <50 years, ≥ 51 years to <65 years,). 
x 
Height at baseline (cm) 
x 
Weight at baseline (kg) 
x 
Body mass index at baseline (kg/m2) defined as Weight (kg)/[Height (m)]2 
x 
Child-bearing potential  
x 
Fitzpatrick skin type 
x 
Baseline AD severity (moderate vs severe) 
 
Demographic and baseline characteristics will also be listed. No statistical testing will be performed on the 
aforementioned demographic data.  
12.2.2. 
Medical History 
Medical history will be summarized by treatment arm and overall for all patients in the FAS. Medical history data will 
be coded using Medical Dictionary for Regulatory Activities (MedDRA) 220 and summarized by system organ class 
(SOC) and preferred term (PT). No inferential testing will be performed in this section. Medical history data will be 
presented in a data listing. 
12.3. 
Treatments 
12.3.1. 
Prior, Concomitant and Prohibited Medications 
Medications that stop prior to the first dose of study drug will be classified as prior medication. Medications that start 
on or after the first dose of study drug until the Day 42/PTFU visit will be classified as concomitant. If a medication 
starts before the first dose of study drug and stops on or after the first dose of study drug, then the medication will be 
classified as both prior and concomitant.  
Medications will be categorized by medication group and subgroup according to World Health Organization Drug 
Dictionary Enhanced (WHODRUG 2017JUL DDE B2). 
For any medications/nondrug therapies taken from 3 months before the screening visit until the end of the PTFU, 
inclusively, the medication name, the start and stop date, dose, unit, frequency, route of administration, and indication 
will be recorded.  
Use of any of the following treatments is prohibited during the study:  
x 
Phototherapy (ultraviolet A, ultraviolet B, or psoralen and ultraviolet A therapy) 
x 
Systemic biologic immunosuppressant or immunomodulatory therapy (e.g., etanercept, alefacept, 
infliximab, dupilumab) 
x 
Non-biologic immunosuppressants (e.g., methotrexate, retinoids, calcineurin inhibitors, cyclosporine, 
hydroxycarbamide [hydroxyurea], azathioprine) 
x 
Janus kinase (JAK) inhibitors (systemic and topical) 
x 
Systemic or topical corticosteroids (intranasal, inhaled, and topical ocular corticosteroids are allowed if 
used to treat other medical conditions) 


Statistical Analysis Plan (SAP) 
Version Date: 06NOV2020  
 
Sponsor: Aclaris Therapeutics 
 
Protocol no: ATI-1777-AD-201 
PRA-QMS-02745 9.0 
Page 15 of 30 
Strictly Confidential.  © 2020, PRA Health Sciences.  All rights reserved. 
x 
Cytostatic agents 
x 
Crisaborole 
x 
Systemic antibiotics 
x 
Topical treatments for AD (corticosteroids, calcineurin inhibitors, topical H1 and H2 antihistamines, topical 
antimicrobials, and other medicated topical agents) 
x 
Live attenuated vaccine treatment 
x 
Other investigational products 
x 
Use of potent inhibitors of cytochrome P450 3A4 such as (but not limited to) clarithromycin, erythromycin, 
diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal, and grapefruit 
In order to flag prohibited medications taken in the study, each medication taken will be compared against the list of 
the prohibited medications the clinical medical officer provided after reviewing the concomitant medication database. 
Prior, Concomitant and Prohibited medications will be summarized based on the number and percentage of patients 
using each medication along with the number and percentage of patients using at least one medication within each 
medication group and subgroup. 
Missing or partial medication start/stop date will be imputed as described in Appendix 4. A conservative approach 
will be used when flagging medications. The medication will be classified as concomitant when a decision is unable 
to be made even with imputed start/stop medication date.  
Prior, Concomitant and Prohibited medications will be summarized for the FAS by treatment arm and overall. 
Medication data will also be presented in a data listing. 
12.3.2. 
Extent of Study Drug Exposure 
The duration of exposure to study drug, number of days dosed is taken and compliance with study drug dosing will 
be summarized by treatment arm using the FAS. Study drug accountability including the weight of the dispensed and 
returned bottles will be listed. Study drug not returned will be assumed to have been taken. 
Study drug compliance (percentage) will be derived using values from the Patient Diary as shown below: 
[# of days patient reported taking study drug / # of days patient was in the study] * 100% 
The descriptive statistics of the continuous study drug compliance will be summarized by treatment group and overall. 
Days with missing patient diary data will not be included in the calculation above. Percentage of patients meeting 
Study Drug Compliance will be presented in the following categories: < 80%, ≥ 80% to < 90%, ≥ 90% to <100%, ≥ 
100% to <110%, ≥ 110% to <120%, and ≥ 120%. 
Major non-compliance is defined as compliance < 80% or compliance > 120%. 
12.4. 
Efficacy Analyses 
All efficacy analyses will be performed on both the FAS and PP analysis set. Efficacy data will also be presented in  
data listing. 
12.4.1. 
Multiplicity 
No adjustments or analysis to detect multiplicity will be performed. 
12.4.2. 
Imputation Methods  
For the continuous efficacy analysis on the FAS population, missing data will be imputed using last observation carried 
forward (LOCF). Missing data will not be imputed for continuous efficacy analyses that are based on the PP 
population. For responder-type categorical endpoints (such as EASI-50, EASI-75, and EASI-90), missing data will be 
treated as a non-response. 
12.4.3. 
Primary Estimand 
Given the primary objective described in Section 7, we seek an estimand that will measure the effect of ATI-1777 
administration on the signs and symptoms of AD as measured by the percent change from baseline in EASI scores in 


