Clinical trial NCT03315689
Conditions: Alopecia Universalis (AU) Alopecia Totalis (AT)
Sponsor: Aclaris Therapeutics, Inc.
Start date: 2017-12-14; Completion date: 2019-06-20
Enrollment: 11 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of ATI-50002 Topical Solution compared to vehicle in subjects with AU and AT.

Detailed description:
This study is designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of ATI-50002 Topical Solution in patients with Alopecia Universalis and Alopecia Totalis. Concentrations of ATI-50002 in the blood and skin will be assessed after 28 days of treatment with ATI-50002 Topical Solution.

Arms: arm 1: Vehicle arm 2: ATI-50002 Topical Solution
Interventions: intervention 1: Vehicle intervention 2: ATI-50002
Intervention descriptions: intervention 1: Vehicle Topical Solution intervention 2: ATI-50002 Topical Solution

Protocol documents:
Prot_000.pdf: 
Protocol: ATI-50002-AA-202 
Aclaris Therapeutics, Inc. 
 
 
                                                                           CONFIDENTIAL                                          
Date: 14AUG2018, Version 3.0                          Page 1 of 68 
 
CLINICAL STUDY PROTOCOL 
Protocol Number: ATI-50002-AA-202 
 
A Randomized, Double-blind, Vehicle-controlled Multicenter Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of ATI-50002 Topical Solution 
Administered Twice-Daily for 28 Days in Adult Subjects with Alopecia Universalis and 
Alopecia Totalis with a 12-Month Long-term Open-label Extension 
 
 
Sponsor 
 
Aclaris Therapeutics, Inc. 
640 Lee Rd 
Suite 200 
Wayne, PA 19087 
Telephone: 484-324-7933 
Facsimile: 484-320-2344 
 
Study Contact 
Sue Moran, RN, MSN 
Sr. Director, Clinical Development 
Aclaris Therapeutics, Inc. 
640 Lee Rd 
Suite 200 
Wayne, PA 19087 
Telephone: 484-329-2129 
Cell: 484-999-7492 
E-mail: smoran@aclaristx.com 
 
Medical Monitor 
Terrence Chew, MD, RAC 
Aclaris Therapeutics, Inc. 
640 Lee Road 
Suite 200 
Wayne, PA 19087 
Telephone: 858-922-6307 
Serious Adverse Event Facsimile: 484-324-2359 
E-mail: tgchew@icloud.com 
 
 
 
 
 
This document is a privileged and confidential communication of Aclaris Therapeutics, Inc. Acceptance of this 
document constitutes an agreement by the recipient that no unpublished information contained herein will be used, 
published or disclosed without prior written approval from Aclaris Therapeutics, Inc. 


Protocol: ATI-50002-AA-202 
Aclaris Therapeutics, Inc. 
 
 
 
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Date: 14AUG2018, Version 3.0                          Page 2 of 68 
 
PROTOCOL APPROVAL SIGNATURE PAGE 
 
Protocol Number:  ATI-50002-AA-202 
Version 3.0:  14AUG2018 
 
Protocol Title: A Randomized, Double-blind, Vehicle-controlled Multicenter Study to Evaluate 
the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ATI-50002 Topical Solution 
Administered Twice-Daily for 28 Days in Adult Subjects with Alopecia Universalis and Alopecia 
Totalis with a 12-Month Long-term Open-label Extension.  
 
 
 
 
Sponsor Signatures: 
 
 
 
____________________________________ 
________________________ 
David Gordon, MB, ChB 
Date 
Chief Medical Officer 
Aclaris Therapeutics, Inc. 
 
 
 
 
____________________________________ 
________________________ 
Christopher Powala 
Date 
Chief Regulatory and Development Officer 
Aclaris Therapeutics, Inc. 
 
 
 
 
 
 


Protocol: ATI-50002-AA-202 
Aclaris Therapeutics, Inc. 
 
 
 
                                                                           CONFIDENTIAL                                          
Date: 14AUG2018, Version 3.0                          Page 3 of 68 
 
INVESTIGATOR SIGNATURE PAGE 
Protocol Number:  ATI-50002-AA-202 
Version 3.0:  14AUG2018 
 
Protocol Title: A Randomized, Double-blind, Vehicle-controlled Multicenter Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of ATI-50002 Topical Solution Administered 
Twice-Daily for 28 Days in Adult Subjects with Alopecia Universalis and Alopecia Totalis with a 12-
Month Long-term Open-label Extension  
 
I have reviewed the above-titled protocol and agree that it contains all the information necessary to conduct 
the study as required.  I will conduct the trial in accordance with the principles of ICH Good Clinical 
Practice and the Declaration of Helsinki. 
I will maintain as confidential all written and verbal information provided to me by the Sponsor, including 
but not limited to, the protocol, case report forms, investigator’s brochure, material supplied at investigator 
meetings, minutes of teleconferences, etc.  Such materials will only be provided as necessary to site 
personnel involved in the conduct of the trial, involved IRBs or local regulatory authorities. 
I will obtain written informed consent from each prospective trial subject or each prospective trial subject’s 
legal representative prior to conducting any protocol-specified procedures.  The Informed Consent 
Document used will have the approval of the IRB appropriate for my institution. 
 
I will maintain adequate source documents and record all observations, treatments and procedures pertinent 
to trial subjects in their medical records.  I will accurately complete the case report forms supplied by the 
Sponsor in a timely manner.  I will ensure that my facilities and records will be available for inspection by 
representatives of the Sponsor, the IRB, and/or local regulatory authorities.  I will ensure that I and my staff 
are available to meet with Sponsor representatives during regularly scheduled monitoring visits. 
I will notify the Sponsor within 24 hours of any serious adverse events.  Following this notification, a 
written report describing the serious adverse event will be provided to the Sponsor as soon as possible, but 
no later than five days following the initial notification. 
 
 
Investigator Signature: 
 
 
____________________________________ 
________________________ 
Investigator signature 
 
Date 
 
 
____________________________________ 
 
Investigator printed name 
 
 
 
 


Protocol: ATI-50002-AA-202 
Aclaris Therapeutics, Inc. 
 
 
 
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Date: 14AUG2018, Version 3.0                          Page 4 of 68 
 
AMENDMENT HISTORY: 
Protocol Amendment 1, Version 2.0, dated 06FEB2018 added a 6-month open-label extension to allow 
subjects to receive ATI-50002 Topical Solution, 0.46%.  In addition, to assist with enrollment and to 
facilitate enrollment of subjects less than 60 years of age, the amendment specified that after the first 6 
subjects were enrolled in the study, the blood PK samples were no longer collected.  Administrative 
Letters 1 through 5 were incorporated into Protocol Amendment 1.  Administrative Letter #1 (dated 
October 2, 2017) outlined the change from a single center to a multicenter study, clarified that M689 
would not be measured and that the method for the detection of ATI-50002 in the scalp was a qualified 
method.  Administrative Letter #2 (dated December 19, 2017) added superficial tape stripping of the scalp 
biopsy site for pharmacokinetic analysis to remove any residual study medication in the upper layers of 
the stratum corneum prior to biopsy.  Administrative Letter #3 (dated January 22, 2018) allowed for a 
decrease in the volume of study medication applied from 4 mL to 1.5 mL to 4 mL, and Administrative 
Letter #4 (dated January 29, 2018) updated the address for Aclaris Therapeutics, Inc.  Administrative 
Letter #5 (dated 03AUG2018) clarified the treatment duration of the Open Label Extension (OLE) portion 
of the study for subjects with a gap between Visit 7 and entry into the OLE due to an administrative 
delay. 
 
AMENDMENT RATIONALE: 
The primary purpose of Amendment 2, Version 3.0 dated 14AUG2018 is to increase the duration of the 
open-label extension (OLE) to 12 months. 
 
Protocol 
Version 
Date 
Section 
Revision 
Version 1.0 
26JUL2017 
NA 
NA 
Version 2.0 
06FEB2018 
Title page 
Protocol Approval Signature Page 
Investigator Signature Page 
Synopsis 
Replaced single center with multicenter 
in the title and added 6-Month Long-term 
open label Extension 
Title page 
Removed Julian McKay-Wiggan 
Title page 
Section 10.2.2, Procedure for 
Reporting Adverse Events 
Updated the Medical Monitor to:  
Terrence Chew, MD, RAC 
Synopsis, Number of Study Sites 
Section 6.1, Number of Subjects 
Updated site number to two. 
Synopsis, Study Design, Endpoints, 
Statistical Methods 
Section 7.1 Overall Study Design 
Section 9.3.2 Blood Samples 
Section 12.4 Pharmacokinetic 
Analysis 
Concentrations of M689 in the blood will 
not be measured. 
Synopsis:  Endpoints section 
Clarified that the bioanalytical methods 
for the skin biopsy are qualified and not 
fully validated methods. 
Section 9.3.1, Scalp Biopsy 
Appendix 5, Scalp Biopsy 
Added tape stripping of the area of the 
scalp that will be biopsied for 
pharmacokinetic analysis with 5 D-
Squame circular discs. 
Synopsis: Study Design, Study 
Medication Administration 
Section 7.1 Overall Study Design 
Section 8.3 Application of Study 
Medication 
Appendix 1, Subject Instructions 
Changed the volume of study medication 
applied to the scalp from 4 mL to a 
minimum of 1.5 mL up to a maximum of 
4 mL of study medication. 


Protocol: ATI-50002-AA-202 
Aclaris Therapeutics, Inc. 
 
 
 
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Date: 14AUG2018, Version 3.0                          Page 5 of 68 
 
Protocol 
Version 
Date 
Section 
Revision 
Synopsis, multiple sections 
Applicable sections throughout the 
protocol 
Clarified Double-blind period and Added 
Open-Label Extension information, 
including additional visits, study 
medication and statistical analyses. 
Synopsis, Inclusion Criteria 
Section 6.3, Inclusion Criteria 
Added Inclusion Criteria 11: Sexually 
active male subjects must agree to use a 
barrier method of contraception from the 
first application of study medication to at 
least 30 days after the last application of 
study medication. 
 
 
Synopsis, Exclusion Criteria 
Section 6.5.2, Prohibited and/ or 
Restricted Medications 
Clarified Exclusion Criterion #15; JAK 
inhibitor exclusion is for both topical and 
oral. 
Clarified Exclusion Criterion #16; 
alopecia areata includes (AA, AU, AT) 
Section 3.1, Summary 
Clarified the purpose of the study is to 
determine if topical application of ATI-
50002 will result in regrowth of the scalp 
hair loss and if applicable, eyebrow hair 
loss due to AU and AT. 
Section 4.1, Study Rationale 
Added a description of how subjects will 
enter the open label extension and 
nonclinical justification for 6-month 
treatment duration. 
Synopsis, Study Design, Statistical 
Methods 
Section 7.1, Overall Study Design 
Section 7.3, Schedule of Assessments 
Section 12.4, PK analyses 
Added that only the first 6 subjects 
enrolled will have the pharmacokinetic 
blood samples will not be collected. 
Section 7.3, Schedule of Assessments 
Update Table to reflect additional study 
visits for open-label extension. 
Section 8.8, Other Study Supplies 
Added ECG equipment and supplies for 
PD samples. 
Section 8.10, Study Medication 
Packaging 
Added subjects must complete double-
blind treatment to be eligible for entry 
into the open-label extension, 
Clarified controlled room temperature 
conditions for study medication storage, 
Described open-label study medication 
supplies. 
Section 9.4, Eyebrow Assessments 
(Open-Label Extension) 
Added the Clinician’s Eyebrow 
Assessment and Subject’s Eyebrow 
Assessments at Day 29 and monthly 
throughout the open-label extension 
period. 
Section 10.2.4.1, Study Medication 
Interruption 
Replaced hold with interrupt and clarified 
that Study medication can be resumed 
after the abnormal laboratory value 
returns to normal or baseline, if in the 
opinion of the Investigator, it is in the 
best interest of the subject to continue.  
Section 11.2 Highly Effective Methods 
of Birth Control 
Added Obstruction of fallopian tubes via 
medical device (EssureTM). 


Protocol: ATI-50002-AA-202 
Aclaris Therapeutics, Inc. 
 
 
 
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Date: 14AUG2018, Version 3.0                          Page 6 of 68 
 
Protocol 
Version 
Date 
Section 
Revision 
Section 12.5.4 Secondary Analyses 
Added efficacy and satisfaction analyses 
consistent with potential hair regrowth 
from longer treatment duration. 
Appendix 1, Subject Instructions for 
Study Medication Application to the 
Scalp 
Added study subjects should avoid 
strenuous exercise that would cause 
profuse sweating for at least 6 hours after 
study medication application. 
Added instructions for avoidance of 
exposure of scalp to excessive natural or 
artificial ultraviolet radiation and 
sunscreen information. 
 
Appendix 2, Subject Instructions for 
Study Medication Application to the 
Eyebrow(s) 
Added study medication instructions for 
subjects with eyebrow loss who are 
participating in the open-label extension. 
Appendix 3, Alopecia Areata History 
Simplified the AA history  
 
 
Protocol 
Minor editorial changes and corrections 
of typographical errors were made. 
Version 3.0 
14AUG2018 
Synopsis  
  Study Design 
  Duration of Treatment 
  Endpoints 
  Study Medication Administration 
Section 4.1, Study Rationale 
Section 6.5.1 Permitted Concomitant 
Therapies and Over the Counter 
Products (OTC) 
Section 6.8, Subject Withdrawal 
criteria 
Section 7.1, Study Design 
Section 7.3, Schedule of Assessments 
Section 7.5, Duration of the Study 
Section 8.1, Investigational Study 
Medication 
Section 8.2, Subject Randomization 
Section 8.4, Study Medication 
Weights 
Section 8.5, Treatment Compliance 
Section 9.1.1, SALT Score 
Section 9.1.2, ALODEX Score 
Section 9.4, Eyebrow Assessments 
Section 9.4.1, Clinician’s Eyebrow 
Assessment 
Section 9.4.2, Subject’s Eyebrow 
Assessment 
Section 9.5.2, Physical Examination 
Section 9.5.3, Clinical Laboratory 
Assessments 
Section 9.5.4, Pregnancy Tests 
Section 9.6.2, Photographic 
Assessment 
 
Revised the duration of open-label 
treatment from 6 months to 12 months 
and added two additional visits (Visit 15 
and 16).  Post-treatment follow-up Visit 
14 is now Visit 16. Maximum duration of 
study participation is 400 days (393 + 7 
days). 


Protocol: ATI-50002-AA-202 
Aclaris Therapeutics, Inc. 
 
 
 
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Protocol 
Version 
Date 
Section 
Revision 
 
Synopsis, Efficacy Assessments 
Section 12.5.4, Secondary Analyses 
 
Added Week 40 and 52 to the SALT, 
ALODEX, Subject Satisfaction, CEA and 
SEA analyses 
Section 3.1, Summary, Overview of 
Alopecia Areata 
Revised statement from AA is “the most 
prevalent” to “a prevalent” autoimmune 
disease in the United States 
 
Section 4.2 Study Rationale 
Removed “6 month update” from the 9-
month minipig study with dermal 
administration since full 9-month report 
is completed. 
Added update from currently enrolled 
subjects. 
 
Section 8.7, Study Medication 
Accountability  
Added language to allow sites with a 
written drug destruction/disposal policy 
to dispose of unused and used 
investigational product on-site rather than 
returning to Aclaris. 
 
Section 8.10 Study Medication 
Packaging, Labeling, Storage and 
Security 
Revised number of bottles to be 
dispensed. 


Protocol: ATI-50002-AA-202 
Aclaris Therapeutics, Inc. 
 
 
 
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SYNOPSIS 
Protocol Number: 
ATI-50002-AA-202 
 
 
Protocol Title:  
Double-blind, Vehicle-controlled Multicenter Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of ATI-50002 
Topical Solution Administered Twice-Daily for 28 Days in Adult Subjects 
with Alopecia Universalis and Alopecia Totalis with a 12-Month, Long-
Term, Open-Label Extension  
 
Sponsor: 
Aclaris Therapeutics Inc. 
 
Phase of Development:  Phase 2 
 
 
Study Medication Description: 
ATI-50002 Topical Solution, 0.46% 
Vehicle Topical Solution 
Study Objectives: 
Primary: 
To assess safety, tolerability, pharmacokinetics and pharmacodynamics of ATI-50002 Topical 
Solution, 0.46% compared to vehicle in subjects with alopecia universalis (AU) and alopecia totalis 
(AT)  
Secondary Objectives: 
To assess the efficacy of ATI-50002 Topical Solution, 0.46% for the treatment of scalp hair loss and 
eyebrow in subjects with AU or AT. 
 
To assess subject satisfaction following treatment with ATI-50002 Topical Solution, 0.46% for the 
treatment of scalp hair loss in subjects with AU or AT.  
Study Design:   
During the double-blind period, this Phase 2, multicenter, randomized study is designed to evaluate the 
safety, tolerability, pharmacokinetics and pharmacodynamics of ATI-50002 Topical Solution in 
subjects with AU and AT.  Subjects will be required to have a clinical diagnosis of stable, clinically 
typical, AU or AT for a duration of at least 6 months up to and including seven years.  In the double-
blind phase, a total of approximately 12 subjects will be randomized to a 2:1 ratio: 
• 
ATI-50002 Topical Solution, 0.46%, BID for 28 days (8 subjects) 
• 
Vehicle Solution BID for 28 days (4 subjects) 
 
During the screening period, subjects will be assessed for eligibility into the study.  Subjects who meet 
all the entry criteria will be randomized to ATI-50002 Topical Solution, 0.46% or Vehicle Topical 
Solution and will apply a minimum of 1.5 mLs up to a maximum of 4 mLs of study medication to the 
entire scalp twice-a-day (BID) for 28 days (except for Day 1 and Day 28 when study medication will 
only be applied once a day). For the first 6 subjects enrolled in the study, blood samples for 
concentrations of ATI-50002 will be collected on Day 1 (Visit 2) and Day 28 (Visit 6) at pre-dose and 
1, 2, 4, 8 hours post dose and on Day 2 (Visit 3) and Day 29 (Visit 7) at 24 hours post-dose.  Blood 
samples for immunology will be collected on Day 1 (Visit 2) before study medication application and 
on Day 29 (Visit 7), 24 hours after study medication application on Day 28 (Visit 6).  A 4-mm punch 
biopsy of the scalp will be obtained to determine the concentration of ATI-50002 in the scalp skin on 
Day 2 (Visit 3) and on Day 29 (Visit 7) 24 hours after study medication application on Day 1 (Visit 2) 
and on Day 28 (Visit 6).  A 4-mm punch biopsy will be obtained to determine histology and 
immunology, prior to study medication application on Day 1 (Visit 2) and on Day 29 (Visit 7), 24 
hours after study medication application on Day 28 (Visit 6).  Safety and tolerability will be evaluated 


Protocol: ATI-50002-AA-202 
Aclaris Therapeutics, Inc. 
 
 
 
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Date: 14AUG2018, Version 3.0                          Page 9 of 68 
 
at each study visit by assessment of adverse events and vital signs, and at select visits, ECGs and 
clinical laboratory tests will be completed. 
 
Open-Label Extension: 
On Day 29 (Visit 7) subjects who complete Visit 7, continue to meet the entry criteria, have no 
clinically significant AEs or tolerability issues and in the opinion of the investigator have experienced 
or are capable of re-growing scalp hair will be eligible to enter a 12-month open-label extension.    In 
the open-label extension, safety, tolerability and efficacy will be assessed.  All subjects enrolled in the 
open-label extension will apply ATI-50002 Topical Solution, 0.46% to the entire scalp, twice daily for 
52 weeks (12 months).  In addition, subjects with eyebrow loss may apply a thin film of study 
medication to the affected eyebrow(s) twice-daily for 52 weeks (12 months).  Subjects will be followed 
for safety, tolerability and efficacy as detailed in Section 7.3.  Subjects who decline or are not eligible 
for the open-label extension should be seen for the Visit 16 (Post-treatment) assessments 30 days 
following the Day 28 (Visit 6). The duration of the open-label extension (OLE) should be based on the 
date of the visit that the subject initiated OLE treatment rather than the days from Baseline (Visit 2).  
For subjects who entered the open-label extension and had a gap between Visit 7 and entry into the 
open-label extension due to an administrative delay total study participation may be longer than 400 
days.    
Number of Subjects (planned): 
12 subjects will be enrolled into the study. 
Number of Study Sites: 
This study will be conducted at two clinical sites. 
Inclusion Criteria: 
Subjects must meet all the following criteria to be eligible for participation in the study.   
1. Able to comprehend and willing to sign an Informed Consent Form (ICF). 
2. Male or non-pregnant, non-nursing female ≥18 years old at the time of informed consent. 
3. Have a clinical diagnosis of stable, clinically typical, alopecia universalis or alopecia totalis. 
4. Have a duration of the current episode of AU or AT for a minimum of 6 months and a 
maximum of seven years.  
5. Have > 95% total scalp hair loss as measured by the Severity of Alopecia Tool (SALT). 
6. If a woman of childbearing potential (WOCBP), must have a negative serum pregnancy test at 
Screening (Visit 1) and a negative urine pregnancy test (UPT) at Baseline (Visit 2) and agree 
to: use a highly effective method of birth control for the duration of the study; not be planning 
a pregnancy during the study duration and use contraception for 30 days after last application 
of study medication (Refer to Section 11). 
7. Be in good general health and free of any known disease state or physical condition which, in 
the investigator’s opinion, might impair evaluation of the subject or which might expose the 
subject to an unacceptable risk by study participation. 
8. Be willing and able to follow all study instructions and to attend all study visits. 
9. Subjects taking hormonal replacement therapies must be on stable doses for 6 months prior to 
enrollment and remain on the same maintenance dose throughout the study.  
10. Subjects taking thyroid replacement medication must be on stable doses for 6 months prior to 
enrollment and remain on the same maintenance dose throughout the study.  
11. Sexually active male subjects must agree to use a barrier method of contraception from the first 
application of study medication to at least 30 days after the last application of study 
medication. 
 
Exclusion Criteria: 
Subjects are excluded from this study if any 1 or more of the following criteria is met: 
1. Females who are nursing, pregnant, or planning to become pregnant for the duration of the study 
including 30 days after the last application of study medication.  


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2. Patchy alopecia areata, diffuse alopecia areata or a history of an atypical pattern of AA (e.g., 
ophiasis, sisaipho). 
3. Concomitant hair loss disorder (by history or physical exam) such as androgenetic alopecia or 
scarring alopecia (e.g., cicatricial alopecia, frontal fibrosing alopecia, etc.).  
4. Active skin disease on the scalp (such as psoriasis or seborrheic dermatitis) or a history of skin 
disease on the scalp that in the opinion of the investigator would interfere with the study 
assessments of efficacy or safety. 
5. Active scalp trauma or other condition affecting the scalp that, in the investigator’s opinion, may 
affect the course of AU or AT or interfere with the study conduct or evaluations. 
6. The presence of a permanent or difficult to remove hairpiece or wig that will, in the opinion of 
the investigator, interfere with study assessments if not removed at each visit.   
7. History of or current severe, progressive or uncontrolled renal, hepatic, gastrointestinal, 
pulmonary, cardiovascular, genitourinary (renal disease) or hematological disease, neurologic 
or cerebral disorders, infectious disease or coagulation disorders that, as determined by the 
Investigator, would preclude participation in and completion of study assessments. 
8. History of, current or suspected systemic or cutaneous malignancy and/or lymphoproliferative 
disease, other than subjects with a history of adequately treated and well healed and completely 
cleared non-melanoma skin cancers (basal or squamous cell carcinoma) treated successfully at 
least 1 year prior to study entry with no evidence of disease.   
9. Evidence of active or latent bacterial (including tuberculosis) or viral infections at the time of 
enrollment, or history of incompletely treated or untreated tuberculosis.  Subjects who have 
completed therapy for latent tuberculosis may participate. 
10. History of a serious local infection (e.g., cellulitis, abscess) or systemic infection including but 
not limited to a history of treated infection (e.g., pneumonia, septicemia) within 3 months of 
baseline (Visit 2). Subjects on an antibiotic for a non-serious, acute local infection must complete 
the course prior to enrollment into the study. 
11. Positive for HIV, Hepatitis B or C.  Subjects with serologic evidence of Hepatitis B vaccination 
(HepB surface Ab without the presence of HepB sAg) will be allowed to participate. 
12. Herpes zoster or cytomegalovirus (CMV) that resolved less than 2 months before study 
enrollment. Subjects with a history of frequent outbreaks of Herpes Simplex Virus (defined as 4 
or more outbreaks a year). 
13. Clinically significant laboratory abnormalities at screening that, in the opinion of the 
Investigator, would make the subject a poor candidate for the study.   
14. Subjects with absolute neutrophil count <1,000/mm3, or platelet count <50,000/mL. 
15. Subject unable to comply with the following required washout periods: 
 
Therapy/Medication 
Washout Period 
Systemic Therapies 
Disease Modifying Anti-Rheumatic Drugs (DMARDS), 
Biologics or immunosuppressants, such as: anakinra, 
adalimumab, azathioprine, corticosteroids, cyclosporine, 
etanercept, infliximab, methotrexate, TNF inhibitors, 
ustekinumab 
1 month or 5 half-lives whichever is 
greater 
Plaquenil 
2 months 
 