Statistical Analysis Plan (SAP) 
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Sponsor: Aclaris Therapeutics 
 
Protocol no: ATI-1777-AD-201 
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adult patients with moderate to severe AD as compared to placebo in the absence of other interventions or 
interruptions. This estimand will not be directly measurable if, in the judgment of the investigator, interventions are 
required for the sake of the patient safety and/or comfort. This estimand will also not be directly measurable if missing 
data result from a patient withdrawing consent or losing interest in study participation (loss to follow-up). This section 
outlines the measures and methods that will be used adjust the primary endpoint to account for these types of 
intercurrent events to obtain as close an estimand to the desired objective as possible. 
12.4.3.1. 
The Population 
The patients of primary interest in this study are adult patients with moderate or severe AD. This population of patients 
is largely reflected by the inclusion/exclusion criteria in the protocol. Generally, the targeted population for this 
estimand is agnostic to the degree of compliance to treatment administration and adherence to protocol specified 
procedures; in the spirit of the Intention-To-Treat principle. However, the targeted population is required to have been 
treated with at least one dose of study medication (see FAS analysis population description in Section 9.2.1). 
There is no stratum of patients based on the potential for an intercurrent event that is needed to define the targeted 
population for this study. It is anticipated that the group of severe AD patients in this study will be more difficult to 
treat. The randomization strategy for this study incorporates stratification by AD severity to help balance in the 
treatment groups within the AD severity. This stratification group will also be accounted for in the population-level 
summary methods used to compute the estimand. 
12.4.3.2. 
Primary Endpoint 
The primary endpoint is the percent change from baseline in EASI score at Week 4 on FAS. Missing data will be 
imputed using LOCF. 
The EASI (Hanifin et al 2001; Rullo et al 2008) assesses the extent and severity of AD. This study will employ a 
modified EASI that excludes evaluation of the scalp, face, palms of hands, soles of feet, groin, and genitalia. The 
modified EASI will evaluate AD in each of 3 body regions (trunk [excluding groin and genitalia], upper extremities 
[excluding palms of hands], and lower extremities [excluding soles of feet]). The EASI scoring system uses a defined 
process to grade the severity of the signs of AD and the extent affected. If possible, the same individual should conduct 
the extent and severity evaluations at each visit. 
Each respective body region will be given a score between 0 and 6 based on the percentage involvement in that region 
according to Table 4. Precise measurements are not required. 
Table 4 Extent of Atopic Dermatitis in Each Body Region 
% Involvement 
0% 
1% to 9% 
10-29% 
30-49% 
50-69% 
70-89% 
90-100% 
Region Score 
0 
1 
2 
3 
4 
5 
6 
For each respective body region, the severity of each of 4 signs (erythema, edema/papulation, excoriation, 
lichenification) will be graded by the investigator or qualified designee on a 0- to 3-point scale ([0] none, [1] mild, [2] 
moderate, [3] severe) in AD-affected areas. Half scores are allowed. The average severity across AD-affected areas 
in each body region will be used as the score for that region. 
The final EASI score will then be calculated by an electronic data capture system as described in Table 5. 


Statistical Analysis Plan (SAP) 
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Sponsor: Aclaris Therapeutics 
 
Protocol no: ATI-1777-AD-201 
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Table 5 EASI Score Calculation 
Body 
Region 
Erythema 
Edema/ 
papulation 
Excoriation 
Lichenification 
Area 
Score 
Multiplier 
Score 
Trunk 
( X 
+ 
X + 
Z + 
AA)? 
× 
× 0.3 
 
Upper 
extremity 
( 
+ 
+ 
+ 
) 
× 
× 0.2 
 
Lower 
extremity 
( 
+ 
+ 
+ 
) 
× 
× 0.4 
 
Final EASI score is the sum of the 3 region scores: 
 