JAK inhibitors (oral or topical) 
Prior or current treatment with a JAK 
inhibitor is prohibited at any time 
Intralesional Steroids on the Scalp 
1 month 


Protocol: ATI-50002-AA-202 
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Topical Treatments on the Scalp 
 
Anthralin, bimatoprost, corticosteroids, diphencyprone, 
diphenylcycloprophenone (DPCP), Squaric acid dibutylester 
(SADBE), minoxidil, pimecrolimus, tacrolimus 
1 month 
Phototherapy, Laser Therapy, Excimer Laser 
3 months 
  
16. Participation in an investigational drug or device trial in which administration of an 
investigational study drug or device occurred within 30 days or 5 half-lives (whichever is longer) 
of Screening (Visit 1).  Subjects who have participated in a study of an investigational drug, 
device or biologic agent for alopecia areata (AA, AU or AT) within 1 year of screening will be 
eligible to participate only with individual permission from the Medical Monitor. 
17. Sensitivity to any of the ingredients in the study medications. 
18. History of or current alcohol or drug abuse within 2 years of assessment for study enrollment. 
19. Screening ECG findings of: 
• 
QTcF >450msec for males or >470msec for females (use of the ECG algorithm is 
acceptable for this purpose) 
• 
Heart rate < 45 or > 100 beats/minutes (inclusive) 
• 
Rhythm disturbance other than sinus arrhythmia or ectopic supraventricular rhythm 
(ectopic atrial rhythm) 
• 
Conduction disturbance including PR >240msec, pre-excitation (delta wave and PR 
<120msec), second degree or higher AV block 
• 
Acute or chronic signs of ischemia  
• 
Left Bundle Branch Block 
• 
Prior myocardial infarction 
 
Duration of Treatment 
Double-blind Treatment 
Screening period up to 30 days.   
Double-blind treatment period is 29 days (maximum of 28 days of study medication application).   
Post-treatment Visit 16 is up to 33 days (30 +3 days) following Day 29 for subjects not continuing into 
the open-label extension.   
Total study participation for subjects from Baseline (Visit 2) through Post-treatment Visit 16(Day 59 + 
3 days) is up to 62 days (29 + 33).  
Double-Blind + Open-Label Extension 
The duration of the total study participation from Baseline (Visit 2) to Week 56 (Visit 16) is anticipated 
to be a maximum of 400 days (393 + 7 days). 
The duration of the open-label extension (OLE) should be based on the date of the visit that the subject 
initiated OLE treatment rather than the days from Baseline (Visit 2).  For subjects who entered the 
open-label extension and had a gap between Visit 7 and entry into the open-label extension due to an 
administrative delay total study participation may be longer than 400 days. 
 
Endpoints 
Pharmacokinetic: 
Concentrations of ATI-50002 in the blood and ATI-50002 in the skin will be measured by a 
bioanalytical lab using fully validated analytical methods for the blood and qualified methods for the 
skin. 
   
Pharmacodynamic: 


Protocol: ATI-50002-AA-202 
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Change from Baseline in the effects of ATI-50002 induced Janus kinase (JAK) 1/3 inhibition on the 
ALADIN scores, peribulbar infiltrate and other inflammatory biomarkers. 
 
 
Safety: 
Safety variables to be assessed include: adverse events, clinical laboratory tests (hematology, clinical 
chemistry, and urinalysis), vital sign measurements (systolic and diastolic blood pressures, respiration 
rate, heart rate, and oral body temperature), and electrocardiograms. 
 
Efficacy Assessments: 
Early signs of vellus hair regrowth are expected to take a minimum of 3 to 6 months in this population. 
Measurable terminal hair regrowth may take at least 6 months or longer.   
 
Change from baseline in Severity of Alopecia Tool (SALT) score at Week 28 (Visit 13), Week 40 
(Visit 14) and Week 52 (Visit 15). 
 
Change from baseline in Alopecia Density and Extent Score (ALODEX) at Week 28 (Visit 13) Week 
40 (Visit 14) and Week 52 (Visit 15). 
 
Subject Satisfaction at Week 28 (Visit 13), Week 40 (Visit 14) and Week 52 (Visit 15). 
 
Descriptive summaries of changes from entry into long-term open-label extension in CEA and SEA at 
Week 28 (Visit 13), Week 40 (Visit 14) and Week 52 (Visit 15) will be performed for those subjects 
with eyebrow loss.   
Study Medication Administration 
Double-blind Period:  Subjects will apply a minimum of 1.5 mLs up to a maximum of 4 mLs of 
topical solution to the entire scalp twice-daily as directed. 
 
Open-label Period:  Subjects will apply a minimum of 1.5 mLs up to a maximum of 4 mLs of topical 
solution to the entire scalp twice-daily as directed.  In addition, subject may apply a thin film of study 
medication to the entire affected eyebrow(s) twice-daily for up to 12 months. 
 
Statistical Methods 
Sample Size/ Power Calculations 
The planned sample size is 12 subjects.   
 
Statistical Methods 
Pharmacokinetic Analyses 
Blood Samples  
Blood samples for analysis of the concentration of ATI-50002 will be taken from the first 6 subjects 
enrolled into the study at Day 1 (Visit 2) and Day 28 (Visit 6) at predose (0 hr), 1, 2, 4, 8 and on Day 2 
(Visit 3) and Day 29 (Visit 7) at 24 hours post dose.  For each subject, standard PK parameters will be 
calculated, based on the plasma concentrations of ATI-50002.   
 
Scalp Biopsy 
The concentration of ATI-50002 will be determined in a 4-mm punch biopsy of the scalp taken 24 hours 
post study medication application in the office on Day 2 (Visit 3) and Day 29 (Visit 7).     
 
Pharmacodynamic (Biomarker) Analyses 
ALADIN Scores         


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The cytotoxic T lymphocyte infiltration (CTL), Interferon (IFN-gamma), and hair keratin (KRT) 
ALADIN scores will be calculated for each scalp biopsy sample as previously described in Xing et al, 
2014, Jabbari 2016.  Change in ALADIN scores within individual subjects will be assessed between 
Baseline (Visit 2), Day 29 (Visit 7) and Week 28 (Visit 13) for subjects enrolled into the open-label 
extension.  
 
Histology 
Scalp punch-biopsies will be formalin-fixed and paraffin-embedded and will be sectioned both vertically 
and horizontally by a qualified dermatopathologist.  Specimens will be stained with hematoxylin and 
eosin (H&E) for routine histopathologic evaluation that will include (but is not limited to) diagnosis and 
evaluation of the presence, quantity, location, and quality of any hair, hair follicles, and inflammatory 
infiltrate present.  Additionally, immunohistochemical (IHC) stains will be employed to identify immune 
cell populations (e.g., Lymphocytes, cytotoxic T-lymphocytes [CTLs]), and hair-specific keratins.  IHC 
stains to assess inflammatory responses will include (but not be limited to) CD8, HLA-DR and ICAM-
1.  Data will be presented as percent change from baseline in the number of cells/ high power field in 
regions of interest (peribulbar areas) and in percent change from baseline in the number of cells/mm2. 
 
Blood for Immunology 
Blood samples will be stained with cell surface antibodies for fluorescence acquisition cell sorting 
(FACS) analysis.  FACS experiments will allow for assessment of the subset and activation status of 
immune cells involved in AA.  
 
Safety Data 
Safety analyses will include descriptive statistics calculated on the safety parameters using the safety 
population. The proportion of subjects with treatment-emergent adverse events will be tabulated and 
presented by treatment and Medical Dictionary for Regulatory Activities (MedDRA) System Organ 
Class. Vital signs and clinically significant abnormal laboratory results will also be tabulated and 
presented by treatment group. Overall incidence of adverse events will be compared between groups 
using a chi-square test. 
 
Data from all randomized and treated subjects will be presented and summarized. Safety summaries by 
study treatment group will include listings by study medication of adverse events incidences within 
each MedDRA System Organ Class, and changes from pre-application values in vital signs. Adverse 
event summaries will be presented by study medication showing the proportion of subjects 
experiencing adverse events, both overall and by MedDRA System Organ Class.  
 
 
 
 


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TABLE OF CONTENTS 
 
SYNOPSIS ........................................................................................................................................... 8 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................................... 18 
 
INTRODUCTION ............................................................................................................................. 21 
3.1. 
Summary ...................................................................................................................................... 21 
 
STUDY RATIONALE........................................................................................................................ 24 
4.1. 
Study Rationale ........................................................................................................................... 24 
 
STUDY OBJECTIVE ......................................................................................................................... 25 
5.1.1. 
Primary Objective .................................................................................................................... 25 
5.1.2. 
Secondary Objectives .............................................................................................................. 25 
 
SELECTION AND DISPOSITION OF STUDY POPULATION ....................................................... 26 
6.1. 
Number of Subjects ..................................................................................................................... 26 
6.2. 
Study Population Characteristics ............................................................................................ 26 
6.3. 
Inclusion Criteria ........................................................................................................................ 26 
6.4. 
Exclusion Criteria ....................................................................................................................... 26 
6.5. 
Previous and Concomitant Medications and Therapies ..................................................... 28 
6.5.1. 
Permitted Concomitant Therapies and Over the Counter Products (OTC) .................. 28 
6.5.2. 
Prohibited and/ or Restricted Medications ........................................................................ 29 
6.6. 
Subject Identifier (SI) ................................................................................................................. 30 
6.7. 
Replacement Subjects ................................................................................................................ 30 
6.8. 
Subject Withdrawal Criteria ..................................................................................................... 30 
6.9. 
Study Termination ...................................................................................................................... 30 
 
INVESTIGATIONAL PLAN.............................................................................................................. 31 
7.1. 
Overall Study Design .................................................................................................................. 31 
7.2. 
Study Procedures ........................................................................................................................ 32 
7.3. 
Schedule of Assessments ........................................................................................................... 33 
7.4. 
Subject Nourishment .................................................................................................................. 37 
7.5. 
Duration of the Study ................................................................................................................. 37 
 
STUDY TREATMENT ...................................................................................................................... 37 
8.1. 
Investigational Study Medication ............................................................................................ 37 
8.2. 
Subject Randomization .............................................................................................................. 38 
8.3. 
Application of Study Medication .............................................................................................. 38 
8.4. 
Study Medication Weights ........................................................................................................ 39 
8.5. 
Treatment Compliance .............................................................................................................. 39 


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8.6. 
Dose Modification ....................................................................................................................... 39 
8.7. 
Study Medication Accountability ............................................................................................. 40 
8.8. 
Other Study Supplies .................................................................................................................. 40 
8.9. 
Blinding ........................................................................................................................................ 40 
8.9.1. 
Unblinding the Study Medication (Double-blind Period) ................................................ 40 
8.10. 
Study Medication Packaging, Labeling, Storage and Security ............................................ 41 
 
STUDY ASSESSMENTS ................................................................................................................... 42 
9.1. 
Efficacy Assessments .................................................................................................................. 42 
9.1.1. 
Severity Alopecia Tool (SALT) Score .................................................................................... 42 
9.1.2. 
Alopecia Density and Extent Score (ALODEX) .................................................................... 42 
9.2. 
Pharmacodynamic (Biomarker) Assessment ....................................................................... 42 
9.2.1. 
Scalp Biopsy (PD) ..................................................................................................................... 42 
9.2.2. 
Blood for Immunologic Evaluation (T-cells)....................................................................... 42 
9.3. 
Pharmacokinetic Assessment .................................................................................................. 43 
9.3.1. 
Scalp Biopsy (PK) ..................................................................................................................... 43 
9.3.2. 
Blood Samples (Double-blind Period) ................................................................................. 43 
9.4. 
Eyebrow Assessments (Open-Label Extension) ................................................................... 43 
9.4.1. 
Clinician’s Eyebrow Assessment (CEA) (Open-Label Period) ......................................... 43 
9.4.2. 
Subject’s Eyebrow Assessment (SEA) (Open-Label Period): ........................................... 44 
9.5. 
Assessment of Safety .................................................................................................................. 44 
9.5.1. 
Vital signs ................................................................................................................................... 45 
9.5.2. 
Physical Examination .............................................................................................................. 45 
9.5.3. 
Clinical Laboratory Assessments .......................................................................................... 45 
9.5.4. 
Pregnancy tests......................................................................................................................... 46 
9.5.5. 
ECGs ............................................................................................................................................ 46 
9.6. 
Other Assessments ..................................................................................................................... 47 
9.6.1. 
Demographics, Medical History and Alopecia Areata History ........................................ 47 
9.6.2. 
Photographic Assessment ...................................................................................................... 47 
 
ADVERSE EVENTS .......................................................................................................................... 47 
10.1. 
Definitions .................................................................................................................................... 47 
10.1.1. Adverse Events (AE) ................................................................................................................ 47 
10.1.2. Serious Adverse Event (SAE).................................................................................................. 48 
10.1.3. Unexpected Adverse Event ..................................................................................................... 49 
10.1.4. Adverse Event Reporting Period ........................................................................................... 49 


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10.1.5. Severity ...................................................................................................................................... 49 
10.1.6. Relationship to Study Medication ......................................................................................... 49 
10.2. 
Reporting Procedures ................................................................................................................ 49 
10.2.1. Procedures for Reporting Adverse Events .......................................................................... 49 
10.2.2. Procedure for Reporting a Serious Adverse Event ............................................................ 50 
10.2.3. Safety Monitoring ECG Discontinuation Criteria ............................................................... 50 
10.2.4. Study Medication Interruption and Discontinuation........................................................ 51 
10.2.4.1 Study Medication Interruption ........................................................................................... 51 
10.2.4.2 Study Medication Discontinuation ..................................................................................... 52 
 
PREGNANCY .................................................................................................................................... 52 
11.1. 
Definition of Women of Child Bearing Potential (WOCBP) ................................................ 52 
11.2. 
Highly Effective Methods of Birth Control ............................................................................. 52 
 
STATISTICAL ANALYSES ............................................................................................................... 54 
12.1. 
Sample Size and Power Calculations ....................................................................................... 54 
12.2. 
Analysis Populations .................................................................................................................. 54 
12.3. 
Demographic and Baseline Characteristics ........................................................................... 54 
12.4. 
Pharmacokinetic Analyses ........................................................................................................ 54 
12.5. 
Pharmacodynamic (Biomarker) Analyses............................................................................. 54 
12.5.1. ALADIN Scores .......................................................................................................................... 54 
12.5.2. Histology .................................................................................................................................... 55 
12.5.3. Blood for Immunology ............................................................................................................ 55 
12.5.4. Secondary Analyses ................................................................................................................. 55 
12.6. 
Safety Analyses ............................................................................................................................ 56 
 
TRAINING, MONITORING, DATA MANAGEMENT AND QUALITY ASSURANCE .................... 56 
13.1. 
Training ........................................................................................................................................ 56 
13.2. 
Monitoring ................................................................................................................................... 56 
13.3. 
Data Management ....................................................................................................................... 57 
13.4. 
Quality Assurance ....................................................................................................................... 57 
 
ETHICS AND GENERAL STUDY CONDUCT CONSIDERATIONS ................................................ 57 
14.1. 
Institutional Review Board (IRB)/Ethics Committee (EC) ................................................. 57 
14.2. 
Ethical Conduct of the Study ..................................................................................................... 57 
14.3. 
Subject Information and Consent ............................................................................................ 58 
14.4. 
Study Conduct and Protocol Amendments ............................................................................ 58 
14.5. 
Regulatory Documents .............................................................................................................. 58 


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14.6. 
Contractual Requirements ........................................................................................................ 58 
14.7. 
Data Collection and Archiving .................................................................................................. 59 
14.7.1. Data collection .......................................................................................................................... 59 
14.7.2. Source documentation ............................................................................................................ 59 
14.7.3. Archiving .................................................................................................................................... 59 
 
References ...................................................................................................................................... 60 
:  Subject Instructions for Study Medication Application to the Scalp .................... 62 
:  Subject Instructions for Study Medication Application to the 
Eyebrow(s) ..................................................................................................................................... 64 
:  Alopecia Areata History ................................................................................................ 66 
:  Fitzpatrick’s Skin Type Chart ....................................................................................... 67 
:  Scalp Biopsy ..................................................................................................................... 68 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AA 
Alopecia Areata 
AE  
Adverse Event 
AGA 
Androgenic Alopecia 
ALADIN 
Alopecia Areata Disease Activity Index 
ALODEX 
Alopecia Density and Extent Score 
ALT 
Alanine aminotransferase 
ANC 
Absolute Neutrophil Count 
ANOVA 
Analysis of Variance 
AST 
Aspartate Aminotransferase 
AT 
Alopecia Totalis 
AU 
Alopecia Universalis 
AUC 
Area Under the Curve 
BID, b.i.d. 
Twice-daily 
BUN 
Blood Urea Nitrogen 
°C 
Degrees Centigrade 
CD 
Cluster of Differentiation 
CEA 
Clinician’s Eyebrow Assessment 
CI 
Confidence Interval 
Cmax 
Maximum concentration 
CMV 
Cytomegalovirus 
CRA 
Clinical Research Associate 
eCRF 
Electronic Case Report Form 
CRO 
Contract Research Organization 
CS 
Clinically Significant 
CTL 
Cytotoxic T-lymphocytes 
DMARDs 
Disease Modifying Anti-Rheumatic Drugs 
DPCP 
Diphenylcyclopropenone 
e.g.  
for example (Latin; exempla gratia) 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ERT 
eResearchTechnology, Inc. 
et al. 
and others (Latin; et alia) 
°F 
Degrees Fahrenheit 
FACS 
Fluorescence Acquisition Cell Sorting 
FDA 
Food and Drug Administration 
G 
Gram 
GCP 
Good Clinical Practice 


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Abbreviation 
Term 
HCl 
Hydrochloride 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
Human Immunodeficiency Virus 
H&E 
Hematoxylin and Eosin 
HLA-DR 
Human Leukocyte Antigen- antigen D Related 
ICAM-1 
Intercellular Adhesion Molecule 1 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
i.e.  
that is (Latin; id est) 
IFN 
Interferon 
IHC 
Immunohistochemical  
IL 
Interleukin 
ITT 
Intent-to-Treat 
IRB 
Institutional Review Board 
JAK 
Janus Kinase  
KER 
Hair keratin panel 
KRT 
Hair Keratin 
LDH 
Lactate dehydrogenase 
MeDRA 
Medical Dictionary for Regulatory Activities 
MHC 
Major Histocompatibility Complex 
mL 
Milliliter 
Mm 
Millimeter 
NCS 
Not Clinically Significant 
NK/ NKG 
Natural Killer/ Natural Killer Group 
NMSC 
Nonmelanoma Skin Cancer 
OLE 
Open Label Extension 
OTC 
Over-The-Counter 
PDT 
Photodynamic Therapy 
PP 
Per-protocol 
PUVA 
Psoralen and Ultraviolet A 
SADBE 
Squaric Acid Dibutyl Ester 
SAE 
Serious Adverse Event 
SALT 
Severity of Alopecia Tool 
SEA 
Subject’s Eyebrow Assessment 
SI 
Subject identifier 
SN 
Subject Number 
SOP 
Standard Operation Procedure 
STAT 
Signal Transducer and Activator of Transcription 
T1/2 
Elimination half-life 


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Abbreviation 
Term 
TEAE 
Treatment Emergent Adverse Event 
Tmax 
Time to Maximum Concentration 
TNK 
Tumor Necrosis Factor 
Tyk2 
Tyrosine Kinase 2 
UPT 
Urine Pregnancy Test 
US 
United States 
UVA 
Ultraviolet A  
UVB 
Ultraviolet B 
WOCBP 
Women of childbearing potential  


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INTRODUCTION 
Aclaris Therapeutics, Inc. is developing ATI-50002 Topical Solution for the treatment of alopecia 
areata.  ATI-50002 is a potent highly selective inhibitor of Janus kinase 1 (JAK1) and Janus kinase 
3 (JAK3). 
 
3.1. 
Summary 
Overview of Alopecia Areata 
 
Alopecia areata (AA) is an autoimmune dermatologic condition, which, in its mildest form, is 
typically characterized by patchy non-scarring hair loss on the scalp and/or body.  More severe 
forms of AA include total scalp hair loss, known as alopecia totalis (AT), and total loss of all the 
hair on the scalp and body- importantly, including loss of eyebrows, eyelashes, and intranasal hair- 
known as alopecia universalis (AU).  While spontaneous regrowth of hair is common in the milder 
form of AA (patchy), where the hair loss may wax and wane, in patients with the extensive hair 
loss of AT or AU, spontaneous hair regrowth is rare.  AA affects both males and females across 
all ethnic groups and is a  prevalent autoimmune disease in the United States, with a lifetime risk 
of 1.7% (Safavi 1995).  About two-thirds of affected individuals are 30 years old or younger at the 
time of disease onset.  
 
The course of AA is unpredictable and while up to 50% of patients may recover within 1 year even 
without treatment, most patients will have more than one episode of hair loss (Price 2008).   Factors 
portending a poorer prognosis for regrowth are more extensive hair loss presentations (extensive 
AA, AT, AU), an ophiasis pattern of hair loss, a long duration of hair loss, a positive family history, 
the presence of other autoimmune diseases, nail involvement, and young age of first onset (Tosti 
2006, Weise 1996).  In children, the disease may have a tendency towards worsening with time 
even if the initial presentation was mild, and the progressively disfiguring nature of the disease 
can be psychologically devastating. AA is highly associated with numerous psychiatric 
comorbidities including adjustment disorders, anxiety disorders and depression in both children 
and adults, and an effective treatment for AT and AU, the more severe forms of the disease, 
represents a significant unmet medical need (Bilgic 2014, Ruiz-Doblado 2003, Alkhalifah 2010).  
 
The clinical development of innovative therapies in AA has lagged far behind other autoimmune 
conditions and there are currently no evidence-based treatments for AA. A Cochrane database 
review highlighted that few therapies for AA have been comprehensively evaluated in randomized 
clinical trials and that no treatment has demonstrated significant benefit compared to placebo 
according to evidence-based assessments (Delamere, 2008).  This lack of good evidence-based 
data remains a challenge for physicians attempting to select efficacious treatments for their patients 
and, as a result, numerous approaches to treatment exist and are typically based on considerations 
such as the age of the patient, the extent and/or duration of the disease, patient expectations, cost 
considerations (both time and financial resources) and physician preferences and experience. 
 
Common treatments for the less severe (patchy) form of AA include corticosteroids, either 
topically applied or injected intralesionally into the alopecic areas, or the induction of an allergic 
reaction at the site of hair loss using a topical contact sensitizing agent- an approach known as 
topical immunotherapy- typically with the topical contact sensitizers diphenylcycloprophenone 


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(DPCP), squaric acid dibutyl ester (SADBE), or treatment with topical anthralin.  While these 
same treatment options may be utilized for the more severe forms of AA, their use in the more 
severe forms of AA is limited not only due to limited efficacy, but also because of the 
impracticality of using them over extensive body surface areas.  Additional treatments used for 
extensive forms of AA (AT, AU) have included systemic steroids (pulsed or chronically 
administered), immunosuppressive agents such as cyclosporine or methotrexate, phototherapy 
with psoralen +UVA (PUVA), narrow-band UVB, photodynamic therapy (PDT), laser therapy 
(e.g., excimer laser, fractional photothermolysis lasers), prostaglandin analogs, etanercept, 
bexarotene and others, all with varying degrees of success and each with its inherent risk of adverse 
effects and unproven efficacy (Alkhalifah 2010, Price 1999, Hordinsky 2015, Strober 2005).  Most 
recently, however, a breakthrough in the understanding of the pathophysiology of AA and several 
case reports in the literature have suggested that a group of inhibitors of the JAK-STAT pathway, 
the Janus Kinase (JAK) inhibitors, or “jakinibs” may be efficacious in the treatment of AA even 
in its most severe phenotypes, AT and AU (Jabbari, 2015, Pieri, 2015, Xing 2014).  
 
The JAKs are members of a family of tyrosine kinases that are involved in cytokine receptor 
signaling.  The JAK family of enzymes (JAK1, JAK2, JAK3, Tyk2) plays an essential role in 
regulating the signaling process of most cytokines in cells by linking the cytokine-induced 
signaling from the cell surface membrane receptors to signal transducers and activators of 
transcription, or STATs, within the cells. Once these JAK receptors are activated by the binding 
of a cytokine to the appropriate receptor, they initiate a JAK-STAT signaling pathway which can 
modify gene expression and modulate important regulatory functions in the cell, including 
regulating immune and inflammatory responses.  JAK1 and JAK3 are constitutively associated 
with the alpha chain and the common gamma chain (γc), respectively, of the receptors for 
interleukin-2 (IL2), interleukin-4 (IL-4), interleukin-7 (IL-7) interleukin-9 (IL-9), interleukin-15 
(IL-15), and interleukin-21 (IL-21).  When these cytokines bind to their respective receptors, JAK1 
and JAK3 are activated and initiate a signaling cascade that drives key inflammatory events, 
including lymphocyte activation and proliferation. The JAK inhibitors can block the cytokine 
receptor signaling pathways, (in this instance JAK1 and JAK3) blocking JAK-STAT transcription 
activation, and can therefore modulate inflammatory or immune responses, which can be 
beneficial in a variety of disease states, particularly, as recently reported, AA (Xing 2014).   In that 
report, pharmacologic inhibition of JAK kinase signaling (JAK-STAT signaling) was reported to 
promote hair growth in both genetic mouse models of alopecia and in human patients. 
 