 
EASI = Eczema Area and Severity Index 
12.4.3.3. 
Imputation for Intercurrent Events 
An intercurrent event is one that occurs after the first dose of study medication and either precludes the observation 
of the primary variable/endpoint or affects its interpretation. The following is a list of intercurrent events that could 
occur during this study: 
x 
Death 
x 
Withdrawal from study 
x 
Withdrawal of study medication due to an AE 
x 
Rescue with a non-protocol specified treatment for AD 
Missing data and data following these intercurrent events will be imputed using the LOCF methodology. 
12.4.3.4. 
Primary Analysis 
The primary efficacy analysis will be the treatment comparison between ATI-1777 and vehicle for the percent change 
from baseline in EASI scores at Week 4 based on the FAS. Change from baseline is calculated as described in section 
10.1.3. This treatment comparison will be made within the context of a Mixed Model Repeated Measures (MMRM) 
analysis where the EASI scores over time are treated as repeated measures within a given patient. Treatment group, 
time (study visit), treatment by time interaction, and baseline severity of AD will enter the model as categorical factors, 
baseline EASI score will be included as a continuous covariate, and patient ID will enter the model as a random effect. 
Treatment group model-based means and model-based differences in treatment groups will be provided along with 
corresponding 90% confidence intervals and p-values. If the MMRM model will not converge or if there is strong 
collinearity between the baseline EASI score and the baseline severity of AD, one or both of the covariates may be 
excluded from the primary analysis.  
For the primary efficacy analysis on the FAS population, missing data will be imputed using LOCF. Missing data will 
not be imputed for the analyses that are based on the PP population. 
The null hypothesis is that the LSM contrast between ATI-1777 and vehicle at Week 4 equals zero. Significance tests 
will be based on least-squares means using a one-sided test at α = 0.05 (one-sided p-value compared to 0.05). A 
symmetric two-sided 90% confidence interval will accompany the corresponding p-value. The MMRM will be fit 
with covariance matrices of UN (unstructured), CS (compound symmetry), TOEPH (Heterogeneous Toeplitz) and 
ARH(1) (Heterogeneous auto-regressive 1). The analysis with the lowest Akaike’s information criterion (AIC) will 
be reported in the table. Other covariance matrix structures may be used if none of these converge. The Kenward-
Roger approximation will be used to estimate the denominator degrees of freedom. 
The estimates at the timepoint Week 4 will be considered as primary. Least squares mean, Standard Errors, for each 
treatment group, least squares mean difference (ATI-1777 minus vehicle), and 90% confidence intervals for the 


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difference between the treatment groups and the corresponding one-sided p-value will be reported. The following SAS 
code will be used. 
   proc mixed data= datain method=ml; 
 
class treatment visit baseline ADseverity; 
 
model pchg_EASI = baseline_EASI baseline_ADseverity visit treatment treatment*visit  
 
 
 
/ cl solution ddfm=kr alpha=0.10; 
 
repeated /type=un subject=usubjid; 
 
slice treatment * visit /sliceby=visit means diff nof cl; 
 
ods output slices = lsm sliceDiffs = diffs; 
   run; 
Summary statistics (n, mean, SD, minimum, Q1, median, Q3, and maximum) of the baseline value, the value at Week 
4 and the corresponding change from baseline for EASI score will be presented by treatment group and overall using 
the FAS.. 
12.4.3.5. 
Sensitivity Analyses  
The population-level summary for the primary estimand based on the FAS population will be repeated using the Per-
Protocol population to assess the sensitivity of the analysis to compliance to treatment administration and adherence 
to protocol specified procedures. Other secondary efficacy analyses and summaries are intended to support the primary 
estimand and do not qualify as sensitivity analyses. 
12.4.4. 
Secondary Analyses 
Treatment comparisons between ATI-1777 and vehicle for each of the continuous efficacy endpoints that are 
conducted over time (change in IGA, BSA, and PP-NRS) will be analyzed using a similar model as described for the 
primary endpoint. Treatment comparisons will be made for each post-baseline scheduled visit utilizing the analysis 
window scheme described in Section 10.1.1. Change from baseline is calculated as described in section 10.1.3. 
Treatment group comparisons for categorical efficacy endpoints (IGA response, EASI-50, EASI-75, and EASI-90) 
that are conducted over time will employ a logistic regression model fit at each scheduled visit separately, where 
appropriate. The logistic regression model will include treatment group and baseline severity of AD as a factor, and 
the baseline value as a covariate. Model-based point estimates for the treatment proportions will be provided as well 
as model-based differences and corresponding symmetric 90% confidence intervals and one-sided p-values. If the 
Logistic model will not converge or if there is strong collinearity between the baseline EASI score and the baseline 
severity of AD, one or both of the covariates may be excluded from the secondary analysis. 
The secondary efficacy endpoints are 
x 
Percent change from baseline in EASI score at each study visit 
x 
Proportion of patients achieving an IGA score of 0 to 1 combined with an improvement of 2 or more points 
from baseline within 4 weeks of the start of treatment 
x 
Proportions of patients who achieve EASI-50, EASI-75, and EASI-90 within 4 weeks of the start of 
treatment 
x 
Change from baseline in IGA score at each study visit 
x 
Change from baseline in BSA at each study visit 
x 
Change from baseline in PP-NRS score over time 
12.4.4.1. 
EASI, EASI-50, EASI-75 and EASI-90 
The analysis of percent change from baseline in EASI score at each visit for FAS will be in the same model as the 
primary efficacy analysis. The estimates at the timepoint other than Week 4 will be considered as secondary endpoints. 
EASI-50, EASI-75 and EASI-90 are the proportions of patients achieve 50%, 75%, 90% improvement in EASI 
score respectively within 4 weeks of the start of the treatment. The follow is an example of EASI-50 definition. 
EASI-50 = “YES” If (EASI score at Day 28 – baseline EASI)/baseline EASI ≥ 50% 