Immunopathology & Pathophysiology of AA 
Alopecia areata (AA) results from an autoimmune attack on the hair follicles that results in 
growing anagen-phase terminal hairs being induced to prematurely enter the telogen-phase and 
then shed.  In its most acute state, AA demonstrates a histopathologically characteristic white cell 
infiltrate- the so called “swarm of bees”- encircling the human hair follicle, though more chronic 
forms typically demonstrate a sparser infiltrate (Jabbari 2016, Whiting 2003). Though the exact 
autoantigens expressed in the perifollicular epithelium that allow these specific T-cells to infiltrate 
the normally immunologically privileged hair follicle have been previously unknown, the T-cells 
that home to the hair follicle have been demonstrated to consist of both CD4 and CD8 cells.  Most 
recent studies have further characterized a specific subpopulation of activated NKG2D-bearing 
CD8+ T-cells as being prominent in the peribulbar infiltrate, and it is now currently felt that these 
CD8+NKG2D+ effector T-cells preferentially localize to dermal sheath cells aberrantly expressing 


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high levels of MHC molecules and NKG2D ligands.  Interferons, as key activators of the MHC 
locus and of the cellular immune response, appear to play a key role in eliminating the 
immunologic privilege of the hair follicle and in inducing and maintaining the pathologic 
inflammatory response in AA.  This is also seen in the C3H-HeJ mouse model of AA, in which 
IFN-γ is required for pathogenesis, and in which administration of IFN-γ accelerates disease. 
(Gilhar 2005, Hirota 2003). 
 
AA has been viewed as a Th1-driven disease and, consistent with a pathogenic cellular immune 
response, elevated Th1 cytokines/ chemokines (IFN-induced chemokines [IP-10/CXCL10]) are 
seen in the peripheral blood of AA patients and IFN-inducible gene signatures have been described 
in the skin of AA patients and may correlate with disease activity (Arca 2004, Barahmani 2009, 
Kuwano 2007).  Additionally, transcriptional profiles in human AA patients have shown a Type I 
IFN response in lesional biopsies and Th1 skewing and elevated IFN response 
cytokines/chemokines in both the peripheral blood and in reviewed scalp biopsies (Jabbari 2015, 
Xing 2014, Jabbari 2016).  The cellular source of IFN-γ is hypothesized to be the T-cells, as in the 
AA mouse model IFN-gamma producing CD8+NKG2D+ cells dominate the dermal HF infiltrate, 
and in human AA, IFN-γ producing cells were identified in 4 of 5 dermal crawl-out assays 
(Christiano 2016).  Additionally, data implicate IL- 15 in driving activation of IFN-producing CD8 
T-cells (Xing 2014).  
 
Thus, preclinical and preliminary clinical information, as discussed above, strongly suggests that 
the primary pathophysiologic mechanism in AA (including AT and AU) is a cytokine mediated 
(primarily through T-lymphocyte induced upregulation of IL-15 and IFN gamma) induction of and 
prolonged maintenance of the telogen stage of the hair cycle.  Inhibitors of the JAK/STAT 
pathway, particularly JAK1 and JAK3, are known to downregulate the effects of both IFN-gamma 
(through the inhibition at JAK1), and IL-15 (through inhibition at both JAK1 and JAK 3), and 
several published case reports have demonstrated the potential for compounds that are JAK1/3 
inhibitors to induce hair growth in patients with AA (Kim 2017, Craiglow 2014, Craiglow 2017, 
Gupta 2016, Scheinberg 2016).  As ATI-50002 is a potent inhibitor at JAK 1 and JAK 3, it is 
strongly suggested that ATI-50002 may be effective in the treatment of AA, AU and AT. 
 
Among patients with AA, patients with higher disease burdens are unlikely to have satisfactory 
outcomes with current therapies. Aclaris Therapeutics, Inc. is developing ATI-50002 as a topical 
treatment for stable AA.  Aclaris is also developing ATI-50001 for the treatment of AA, AU and 
AT.  ATI-50001 is an oral pro-drug that is rapidly converted pre-systemically to ATI-50002, a 
potent highly selective inhibitor of Janus kinase 1 (JAK1) and Janus kinase 3 (JAK3).  In this 
study, we will be evaluating whether or not the topically applied JAK1/JAK3 inhibitor, ATI-
50002, will result in regrowth of scalp hair loss and if applicable, eyebrow hair loss due to 
underlying AU and AT. 
 
In a previous Phase 1 study in healthy volunteers, single ascending oral doses of ATI-50001 of 50 
mg to 500 mg and multiple ascending doses of up to 400 mg BID were well-tolerated.  There were 
no SAEs.  All treatment emergent adverse events (TEAEs) were transient and mild in intensity 
with the exception of 4 TEAEs: facial bone fracture, headache (2), and catheter site pain, which 
were classified as moderate.  The most frequently reported drug related TEAEs occurring in > 1% 
of subjects were abdominal pain (10%), flatulence (7%), diarrhea (6%) and headache (6%).  Three 


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subjects showed mildly elevated ALT or AST concentrations, which in two subjects were 
considered not clinically significant.  For the other subject, the mild ALT elevation was reported 
as a treatment emergent adverse event possibly related to the study drug.  No clinically significant 
laboratory abnormalities were observed.  There were no clinically significant findings from 12-
lead ECGs or vital signs assessments.   
 
ATI-50001 was not detected in plasma and there was a dose-related increase in plasma of the 
active metabolite ATI-50002. The half-life of ATI-50002, after 14 days of dosing, was 
approximately 9.0 hours.  Systemic levels of ATI-50002, following oral doses of ATI-50001 in 
healthy volunteers transiently reduced pSTAT5 activity in ex vivo IL-2 stimulated lymphocytes, 
indicating inhibition of the JAK signaling pathway.  Upon multiple dosing, pSTAT5 activity 
showed a more sustained inhibition during the dosing period.   
 
Non-clinical studies conducted with oral administration of ATI-50001 and topical administration 
of ATI-50002 support the topical administration of ATI-50002 (ATI-50002 Topical Solution 
Investigator Brochure).   
 
 
STUDY RATIONALE 
4.1. 
Study Rationale 
Preclinical and preliminary clinical information, as discussed above, strongly suggests that the 
primary pathophysiologic mechanism in AA (including AT and AU) is a cytokine-mediated 
(primarily through T-lymphocyte induced upregulation of IL-15 and IFN gamma) induction of and 
prolonged maintenance of the telogen stage of the hair cycle.  Inhibitors of the JAK/STAT 
pathway, particularly JAK1 and JAK3, are known to downregulate the effects of both IFN-gamma 
(through the inhibition at JAK1), and IL-15 (through inhibition at both JAK1 and JAK 3), and 
several published case reports have demonstrated the potential for compounds that are JAK1/3 
inhibitors to induce hair growth in patients with AA, AU and AT.  As ATI-50002 is a potent 
inhibitor at JAK 1 and JAK 3, it is strongly suggested that ATI-50002 may be effective in the 
treatment of AA, AU and AT.   
 
The double-blind period of the study will evaluate the safety, tolerability, pharmacokinetics and 
pharmacodynamics of ATI-50002 Topical Solution, 0.46% compared to Vehicle Topical 
Solution applied twice-daily for 28 days in subjects with AU or AT.  On Day 1 (Visit 2) and Day 
28 (Visit 6), study medication will only be applied once a day. The study will include the 
assessment of the scalp hair loss at Baseline (Visit 2) and Day 29 (Visit 7) by both SALT and 
ALODEX.  Early signs of hair regrowth are expected to take a minimum of 3 to 6 months in this 
population.  Measurable hair regrowth may take at least 6 months or longer.  Data from SALT 
and ALODEX will be described but no formal statistical comparisons will be made between Day 
1 (Visit 2) and Day 29 (Visit 7) assessments. 
 
Subjects who complete the double-blind period without any clinically significant adverse events 
or tolerability issues as assessed by the Investigator and who continue to meet the entry criteria 
will have the option to enroll in the open-label extension.  The open-label period will evaluate 
the safety, tolerability and efficacy of ATI-50002 Topical Solution, 0.46% for the treatment of 
subjects with AU or AT. Subjects will apply ATI-50002 Topical Solution 0.46% to the entire 


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scalp, twice daily for 12 months.  In addition, subjects with eyebrow loss may apply a thin film 
of study medication to the affected eyebrow(s) twice-daily for 12 months.   
 
The 12-month open-label treatment period is supported by the results of 26-week mouse and 39-
week dog oral toxicity studies with systemic administration and the 9-month minipig study with 
dermal administration. 
 
ATI-50002-AA-202 Study Update 
Eleven subjects have been treated with ATI-50002 Topical Solution.  According to data entered 
into the eCRF as of August 3, 2018, five subjects experienced 7 adverse events; cold sore lesion, 
skin abrasion (scalp), hypertensive urgency, lower leg swelling, worsening depression, elevated 
A1C and headache/ migraine.  All adverse events were considered unrelated to study medication 
and all were reported as mild severity except for hypertensive urgency and worsening depression 
which were moderate in severity.   There were no serious treatment-related adverse events reported 
in the study.  One serious adverse event, worsening of depression, was reported in subject 01-005. 
The subject had a 48-year history of depression and a 3-year history of bipolar disorder.  She was 
treated with electroconvulsive therapy and the event is ongoing and assessed by the investigator 
as not related to study medication.  Levels of ATI-50002 in the blood were all below the limit of 
quantification (1 ng/mL) at all timepoints on Day 28.  Two subjects have discontinued from the 
study; both subjects withdrew consent.   
 
Early hair growth (reductions in SALT scores) is evident in 3 subjects who are currently on active 
treatment.  In order to continue to assess response to treatment given the favorable safety to date, 
this amendment will allow subjects to continue with twice-daily active study medication 
applications up to 12 months.    
   
 
STUDY OBJECTIVE 
5.1.1. 
Primary Objective 
The primary objective is to assess the safety, tolerability, pharmacokinetics and 
pharmacodynamics of ATI-50002 Topical Solution, 0.46% in subjects with AU or AT. 
 
5.1.2. 
Secondary Objectives 
Secondary objectives are: 
 
To assess the efficacy of ATI-50002 Topical Solution, 0.46% for the treatment of scalp hair loss 
and eyebrow in subjects with AU or AT. 
 
To assess subject satisfaction following treatment with ATI-50002 Topical Solution, 0.46% for 
the treatment of scalp hair loss in subjects with AU or AT. 
 


Protocol: ATI-50002-AA-202 
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SELECTION AND DISPOSITION OF STUDY POPULATION 
6.1. 
Number of Subjects 
Approximately 12 subjects will be enrolled in this study at two US investigational centers. 
 
6.2. 
Study Population Characteristics 
Male and female subjects, 18 years of age or older, with a clinical diagnosis of stable, clinically 
typical, alopecia universalis and alopecia totalis of the scalp, who meet all the inclusion criteria 
and none of the exclusion criteria, will be eligible to enroll in this study.  
 
6.3. 
Inclusion Criteria 
Subjects must meet the following criteria to be eligible for participation in the study: 
1. Able to comprehend and willing to sign an Informed Consent Form (ICF). 
2. Male or non-pregnant, non-nursing female ≥ 18 years old at the time of informed consent. 
3. Have a clinical diagnosis of stable, clinically typical, alopecia universalis or alopecia totalis. 
4. Have a duration of the current episode of AU or AT for a minimum of 6 months and a 
maximum of seven years.  
5. Have > 95% total scalp hair loss as measured by the Severity of Alopecia Tool (SALT). 
6. If a woman of childbearing potential (WOCBP), must have a negative serum pregnancy test 
at Screening (Visit 1) and a negative urine pregnancy test (UPT) at Baseline and agree to: use 
a highly effective method of birth control for the duration of the study; not be planning a 
pregnancy during the study duration and use contraception for 30 days after last application 
of study medication. (Refer to Section 11). 
7. Be in good general health and free of any known disease state or physical condition which, in 
the investigator’s opinion, might impair evaluation of the subject or which might expose the 
subject to an unacceptable risk by study participation. 
8. Be willing and able to follow all study instructions and to attend all study visits. 
9. Subjects taking hormonal replacement therapies must be on stable doses for 6 months prior to 
enrollment and remain on the same maintenance dose throughout the study.  
10. Subjects taking thyroid replacement medication must be on stable doses for 6 months prior to 
enrollment and remain on the same maintenance dose throughout the study.  
11. Sexually active male subjects must agree to use a barrier method of contraception from the 
first application of study medication to at least 30 days after the last application of study 
medication. 
 
6.4. 
Exclusion Criteria 
Subjects are excluded from this study if any 1 or more of the following criteria is met: 
1. Females who are nursing, pregnant, or planning to become pregnant for the duration of the 
study including 30 days after the last application of study medication. 
2. Patchy alopecia areata, diffuse alopecia areata or a history of an atypical pattern of AA (e.g., 
ophiasis, sisaipho). 
3. Concomitant hair loss disorder (by history or physical exam) such as; androgenetic alopecia, 
or scarring alopecia (e.g., cicatricial alopecia, frontal fibrosing alopecia, etc.).   


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4. Active skin disease on the scalp (such as psoriasis or seborrheic dermatitis) or a history of 
skin disease on the scalp that in the opinion of the investigator would interfere with the study 
assessments of efficacy or safety. 
5. Active scalp trauma or other condition affecting the scalp that, in the investigator’s opinion, 
may affect the course of AU or AT or interfere with the study conduct or evaluations. 
6. The presence of a permanent or difficult to remove hairpiece or wig that will, in the opinion of 
the investigator, interfere with study assessments if not removed at each visit.   
7. History of or current severe, progressive or uncontrolled renal, hepatic, gastrointestinal, 
pulmonary, cardiovascular, genitourinary (renal disease) or hematological disease, 
neurologic or cerebral disorders, infectious disease or coagulation disorders that, as 
determined by the Investigator, would preclude participation in and completion of study 
assessments. 
8. History of, current or suspected systemic or cutaneous malignancy and/or 
lymphoproliferative disease, other than subjects with a history of adequately treated and well 
healed and completely cleared non-melanoma skin cancers (basal or squamous cell 
carcinoma) treated successfully at least 1 year prior to study entry with no evidence of 
disease.   
9. Evidence of active or latent bacterial infection (including tuberculosis) or viral infections at 
the time of enrollment or history of incompletely treated or untreated tuberculosis.  Subjects 
who have completed therapy for latent tuberculosis may participate. 
10. History of a serious local infection (e.g., cellulitis, abscess) or systemic infection including 
but not limited to, history of treated (e.g., pneumonia, septicemia) within 3 months prior to 
baseline (Visit 2). Subjects on an antibiotic for a non-serious, acute local infection must 
complete the course prior to enrollment into the study. 
11. Positive for HIV, Hepatitis B or C.  Subjects with serologic evidence of Hepatitis B 
vaccination (HepB surface Ab without the presence of HepB sAg) will be allowed to 
participate. 
12. Herpes zoster or cytomegalovirus (CMV) that resolved less than 2 months before study 
enrollment. Subjects with a history of frequent outbreaks of Herpes Simplex Virus (defined 
as 4 or more outbreaks a year). 
13. Clinically significant laboratory abnormalities at screening that, in the opinion of the 
Investigator, would make the subject a poor candidate for the study.  
14. Subjects with absolute neutrophil count <1,000/mm3 or platelet count <50,000/mL.  
15. Subject unable to comply with the following required washout periods: 
 
Therapy/Medication 
Washout Period 
Systemic Therapies 
Disease Modifying Anti-Rheumatic Drugs 
(DMARDS), Biologics or immunosuppressants, 
such as: anakinra, adalimumab, azathioprine, 
corticosteroids, cyclosporine, etanercept, 
infliximab, methotrexate, TNF inhibitors, 
ustekinumab 
1 month or 5 half-lives whichever is greater 
Plaquenil 
2 months 
 
Prior or current treatment with a JAK inhibitor 
is prohibited at any time. 


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Therapy/Medication 
Washout Period 
Systemic Therapies 
JAK inhibitors (oral or topical) 
Intralesional Steroids on the Scalp 
1 month 
Topical Treatments on the Scalp 
 
Anthralin, bimatoprost, corticosteroids, 
diphencyprone, diphenylcycloprophenone 
(DPCP), Squaric acid dibutylester (SADBE), 
minoxidil, pimecrolimus, tacrolimus 
1 month 
Phototherapy, Laser Therapy, Excimer 
Laser 
3 months 
 
16. Participation in an investigational drug or device trial in which administration of an 
investigational drug or device occurred within 30 days or 5 half-lives (whichever is longer) 
of Screening (Visit 1).  Subjects having participated in a study of an investigational drug, 
device or biologic agent for alopecia areata (AA, AU, AT) within 1 year of screening will be 
eligible to participate only with individual permission from the Medical Monitor. 
17. Sensitivity to any of the ingredients in the study medications. 
18. History of or current alcohol or drug abuse within 2 years of assessment for study enrollment. 
19. Screening ECG findings of: 
• QTcF >450msec for males or >470msec for females (use of the ECG algorithm is 
acceptable for this purpose) 
• Heart rate < 45 or > 100 beats/minutes (inclusive) 
• Rhythm disturbance other than sinus arrhythmia or ectopic supraventricular rhythm 
(ectopic atrial rhythm) 
• Conduction disturbance including PR >240msec, pre-excitation (delta wave and PR 
<120msec), second degree or higher AV block 
• Acute or chronic signs of ischemia  
• Left Bundle Branch Block 
• Prior myocardial infarction 
 
6.5. 
Previous and Concomitant Medications and Therapies 
At Screening (Visit 1), the investigator or designee will question the subject to ensure they have 
not used any excluded therapies (Section 6.5.2). 
 
6.5.1. 
Permitted Concomitant Therapies and Over the Counter Products (OTC) 
 
Concomitant therapies are any new or existing therapies received from Screening (Visit 1) until 
Day 393 (Visit 16).  Concomitant therapies include drug (e.g. prescription and over the counter 
[OTC]), and non-drug (e.g., chiropractic, physical therapy, energy-based treatments).  
Subjects will be allowed to use therapies not restricted by the protocol if they have been on a stable 
dose prior to study entry.  Vitamins, minerals, and dietary supplements are permitted while on 


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study if the subject has been on a stable dose prior to study entry and, in the opinion of the 
Investigator, will not affect the safety or efficacy of the subject during the study.  Topical hair/scalp 
products (shampoos, conditioners, other products) should be reviewed by the Investigator and are 
permitted if, in the Investigator’s opinion, they will not affect the safety, pharmacokinetic or 
pharmacodynamic assessments of the subject during the study.  
Topical therapies such as topical corticosteroids are permitted if they are not applied on or near 
the scalp. Inhaled or intranasal corticosteroids are allowed in the study. 
 
Prior permitted concomitant medications taken within 30 days of beginning treatment with study 
medication will be documented in the subject’s source document and eCRF.  In addition, any new 
permitted medications administered during protocol treatment and through Week 56 (Visit 16) will 
be documented in the subject’s source document and eCRF.   
 
6.5.2. 
Prohibited and/ or Restricted Medications 
Any medication, shampoo or hair/ scalp product known to affect hair growth in AU or AT is 
prohibited throughout the study period.  Subjects who are on a stable dose of finasteride for benign 
prostatic hypertrophy for greater than 1 year, are eligible for enrollment into the study as long as 
they maintain the same stable dose throughout the study.  Since subjects with known AGA are 
excluded from the study, treatment with finasteride for alopecia during the study and within one 
year prior to study enrollment is prohibited.     
A list of medications and therapies that require a specific washout period prior to study entry and 
are not permitted during the study is in Table 1.   
Table 1:  Prohibited Medications 
Therapy/Medication 
Washout Period 
Systemic Therapies 
Disease Modifying Anti-Rheumatic Drugs 
(DMARDS), Biologics or immunosuppressants, 
such as: anakinra, adalimumab, azathioprine, 
corticosteroids, cyclosporine, etanercept, infliximab, 
methotrexate, TNF inhibitors, ustekinumab 
1 month or 5 half-lives whichever is greater 
Plaquenil 
2 months 
 
JAK inhibitors (oral or topical) 
Prior or current treatment with a JAK inhibitor is 
prohibited at any time 
Intralesional Steroids on the Scalp 
1 month 
Topical Treatments on the Scalp 
 
Anthralin, bimatoprost, corticosteroids, 
diphencyprone, diphenylcycloprophenone (DPCP), 
Squaric acid dibutylester (SADBE), minoxidil, 
pimecrolimus, tacrolimus 
1 month 
Phototherapy, Laser Therapy, Excimer Laser 
3 months 


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6.6. 
Subject Identifier (SI) 
The investigator will assign a unique five-digit subject identifier (SI) to each subject at Screening 
(Visit 1).  
 
The SI format will be NN-NNN, using leading zeroes as appropriate, where: 
• The first 2 digits are the investigational center site number assigned by Aclaris 
• The final 3 digits are the subject number (SN), assigned in ascending numerical order by 
the investigator or designee, without omitting or repeating any number, starting with 001.  
For example, the SI for the twenty-third subject that signs an informed consent form at site number 
01 would be 01-023. The subject will be identified using the SI in all study documentation for the 
duration of the study. 
6.7. 
Replacement Subjects 
Subject enrollment will continue until approximately 12 subjects have been randomized.  Subjects 
who are randomized and do not complete the study will not be replaced. 
 
6.8. 
Subject Withdrawal Criteria 
Subjects will be informed that they are free to withdraw from the study at any time and for any 
reason. The Investigator may remove a subject from the study if, in the Investigator's opinion, it is 
not in the best interest of the subject to continue the study. Examples of other reasons subjects may 
be discontinued from the study are: a change in compliance with an inclusion or exclusion 
criterion, occurrence of AEs, occurrence of pregnancy or use of a prohibited therapy. The 
Investigator or designee must inform the Aclaris Therapeutics, Inc. study monitor of any subject 
discontinuation.  (Refer to Section 10.2.4 for study medication discontinuation or termination 
criteria). 
 
In case of premature discontinuation of study participation, all efforts will be made to perform all 
Week 56 (Visit 16) assessments. The date the subject is withdrawn from the study and the reason 
for discontinuation must be recorded in the subject’s electronic case report forms (eCRFs). All 
withdrawn subjects with ongoing AEs will be followed until the event has resolved or stabilized, 
until the subject is referred to the care of a local health care professional, or until a determination 
of a cause unrelated to the study medication or study procedures is made. 
 
6.9. 
Study Termination 
This study may be terminated prematurely in whole or in part due to a change in the benefit/risk 
profile for ATI-50002 Topical Solution such that continuation of the study would not be justified 
on medical, business, or ethical grounds.  This determination may be made by the Study 
Investigators in conjunction with the Sponsor, or by IRB or the U.S. Food and Drug Administration 
(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-50002 development is 
discontinued. 


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If the study is terminated prematurely, the Sponsor will notify the Study Investigators and the 
FDA. The Investigator must promptly notify all enrolled subjects and the IRB of study termination. 
 
 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
In the double-blind period, this Phase 2, multicenter, randomized study is designed to evaluate 
the safety, tolerability, pharmacokinetics and pharmacodynamics of ATI-50002 Topical Solution 
in subjects with AU and AT.  Subjects will be required to have a clinical diagnosis of stable, 
clinically typical AU or AT for a duration of at least six months up to and including seven years.  
A total of 12 subjects will be randomized.   
 
During the screening period, subjects will be assessed for eligibility into the study.  Subjects who 
meet all the entry criteria will be randomized 2:1 to ATI-50002 Topical Solution, 0.46% or 
Vehicle Topical Solution and will apply a minimum of 1.5 mLs up to a maximum of 4 mLs of 
study medication to the entire scalp twice-a-day for 28 days. On Day 1 (Visit 2), Day 28 (Visit 
6), and Day 196 (1 day prior to Visit 13), subjects will apply study medication once-a-day. 
 
Blood samples for concentrations of ATI-50002 will be collected from the first 6 subjects 
enrolled into the study on Day 1 (Visit 2), and Day 28 (Visit 6) at pre-dose and 1, 2, 4, 8 hours 
post dose and on Day 2 (Visit 3) and Day 29 (Visit 7), 24 hours post-dose.  Blood samples for 
immunology will be collected on Day 1 (Visit 2) before study medication application, and on 
Day 29 (Visit 7), 24 hours after study medication application on Day 28 (Visit 6).  A 4-mm 
punch biopsy of the scalp will be obtained to determine the concentration of ATI-50002 in the 
scalp skin on Day 2 (Visit 3) 24 hours after study medication application on Day 1 (Visit 2) and 
on Day 29 (Visit 7), 24 hours after study medication application on Day 28 (Visit 6).  A 4-mm 
punch biopsy will be obtained to determine histology and immunology prior to study medication 
application on Day 1 (Visit 2).  Additional 4-mm punch biopsies to determine histology and 
immunology will be collected on Day 29 (Visit 7) and Day 197 (Visit 13), 24 hours after study 
medication application on Day 28 (Visit 6) and Day 196.  Safety and tolerability will be 
evaluated at each study visit by assessment of adverse events and vital signs, and at select visits, 
ECGs and clinical laboratory tests will be completed. 
 