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The follow SAS code is an example for the analysis of EASI-50 at Day 28. 
   proc logistic data= datain; 
 
class treatment baseline_ADseverity; 
 
model EASI 50 = baseline EASI treatment baseline ADseverity / expb; 
 
oddsratio treatment; 
 
lsmeans treatment / e diff oddsratio cl adjust = bon; 
   run; 
12.4.4.2. 
Investigator’s Global Assessment (IGA) 
The IGA is the investigator’s assessment of the overall appearance of the lesions at a particular point in time. At every 
study visit, the investigator will assess the IGA using the scale in Table 6 and report the one score that best describes 
the overall appearance of the lesions. It is not necessary that all characteristics under Morphological Description be 
present. In indeterminate cases, please use extent to differentiate between scores. The investigator or qualified 
designee will enter the score into the eCRF. Whenever possible, the same individual should conduct the evaluation at 
each visit. 
Table 6 IGA Scoring 
Score 
Morphological Description 
0 - Clear 
No inflammatory signs of atopic dermatitis (no erythema, no induration/papulation, 
no lichenification, no oozing/crusting). Post-inflammatory hyperpigmentation 
and/or hypopigmentation may be present. 
1 - Almost clear 
Barely perceptible erythema, barely perceptible induration/papulation, and/or 
minimal lichenification. No oozing or crusting. 
2 - Mild 
Slight but definite erythema (pink), slight but definite induration/papulation, and/or 
slight but definite lichenification. No oozing or crusting. 
3 - Moderate 
Clearly perceptible erythema (dull red), clearly perceptible induration/papulation, 
and/or clearly perceptible lichenification. Oozing and crusting may be present. 
4 - Severe 
Marked erythema (deep or bright red), marked induration/papulation, and/or 
marked lichenification. Disease is widespread in extent. Oozing or crusting may be 
present. 
IGA = Investigator’s Global Assessment 
The change from baseline in IGA score at each study visit is analyzed using similar MMRM model as the primary 
efficacy endpoint except the baseline IGA score will be included as a covariate.  
The patient achieves an IGA score of 0 or 1 combined with an improvement of 2 or more points from baseline within 
4 weeks of the start of treatment is analyzed as categorical variable using logistic regression. 
12.4.4.3. 
Body Surface Area (BSA) 
The total percentage of the patient’s AD-affected BSA will be estimated by the investigator or designee using the 
handprint method, which estimates that the area of a patient’s full handprint (fingers and thumbs together) constitutes 
1% of their total BSA.  
The BSA should be calculated for the EASI score using Regional Percentage Estimates as described in the study 
training video.  
Whenever possible, the same evaluator should perform the estimation at each study visit. If new areas of AD develop 
while the patient is on the study, these new areas will not be assessed. 


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BSA results and corresponding change from study baseline values will be summarized at each time point using 
descriptive statistics by treatment group. The change from baseline in AD BSA at each study visit is analyzed using 
similar MMRM model as the primary efficacy endpoint.  
12.4.4.4. 
Peak Pruritus Numerical Rating Scale (PP-NRS) 
The PP-NRS (Yosipovitch et al 2019) is a single patient‐reported item designed to measure peak pruritus, or ‘worst’ 
itch, over the previous 24 hours based on the following question: ‘On a scale of 0 to 10, with 0 being “no itch” and 10 
being “worst itch imaginable,” how would you rate your itch at the worst moment during the previous 24 hours?’. 
Prior to study medication application on Day 1, the study coordinator should show the PP-NRS scale to the patient, 
explain the scale and ask the patient to indicate which integer best describes the worst pruritus the subject experienced 
for their AD over the previous 24 hours. 
The patient will complete this assessment and record in their diary each morning before applying study medication 
during the Treatment Period. 
The patient will report the diary rating to site staff at each visit, who will enter it into the patient’s source documents 
and eCRF. 
The PP-NRS score on Day 1 prior to study medication application is the baseline. The PP-NRS scores just prior to 
study medication application on Day 8, Day 15 and Day 28 will be flagged and used in the efficacy analysis. PP-NRS 
results and corresponding change from study baseline values will be summarized at each time point using descriptive 
statistics by treatment group. The change from baseline in PP-NRS is analyzed using similar MMRM model as the 
primary efficacy endpoint.  
All PP-NRS score data will be presented in a data listing, the values included in the efficacy analysis will be flagged. 
12.5. 
PK Analyses 
The PK endpoint is the concentration of ATI-1777 in plasma samples obtained using a sparse sampling approach. 
Concentrations that are below the limit of quantitation (BLQ) will be treated as zero for the computation of descriptive 
statistics. Individual and mean plasma concentrations at each nominal sampling time point or time window for ATI-
1777 will be listed and summarized in a tabular form including means, geometric means, ranges, SD, and coefficients 
of variation. Mean concentrations will be plotted versus nominal time on linear and semilogarithmic scales. 
Plasma concentration-time profiles of ATI-1777 will be plotted on semi-log and linear scales for each individual 
patient as spaghetti plots using actual collection times by visit day. For ease of presentation, mean plasma 
concentration-time data of ATI-1777 will be plotted by nominal time on both linear and semi-logarithmic scales by 
visit day. Plasma PK concentrations of ATI-1777 for each patient will be reported to the precision of the raw data in 
listing presentations. In addition, concentration-time profiles will be plotted by patient. 
If concentration data show that sufficient samples are available with quantifiable levels of ATI-1777, scatterplots of 
plasma concentration values versus EASI scores or baseline BMI values will be generated by visit and PK time. For 
Day 28, separate scatterplots will be produced by subgroup and PK time. 
12.6. 
Safety Analyses 
All safety analyses will be completed for the FAS. All safety data will be listed and summarized. No formal statistics 
will be performed for the safety analysis. 
12.6.1. 
Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related.  
TEAEs are defined as AEs with an onset date on or after the first administration of study medication and before the 
date of last administration of study medication + 14 days.  


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An SAE is defined as any AE that results in any of the following outcomes: death, a life-threatening AE, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial 
disruption of the ability to conduct normal activities of daily living, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life-threatening, or require hospitalization may be considered SAEs 
when, based upon appropriate medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  
The severity of AEs will be classified by the investigator as mild, moderate, or severe. 
The causality of AEs will be classified by the investigator as related and not related.  
An overall AE summary will be generated presenting the frequency and percentage of patients and the number of AEs 
using FAS for the following:  
x 
Any TEAE  
x 
Any treatment-related TEAE  
x 
Any severe TEAE  
x 
Any treatment-related severe TEAE  
x 
Any SAE  
x 
Any treatment-related SAE  
x 
Any TEAE leading to study discontinuation  
x 
Any death  
x 
Any Suspected Unexpected Serious Adverse Reaction 
x 
Any Adverse Events of Special Interest 
All AEs will be coded using MedDRA (version to be delineated in the clinical study report [CSR]). The TEAEs will 
also be summarized by SOC, PT, by severity and relationship to study treatment. Missing or partial medication 
start/stop date will be imputed as described in Appendix 3. 
The TEAE summary tables will be sorted by SOC and PT. System organ class will be displayed in descending order 
of overall frequency then alphabetically. Preferred term will be displayed in descending order of overall frequency 
and then alphabetically within SOC. A patient with 2 or more events within the same level of summarization will be 
counted only once in that level using the most severe incident or most related incident. Percentages will be based on 
the number of patients in the FAS.  
A TEAE summary table by prevalence will also be provided. The preferred terms will be sorted by decreasing 
frequency in the active arm. 
All AEs will be presented in a data listing. Separate data listings will be generated for treatment related AEs, SAEs, 
and AEs leading to study discontinuation. 
12.6.1.1. 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is defined as any AE for which there is a reasonable 
possibility that the study medication caused the AE (where ‘reasonable possibility’ means there is evidence to suggest 
a causal relationship between the study medication and the AE), the AE is not listed in the Investigator Brochure (IB) 
or is not listed at the specificity or severity that has been observed, and the AE meets at least one of the criteria for 
seriousness.  
The SUSAR will be summarized by SOC and PT. The SUSAR will also be presented in a data listing. 
12.6.1.2. 
Adverse Events of Special Interest 
The adverse events of special interest (AESIs) for this study are TEAEs of: 
x 
Application site AEs 
x 
Serious infections 
x 
Malignancies 
x 
Thrombosis 