On Day 29 (Visit 7) subjects who complete Visit 7, continue to meet the entry criteria and have 
no clinically significant AEs or tolerability issues will be eligible to enter a 12-month open-label 
extension.  In the open-label extension, safety, tolerability and efficacy will be assessed.  All 
subjects enrolled in the open-label extension will apply ATI-50002 Topical Solution, 0.46% to 
the entire scalp, twice daily for 52 weeks (12 months).  In addition, subjects with eyebrow loss 
may apply a thin film of study medication to the affected eyebrow(s) twice-daily for 52 weeks 
(12 months).  Subjects will be followed for safety, tolerability and efficacy as detailed in Section 
7.3.  Subjects who decline or are not eligible for the open-label extension should be seen for 
suture removal, if applicable per Section 7.3 and Visit 16 (Post-treatment) 30 days ± 3 days 
following the Day 28 (Visit 6).  Subjects enrolled in the initial 6-month Open Label Extension 
outlined by Protocol Amendment 1 (dated 06Feb2018) must be re-consented under Protocol 


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Amendment 2 (dated 14AUG2018) in order to continue for an additional 6 months of Open 
Label treatment.      
 
7.2. 
STUDY PROCEDURES 
The investigator or a designated and appropriately trained staff member should perform the study 
assessments according to the schedule of assessments. The same staff member should perform 
the assessments for a given subject throughout the study. If this becomes impossible, an 
appropriate designee with overlapping experience with the subject and study should perform the 
assessments. The same lighting conditions and subject positioning should be used for all 
evaluations for a given subject. 
 


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7.3. 
Schedule of Assessments 
 
Screening 
Baseline 
 Double Blind Treatment 
Visit  
1 
Visit  
2 
 
Visit 3 
Visit 4 
Visit 5 
 
Call 
Visit 6 
 
Visit 7 
Optional  
Visit 
(Suture Removal) 
Week 
 
0 
0 
1 
2 
4 
4 
4 
6 
Treatment Day 
-30 to 0 
1 
2 
8 
15 
27 
28 
29 
43 
Treatment Window(days) 
N/A 
N/A 
 
± 3 
± 3 
-3 
-3 
-3 
± 3 
Informed consent1 
X 
 
 
 
 
 
 
X17 
 
Inclusion/exclusion criteria  
X 
X 
 
 
 
 
 
 
 
Physical exam2 
X 
 
 
 
 
 
 
X 
 
Demographics & medical history 
X 
 
 
 
 
 
 
 
 
Alopecia Areata History  
X 
 
 
 
 
 
 
 
 
Vital signs3  
X 
X 
X 
X 
X 
 
X 
X 
X 
Clinical laboratory sampling4: CBC, Chemistry with lipids, Virology, Serum Pregnancy, Urinalysis  
X4 
X 
 
 
X 
 
 
X 
 
Urine pregnancy test (WOCBP)5 
 
X 
 
 
 
 
X 
 
 
ECG  
X 
X 
 
 
X 
 
 
X 
 
SALT Score (prior to ALODEX)6 
 
X 
 
 
 
 
 
X 
 
ALODEX Score (after SALT)7 
 
X 
 
 
 
 
 
X 
 
Clinician Eyebrow Assessment 
 
 
 
 
 
 
 
X18 
 
Subject Eyebrow Assessment 
 
 
 
 
 
 
 
X18 
 
Subject Global Impression of Treatment Satisfaction (SGIS) 
 
 
 
 
 
 
 
 
 
Photography8 
 
X 
 
 
 
 
 
X 
 
Subject randomization 
 
X 
 
 
 
 
 
 
 
Subject instructions9 
 
X 
X 
X 
X 
X 
X 
X17 
 
Biopsy for PK10 
 
 
X 
 
 
 
 
X 
 
Biopsy for PD11 
 
X 
 
 
 
 
 
X 
 
Blood sample for PK12 
 
X 
X 
 
 
 
X 
X 
 
Blood for immunologic studies13 
 
X 
 
 
 
 
 
X 
 
Dispense, collect, weigh study medication bottles14 
 
X 
X 
X 
X 
 
X 
X17 
 
In office study medication application9,14 
 
X 
 
 
 
 
X 
 
 
Suture removal, if applicable15 
 
 
 
 
X 
 
 
 
X 
Telephone Call16 
 
 
 
 
 
X 
 
 
 
Concomitant therapies 
 
X 
 
X 
X 
X 
X 
X 
X 
Adverse events  
 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Open-Label Treatment 
Post-
Treatment17 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Visit 12 
Call 
Visit 13 
Optional Visit 
(Suture Removal) 
Visit  
14 
Visit  
15 
Visit  
16 
Week 
8 
12 
16 
20 
24 
28 
28 
30 
40 
52 
56 
Treatment Day17 
57 
(OLE 28) 
85 
(OLE 56) 
113 
(OLE 84) 
141 
(OLE 112) 
169 
(OLE 140) 
196 
(OLE 167) 
197 
(OLE 168) 
211 
(OLE 182) 
281 
(OLE 252) 
365 
(OLE 336) 
59/ 393 
(OLE 364) 
Treatment Window(days) 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
+7 
± 3/± 7 
Informed consent1 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria  
 
 
 
 
 
 
 
 
 
 
 
Physical exam2 
 
 
 
 
 
 
 
 
 
 
X 
Demographics & 
medical history 
 
 
 
 
 
 
 
 
 
 
 
Alopecia Areata History  
 
 
 
 
 
 
 
 
 
 
 
Vital signs3  
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Clinical laboratory 
sampling4: 
CBC, Chemistry with 
lipids, Virology, Serum 
Pregnancy, Urinalysis  
 
X 
 
 
 
 
X 
 
X 
X 
X 
Urine pregnancy test 
(WOCBP)5 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
ECG  
 
X 
 
 
 
 
X 
 
 
 
X 
SALT Score (prior to 
ALODEX)6 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
ALODEX Score (after 
SALT)7 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Clinician Eyebrow 
Assessment 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Subject Eyebrow 
Assessment 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Subject Global 
Impression of Treatment 
Satisfaction (SGIS) 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Photography8 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Subject randomization 
 
 
 
 
 
 
 
 
 
 
 
Subject instructions9 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Biopsy for PD11 
 
 
 
 
 
 
X 
 
 
 
 
Blood for immunologic 
studies13 
 
 
 
 
 
 
X 
 
 
 
 


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Open-Label Treatment 
Post-
Treatment17 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Visit 12 
Call 
Visit 13 
Optional Visit 
(Suture Removal) 
Visit  
14 
Visit  
15 
Visit  
16 
Week 
8 
12 
16 
20 
24 
28 
28 
30 
40 
52 
56 
Treatment Day17 
57 
(OLE 28) 
85 
(OLE 56) 
113 
(OLE 84) 
141 
(OLE 112) 
169 
(OLE 140) 
196 
(OLE 167) 
197 
(OLE 168) 
211 
(OLE 182) 
281 
(OLE 252) 
365 
(OLE 336) 
59/ 393 
(OLE 364) 
Treatment Window(days) 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
+7 
± 3/± 7 
Dispense, collect, weigh 
study medication 
bottles14 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
In office study 
medication 
application9,14 
 
X 
 
 
 
 
 
 
 
 
 
Suture removal, if 
applicable15 
 
 
 
 
 
 
 
X 
 
X 
 
Telephone Call16 
 
 
 
 
 
X 
 
 
 
 
 
Concomitant therapies 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1A written signed ICF must be obtained from each subject prior to performing any study related procedure (i.e., prior to performing vital signs, standardized photography, biopsies, clinical 
laboratory sampling, or UPT). 
2A physical exam includes:  General appearance, examination of head, eyes, ears, nose and throat, respiratory, cardiovascular, abdominal, neurological, musculoskeletal, lymphatic and skin 
assessment. 
3 Vital signs include oral or ear temperature, blood pressure, heart rate, respiration rate (height and weight at Baseline only). 
4 Clinical laboratory sampling includes: CBC, Chemistry with lipids, Urinalysis, at each visit and At Screening only:  Quantiferon Gold, TIBC, Serum iron, Serum Ferritin, Serum pregnancy, T3, 
T4, and TSH. 
5 UPT must be performed prior to randomization at Visit 2 and prior to study medication application at Day 28 (Visit 6) and at each OLE visit. UPT must be negative for the subject to continue in 
the study.  WOCBP must have a negative serum pregnancy test at screening and a negative UPT at baseline prior to randomization. 
6SALT is performed prior to ALODEX score using device provided. 
7 ALODEX is performed after SALT score using device provided. 
8 Photography should be performed on Day 1 (prior to application of study medication application) and on Day 29 & Day 197 prior to the scalp biopsy.   
9Subjects must be instructed to apply the study medication according to the instructions in Appendix 1.  Subjects will apply the first dose of study medication on the morning of Day 1 (Visit 2) and 
the last application of study medication on the morning of Day 28 (Visit 6), under the instruction and supervision of the study staff.  Study medication at these visits should be applied in the 
morning to allow the 8-hour post dose assessments to occur at a reasonable time. On Day 1 (Visit 2) and Day 29 (Visit 7) subjects will only apply study medication once-a-day in the office. 
10 PK: A 4mm punch biopsy must be obtained on Day 2 (Visit 3) and Day 29 (Visit 7) 24 hours (± 30 minutes) after study medication application on Day 1 (Visit 2) and Day 28 (Visit 6). 
11 PD:  A 4mm punch biopsy must be obtained on Day 1 (Visit 2) before application of first dose of study medication and Day 29 (Visit 7) 24 hours (± 30 minutes) after study medication 
application.  Subjects that choose to continue in to open-label extension treatment will also have a 4mm punch biopsy collected on Day 197 (Visit 13). 
12PK: The first 6 subjects enrolled in the study will have the blood PK testing performed.  Blood for PK sampling will be obtained on Day 1 (Visit 2) and Day 28 (Visit 6), just prior to study 
medication application (predose), and 1, 2, 4, 8 hours post dose and on Day 2 (Visit 3) and Day 29 (Visit 7), 24 hours after study mediation application (on Day 1 (Visit 2) and Day 28 (Visit 6). See 
Section 9.3.2 for PK sample draw time windows. 


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Open-Label Treatment 
Post-
Treatment17 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Visit 12 
Call 
Visit 13 
Optional Visit 
(Suture Removal) 
Visit  
14 
Visit  
15 
Visit  
16 
Week 
8 
12 
16 
20 
24 
28 
28 
30 
40 
52 
56 
Treatment Day17 
57 
(OLE 28) 
85 
(OLE 56) 
113 
(OLE 84) 
141 
(OLE 112) 
169 
(OLE 140) 
196 
(OLE 167) 
197 
(OLE 168) 
211 
(OLE 182) 
281 
(OLE 252) 
365 
(OLE 336) 
59/ 393 
(OLE 364) 
Treatment Window(days) 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
+7 
± 3/± 7 
13 Blood for immunology will be obtained prior to administration of study medication on Day 1 (Visit 2) and on Day 29 (Visit 7) 24 hours (± 30 min) after study medication application on Day 28 
(Visit 6).  Subjects that choose to continue in to open-label extension treatment will also have blood for immunology collected on Day 197 (Visit 13). 
14 On Day 1 (Visit 2) and Day 28 (Visit 6) the study medication bottle should be weighed and then dispensed to the subject for the initial application under the supervision of study staff in the 
office.  After the initial application on Day 1, the study medication bottle should be collected, weighed and dispensed to the subject after the 24-hour post-dose blood draw on Day 2 (Visit 3).  For 
Visits 3 -6, each study medication bottle (with the cap) must be weighed before dispensing to the subject and at the time of return using the scale provided by Aclaris.  On Day 28 (Visit 6), the 
study medication bottle should be weighed after subject applies the study medication in the office and not redispensed. 
15 The investigator or designee will remove the sutures approximately 14 days after scalp biopsy, unless an absorbable suture is used. 
16 On Day 27 or the day prior to Day 28 (Visit 6), the study staff will call the subject to remind them not to apply study medication on the morning of Day 28 (Visit 6) and to bring both used and 
unused study medication bottles to the visit.  Study medication will be applied in the office under the supervision of the study staff.  On Day 196 or the day prior to Week 28 (Visit 13) the study 
staff will call the subject to remind them not to apply study medication in that evening and on the morning of Week 28 (Visit 13), and to bring both used and unused study medication bottles to the 
visit.  The scalp biopsy at Week 38 (Visit 13) should be performed 24 hours (±30 minutes) post the last study medication application. 
17On Day 29 (Visit 7) subject may be given the option to move into open-label extension treatment.   
• 
If the subject declines the open-label extension, she/he should be seen for the Visit 16 (Post-treatment) assessments 30 days following the date of Day 29 (Visit 7). 
• 
If the subject chooses to continue in to the open-label extension, she/he must sign an ICF prior to being dispensed open-label drug and receiving continued study medication application 
instructions.  
• 
If the subject enrolls in open-label treatment after Day 29 (Visit 7), an unscheduled visit will be conducted in order to obtain consent, review drug application instructions, and dispense 
drug.  This will be considered the official date that the subject initiated open-label extension treatment and the scheduling of subsequent visits 8-16 should be based off of this date as 
referenced by (OLE xxx) in the treatment day schedule header above. 
 