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x 
Cytopenias 
x 
Liver enzyme elevation AEs (e.g., ALT, AST, bilirubin, GGT, LDH) 
x 
Increased lipid parameter AEs (e.g., TC, LDL-C, HDL-C, TG) 
The AESI will be summarized by SOC and PT. The AESI will also be presented in a data listing.
12.6.2. 
Laboratory Data 
Laboratory parameters will be summarized for FAS. Laboratory data (hematology, serum chemistry, and urinalysis) 
will be converted to Système International units for reporting and processing purposes. Summaries by visit will include 
data from scheduled assessments, and all data will be reported according to the visit window for which it was recorded. 
Absolute values and changes from baseline will be presented descriptively.  
Hematology, serum chemistry, and urinalysis will be summarized using descriptive statistics for numeric variables 
and numbers and percentages for categorical variables at each scheduled assessment. Numeric hematology, chemistry, 
and urinalysis results will be summarized using change from baseline as well. Where it is applicable to categorize a 
laboratory assessment by normal, high, or low according to the normal range provided by the central laboratory, the 
status at the final value at the end of the treatment period will be compared with that at the study baseline and the 
"shifts” from study baseline will be summarized using the number and percentage of patients in each shift category 
by treatment group. 
All clinical laboratory test results will be presented in the data listings. Laboratory values that are outside of the normal 
reference range will be flagged in the data listings. 
12.6.3. 
Vital Signs 
Vital signs will include blood pressure, heart rate, respiratory rate, and body temperature, and will be measured at 
Screening, Day 1, Day 8, Day 15 and Day28/ET. Patients will be resting for at least 5 minutes before taking vital 
signs.  
Body weight will be measured and recorded at each study visit. Height will be measure at Screening visit.  
Summaries by visit will include data from scheduled assessments, and all data will be reported according to the visit 
window . Vital sign results and corresponding change from study baseline values will be summarized at each 
scheduled visit using descriptive statistics by treatment group.  
All vital sign, body weight, and height measurements will be presented in a data listing. The actual values and change 
from baseline values at each time point will be summarized for the FAS. 
12.6.4. 
Physical Examinations 
Full physical examinations will be performed at Screening and abbreviated physical examinations will be performed 
at Day 1 and Day 28 visits. 
All physical examination results will be presented in a data listing. 
12.6.5. 
Electrocardiograms 
Triplicate 12-lead electrocardiograms (ECGs) will be obtained after the patient has been resting for at least 5 minutes 
at Screening and Day 28/ET.  
Heart rate, PR interval, QRS axis, QRS duration, QT interval, RR interval, as well as the interpretation of the ECG 
will be collected in eCRF. All ECG results along with the interpretation by the central reader, including the average 
of triplicate measurements at each timepoint, will be presented in data listings.  
QTcF values will be presented with the implementation of corrections (i.e., Fridericia’s) as defined in ICH Guidelines 
E14 by the following categories:   
Absolute QTcF interval prolongation: 
x 
QTcF interval > 450 ms 


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x 
QTcF interval > 480 ms  
x 
QTcF interval > 500 ms 
Change from baseline in QTcF interval: 
x 
QTcF interval increases from baseline >30 ms  
x 
QTcF interval increases from baseline >60 ms. 
The actual values and change from baseline values at each time point will be summarized for the FAS. An average of 
the triplicates at each timepoint will be used in the summaries. Baseline will be defined as the average of the last 
triplicate measurements before the first dose of study drug.   
13. 
References 
Kim BS, Sun K, Papp K, et al. Effects of ruxolitinib cream on pruritus and quality of life in atopic dermatitis: Results 
from a phase 2, randomized, dose-ranging, vehicle-and active-controlled study. J Am Acad Dermatol. 2020b Feb 11. 
pii; S0190-9622(20)30213-9. doi: 10.1016/j.jaad.2020.02.009. [Epub ahead of print] 
Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The Eczema Area and Severity Index (EASI): 
an assessment of reliability in atopic dermatitis. Exp Dermatol. 2001; 10:11-18. 
Rullo VEV, Segato A, Kirsh A, Sole D. Severity scoring of atopic dermatitis: a comparison of two scoring systems. 
Allergol Immunopathol. 2008; 36(4):201-11. 
SAS Institute Inc. 2015. SAS 9.4 Procedures Guide. 5th ed. Cary, NC: SAS Institute Inc.  
Yosipovitch G, Reaney M, Mastey V, et al. Peak pruritus numerical rating scale: psychometric validation and 
responder definition for assessing itch in moderate-to-severe atopic dermatitis. Br J Dermatol. 2019; 181(4):761-769. 


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14. 
Glossary of Abbreviations 
Glossary of Abbreviations: 
AD 
atopic dermatitis 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration 
BSA 
body surface area 
Cmax 
maximum plasma concentration 
COVID-19 
coronavirus disease 2019 
CPK 
creatine phosphokinase 
CSR 
clinical study report 
eCRF 
electronic case report form 
EASI 
Eczema Area and Severity Index 
ECG 
electrocardiogram 
ET 
Early Termination 
FAS 
Full Analysis Set 
GGT 
gamma glutamyltransferase 
HDL-C 
high-density lipoprotein cholesterol 
IB 
Investigator Brochure 
IC50 
50% inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IGA 
Investigator’s Global Assessment 
LDH 
lactate dehydrogenase 
LDL-C 
low-density lipoprotein cholesterol 
INR 
international normalized ratio 
IRB 
institutional review board 
IXRS 
interactive voice/web response system 
JAK 
Janus kinase 
HIV 
human immunodeficiency virus 
LOCF 
last observation carried forward 


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MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
pharmacokinetic(s) 
PTFU 
Post-treatment Follow-up 
PP 
per-protocol 
PP-NRS 
Peak Pruritus Numerical Rating Scale 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TC 
total cholesterol 
TG 
triglycerides 
TEAE 
treatment-emergent adverse event 
WBC 
white blood cell 
WOCBP 
women of childbearing potential 


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Appendix 1 Possible Hy’s Law Liver Chemistry Action and Follow-up 
Assessments 
Suggested Actions and Follow-up Assessments1  
Actions 
Follow-up Assessments 
x 
Immediately discontinue study medication. 
x 
Report the event to the sponsor or designee within 24 
hours. 
x 
Complete an SAE data collection tool if the event also 
met the criteria for an SAE.2 
x 
Perform liver chemistry follow-up assessments. 
x 
Monitor the participant until liver chemistry test 
abnormalities resolve, stabilize, or return to baseline 
(see MONITORING below). 
x 
Do not restart/rechallenge participant with study 
treatment unless allowed per the protocol and sponsor 
approval is granted. 
x 
If restart/rechallenge is either not allowed per the 
protocol or not granted, permanently discontinue 
study treatment. The participant may continue in the 
study for any protocol-specified follow-up assessments. 
 
MONITORING:  
If ALT ≥ 3×ULN AND bilirubin ≥ 2×ULN or INR > 1.5:  
x 
Repeat liver chemistry tests (ALT, AST, alkaline 
phosphatase, bilirubin) and perform liver event follow-
up assessments within 24 hours. 
x 
Monitor participant twice weekly until liver chemistry 
test abnormalities resolve, stabilize, or return to 
baseline. 
x 
A specialist or hepatology consultation is 
recommended. 
 
If ALT ≥ 3×ULN AND bilirubin < 2×ULN and INR ≤ 
1.5:  
x 
Repeat liver chemistry tests (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
chemistry follow-up assessments within 24 to 72 
hours.  
x 
Monitor participants weekly until liver chemistry 
abnormalities resolve, stabilize, or return to baseline. 
x 
Viral hepatitis serology3 
x 
Obtain INR and recheck with each liver chemistry 
assessment until the transaminases values show 
downward trend  
x 
Obtain blood sample for ATI-1777 drug 
concentration4 
x 
Serum CPK and lactate dehydrogenase 
x 
Fractionate bilirubin, if total bilirubin ≥ 2×ULN 
x 
Obtain complete blood count with differential to 
assess eosinophilia 
x 
Record the appearance or worsening of clinical 
symptoms of liver injury, or hypersensitivity, on 
the AE eCRF 
x 
Record use of concomitant medications (including 
acetaminophen, herbal remedies, and other over-
the-counter medications) on the concomitant 
medications eCRF 
 
If ALT ≥ 3×ULN AND bilirubin ≥ 2×ULN or INR > 
1.5:  
x 
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total immunoglobulin 
G or gamma globulins. 
x 
Serum acetaminophen adduct high performance 
liquid chromatography assay (quantifies potential 
acetaminophen contribution to liver injury in 
participants with definite or likely acetaminophen 
use in the preceding week. 
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
eCRF = electronic case report form; INR = international normalized ratio; SAE = serious adverse event; ULN = upper limit of 
normal 
1. 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not immediately 
available, discontinue study treatment if ALT ≥ 3×ULN and bilirubin ≥ 2×ULN. Additionally, if serum bilirubin 
fractionation testing is unavailable, record the absence/presence of detectable urinary bilirubin on dipstick which is 
indicative of direct bilirubin elevations suggesting liver injury. 
2. 
All events of ALT ≥ 3×ULN and bilirubin ≥ 2×ULN (> 35% direct bilirubin) or ALT ≥ 3×ULN and INR > 1.5 may 
indicate severe liver injury (possible ‘Hy’s Law’) and must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis). The INR measurement is not required and the stated threshold value will not apply to 
participants receiving anticoagulants. 


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3. 
Hepatitis A immunoglobulin M antibody; hepatitis B surface antigen and hepatitis B core antibody; hepatitis C ribonucleic 
acid; cytomegalovirus immunoglobulin M antibody; Epstein-Barr viral capsid antigen immunoglobulin M antibody (or, if 
unavailable, heterophile antibody or monospot testing); and hepatitis E immunoglobulin M antibody. 
4. 
Drug concentration sample may not be required for participants known to be receiving placebo or non-comparator 
treatments. Record the date/time of the blood sample draw and the date/time of the last dose of study treatment prior to the 
blood sample draw in the eCRF. If the date or time of the last dose is unclear, provide the participant’s best approximation. 
If the date/time of the last dose cannot be approximated, do not obtain a blood sample. Instructions for sample handling and 
shipping are in the reference manual. 
 
 
 


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PRA-QMS-02745 9.0 
 
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Strictly Confidential.  © 2020, PRA Health Sciences.  All rights reserved. 
Appendix 2 Study Medication Interruption Criteria 
Laboratory Test 
Hold Study Medication if:  
Resume Study Medication if:  
WBC count  
< 2×109/L  
≥ 2.5×109/L  
ANC 
< 1×109/L  
≥ 1.5×109/L  
Lymphocyte count  
< 0.5×109/L  
≥ 0.75×109/L  
Platelet count  
< 75×109/L  
≥ 100×109/L 
Hemoglobin 
8 g/dL or a decrease > 2g/dL  
≥ 10 g/dL  
AST or ALT 
> 3×ULN  
< 2×ULN or within 20% of baseline 
values  
Serum creatinine 
> 2×ULN  
< 1.5×ULN or within 10% of baseline 
value  
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; ULN = 
upper limit of normal range; WBC = white blood cell 
 


Statistical Analysis Plan (SAP) 
Version Date: 06NOV2020  
 
Sponsor: Aclaris Therapeutics 
 
Protocol no: ATI-1777-AD-201 
PRA-QMS-02745 9.0 
 
Page 29 of 30 
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Appendix 3 Adverse Event Start/Stop Date Study Imputation 
Imputation Rules for Partial Dates (D = day, M = month, Y = year) 
Parameter 
Missing 
Additional Conditions 
Study Imputation 
Start date for 
AEs 
D 
M and Y same as M and Y of first dose of 
study drug 
Date of first dose of study drug 
M and/or Y not same as date of first 
dose of study drug 
First day of month 
D and M 
Y same as Y of first dose of study 
drug 
Date of first dose of study drug 
Y prior to Y of first dose of study drug 
but same as Y of screening date 
Date of screening date 
D, M, Y 
None - date completely missing 
Date of first dose of study drug 
Stop date for 
AEs 
D 
M and Y same as M and Y of last dose 
of study drug 
Date of last dose of study drug 
M and/or Y not same as date of last 
dose of study drug 
Use last day of month 
D and M 
Y same as Y of last dose of study drug 
Date of last dose of study drug 
Y not same as Y of last dose of study 
drug 
Use Dec 31 
D, M, Y 
None - date completely missing 
No imputation, but assume 
ongoing 
Note: In all cases, if an estimated start date is after a complete stop date, use the first day of the stop date month. 
Similarly, if the estimated stop date is before a complete or imputed start date, use the last day of the start day month. 
 
 
 


Statistical Analysis Plan (SAP) 
Version Date: 06NOV2020  
 
Sponsor: Aclaris Therapeutics 
 
Protocol no: ATI-1777-AD-201 
PRA-QMS-02745 9.0 
 
Page 30 of 30 
Strictly Confidential.  © 2020, PRA Health Sciences.  All rights reserved. 
Appendix 4 Prior and Concomitant Medication Start/Stop Date Study 
imputation 
Imputation Rules for Partial Dates (D = day, M = month, Y = year) 
Parameter 
Missing 
Additional Conditions 
Study imputation 
Start date for 
con meds 
D only 
M and Y same as M and Y of first dose 
of study drug 
Date of first dose of study 
drug 
M and/or Y not same as date of first dose 
of study drug 
First day of month 
M and D 
Y same as Y of first dose of study 
drug 
Date of first dose of study drug 
Y not same as Y of first dose of study drug Use Jan 01 of Y 
M, D, and Y 
None - date completely missing 
Day prior to date of first dose of 
study drug 
Stop date for 
con meds 
D only 
M and Y same as M and Y of last dose of 
study drug 
Date of last dose of study drug 
M and/or Y not same as date of last 
dose of study drug 
Last day of month 
M and D 
Y same as Y of last dose of study drug 
Date of last dose of study 
drug 
Y not same as Y of last dose of study drug Use Dec 31 of Y 
M, D, and Y 
None - date completely missing and 
NOT ongoing 
Date of last dose of study drug 
Note: In all cases, if an estimated start date is after a complete stop date, use the first day of the stop date month. 
Similarly, if the estimated stop date is before a complete or imputed start date, use the last day of the start day month.