18Subjects who are eligible and consent to enter the open-label extension will have a baseline CEA and SEA completed at Visit 7 or the unscheduled Visit. 
 
 
 


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7.4. 
Subject Nourishment 
The site should provide meals, snacks and beverages to the subject during the Day 1 (Visit 2) and 
Day 28 (Visit 6) pharmacokinetic and pharmacodynamic sampling times.   
 
7.5. 
Duration of the Study 
The anticipated time for study enrollment is 3 to 6 months.  The duration of the screening period 
is up to 30 days. The expected double-blind treatment period for each subject is 29 days (maximum 
of 28 days of study medication application).  The post-treatment follow-up period is up to 33 days 
(30 + 3-day window).  The maximum total study duration for the double-blind period from the 
subject’s first visit (Visit 1) through the subject’s last visit (Visit 8) is 92 days.  On Day 1 (Visit 2) 
and Day 28 (Visit 6), subjects are required to be confined at the investigational center until all 
study procedures are completed.  The confinement period may last approximately 10 hours.  The 
duration of the total study participation from Baseline (Visit 2) to the open-label post-treatment 
follow up visit, Week 56 (Visit 16) is anticipated to be a maximum of 400 days. The duration of 
the open-label extension (OLE) should be based on the date of the visit that the subject initiated 
OLE treatment rather than the days from Baseline (Visit 2).  For subjects who entered the open-
label extension and had a gap between Visit 7 and entry into the open-label extension due to an 
administrative delay total study participation may be longer than 400 days.  
 
 
STUDY TREATMENT 
8.1. 
Investigational Study Medication 
The study medications for the double-blind period of this study are ATI-50002 Topical Solution, 
0.46% and Vehicle Topical Solution. The study medication for the open-label period is ATI-
50002-Topical Solution, 0.46%.  The study medications are thin clear solutions that are 
indistinguishable as packaged and labeled. The inactive ingredients include: water, Transcutol P, 
propylene glycol, polyethylene glycol 400, dimethyl sulfoxide (DMSO), Kolliphor CS 20, benzyl 
alcohol, poloxamer 188, and povidone K30. 
 
STUDY MEDICATION INFORMATION 
 
Double-Blind Period 
Open-Label Period 
Study medication 
name 
ATI-50002 
Vehicle 
ATI-50002 
Dosage Strength 
0.46% 
- 
0.46% 
Manufacturer 
PMRS, Inc., Horsham, PA 
Pharmaceutical Form 
Topical Solution 
Container 
Amber Glass Bottle, 120 mL with screw cap  
Storage Conditions 
59°F to 77°F (15°C to 25°C)  
Dose regimen 
Route 
Topical 
Frequency Twice-daily (Except for Day 1/Visit 2 and Day 28/Visit 6) 
Duration of 
administration 
28 days 
52 weeks 


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STUDY MEDICATION INFORMATION 
 
Double-Blind Period 
Open-Label Period 
Other supplies 
Disposable, single-use droppers will be provided. 
Applicators for eyebrow application will be provided 
(open-label) 
 
8.2. 
Subject Randomization 
Prior to the start of the study, Aclaris Therapeutics, Inc. or a designated third party will generate a 
list of randomization numbers that shall be transmitted to the assigned clinical packaging 
organization for study medication labeling.  The randomization list will be stored with access 
limited to designated personnel for study medication labeling.  The randomization list will be made 
available, as appropriate, to unblind the database.   
 
For the double-blind period, subjects will be assigned to 1 of the 2 treatment groups in a random 
manner and at a 2:1 ratio. At Baseline (Visit 2), an investigational center staff member will assign 
study medication to eligible subjects by selecting an appropriate Subject Kit.  The staff member 
must select Subject Kits in chronological sequence and in an ascending numerical order starting 
with the lowest available Subject Kit number.  No Subject Kit number may be omitted or reused.  
The Subject Kit number is the randomization number.   
 
The investigational staff member randomizing the subject will enter the subject identifier, subject 
initials, and date randomized on both parts of the Subject Kit label, remove the tear-off part, attach 
it to the subject’s study medication label page and record the Subject Kit number in the subject’s 
eCRF. 
 
The 52-week (12 month) extension is open-label, all eligible subjects will receive ATI-50002 
Topical Solution, 0.46%. 
 
8.3. 
Application of Study Medication 
At Visit 2 (Day 1), the investigational center staff member will instruct each subject to apply a 
minimum of 1.5 mL up to a maximum of 4-mL dose of ATI-50002 Topical Solution, 0.46% or 
Vehicle Topical Solution, twice-daily to the entire scalp; once in the morning and approximately 
12 hours later following the instructions in APPENDIX 1.  On Day 1 (Visit 2) and Day 28 (Visit 
6), study medication will be applied once-a-day due to the 24-hour PK and PD assessments. The 
subject must wash his/her hands thoroughly before and after each study medication application.  
The predose PK sample should be drawn and the baseline PD scalp biopsy should be obtained 
prior to study medication application.  The subject should apply a thin film of the assigned study 
medication to his/her entire scalp and gently rub in the study medication.   
 
On Day 1/ Baseline (Visit 2) the investigational staff member will: 
• Dispense the appropriate study medication bottle. 
• Weigh the bottle with the cap prior to the first study medication application and record in 
the subject’s source document. 
• Instruct the subject on the appropriate application technique (APPENDIX 1).  


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• Instruct the subject not to apply study medication to the biopsy site and to avoid contact 
with the eyes. 
• Observe the subject’s first study medication application to ensure proper coverage and 
monitor the subject for at least 20 minutes. Collect the study medication bottle. 
• Record the first application completion time. 
• Weigh the bottle with the cap after study medication application and record the weight in 
the subject’s source document. 
• Redispense study medication after the 24-hour PK and PD blood and biopsy sample 
collections on Day 2 (Visit 3). 
 
On Day 28 (Visit 6) the investigational staff member will: 
• Collect and weigh all study medication bottles (with the cap on the bottle) returned from 
the subject and record weight(s) in the subject’s source document.  
• Select one study medication bottle for the Day 28 (Visit 6) application. 
• Weigh the bottle and cap prior to study medication application and record weight in the 
subject’s source document. 
• Review the application instructions with the subject (APPENDIX 1).   
• Instruct the subject to avoid contact with the eyes. 
• Observe the subject’s study medication application to ensure proper coverage.  Collect the 
study medication bottle after application. 
• Record the study medication application completion time in the subject’s source document. 
• Weigh the bottle and cap after study medication application. 
• Do not return the study medication bottle to the subject. 
8.4. 
Study Medication Weights 
On Day 1 (Visit 2) and Day 28 (Visit 6), a study staff member will weigh the study medication 
bottles with the cap prior to and after study medication applications.  At the other study visits (Visit 
3-15), the staff will weigh the bottles with the cap prior to dispensing new bottle(s) to the subject 
and after collection of used bottles from the subject.  The weights of the study medication bottles 
must be recorded in the subject’s source documentation.  Bottles that are not dispensed to the 
subject do not need to be weighed. 
 
8.5. 
Treatment Compliance 
The investigator or designee will be responsible for monitoring subject compliance by reviewing 
the amount of study medication used based on the weight of the used study medication bottles and 
by querying the subject on usage at each visit.  At Visits 4-15, an investigational center staff 
member must query each subject to determine compliance with the study medication application 
procedure and frequency.  The staff member will document the study medication usage in the 
source document and eCRF.  Study staff will counsel the subjects, as required to make sure subjects 
are compliant with study medication applications. 
 
8.6. 
Dose Modification 
Subjects should be instructed not to modify the study medication application procedure or 
frequency.  All application modifications must be reported on the appropriate source document 


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and eCRF.  If the subject experiences any significant application site AE(s), after discussion with 
the Sponsor, the investigator or designee may direct the subject to reduce study medication 
application frequency to once a day.   Every effort should be made to resume twice daily 
applications for the week prior to Day 28 (Visit 6).  If a subject cannot resume twice-daily 
applications to the scalp for more than 4 consecutive days, the subject must be removed from the 
study.  Refer to Section 10.2.4 for Study Medication Interruption or Discontinuation due to related 
SAEs or specific abnormal laboratory values.  
 
8.7. 
Study Medication Accountability 
The Investigator or designee is responsible for ensuring accountability for the investigational study 
medication, including reconciliation of study medications and maintenance of study medication 
records.  Upon receipt of study medication, the clinical site will check for accurate delivery and 
acknowledge receipt by signing (or initialing) and dating the documentation provided.  One copy 
of this document will be returned to Aclaris Therapeutics, Inc. (or designee) and one copy will be 
maintained in the study file. In addition, an accurate study medication disposition record will be 
kept up to date, specifying the amount dispensed for each subject and the date of dispensing. This 
inventory record will be available for inspection at any time. The original inventory record will be 
available for review by Aclaris Therapeutics, Inc. upon request.  At the completion of the study, 
all used and unused study medication bottles will be returned to Aclaris Therapeutics, Inc. (or 
designee) for disposal per Aclaris Therapeutics, Inc. (or designee) written instructions.  
Alternatively, drug disposal may be completed by the investigative site (following appropriate 
monitor review of inventory) if the site has a written procedure in place dealing with 
destruction/disposal of investigational products.  
8.8. 
Other Study Supplies 
Aclaris Therapeutics, Inc. or a third party will provide: 
• Equipment, supplies and training for taking standardized photographs 
• Equipment and training for SALT and ALODEX assessments 
• Equipment, supplies and training for capture of ECGs for central reading 
• Scales for weighing the study medication bottles 
• Supplies and shipment instructions of PK and PD samples 
• UPT kits 
  
8.9. 
Blinding 
Blinding of study medication is important for validity of this study.  This study uses a double-blind 
design for the initial 28-day double-blind treatment period.  The study medications used during the 
double-blind period are indistinguishable in appearance, as packaged and labeled. 
 
8.9.1. 
Unblinding the Study Medication (Double-blind Period) 
The blinding may be broken in the event of a medical emergency, in which knowledge of the study 
medication identity is critical to the management of the subject’s course of treatment.  Before 
breaking the blind, the investigator shall determine that the information is necessary (i.e., that is, 
will alter the subject’s immediate course of treatment).  In many cases, particularly when the 


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emergency is clearly not study medication-related, the problem may be effectively managed by 
assuming that the subject is receiving an active study medication without the need for unblinding.   
 
If the investigator deems it necessary to break the blind for a study subject, he/she will attempt to 
contact the Medical Monitor (protocol page 1) to obtain concurrence.  If it is not possible to contact 
the Medical Monitor beforehand, contact her/him as soon as possible after breaking the blind for 
a subject.   
 
To identify a subject’s study medication, locate the second panel of the tear-off label from the 
Subject Kit attached to the subject’s study medication label page, and follow the instructions on 
the label.  Record the date of unblinding, the reason for unblinding, and the initials of the 
investigational staff member who performed the unblinding on the subject’s study medication label 
page.  Any subject whose blind has been broken must be discharged from the study (Section 6.8).  
Subject must complete the double-blind treatment period to be eligible for entry into the open-
label extension.   
 
At the end of the study, the original study medication label page will be returned to Aclaris 
Therapeutics, Inc. with a photocopy placed in the investigator’s study file.  The original study 
medication label page will be available, upon request, to the site if needed to respond to a 
regulatory audit. 
8.10. 
Study Medication Packaging, Labeling, Storage and Security 
The study medication must be used by the study subjects only.  Investigational site staff will 
explain the application of the study medication to subjects.   
 
Study medication will be provided by Aclaris Therapeutics, Inc. and labeled according to 
regulations.  Study medications must be stored in a secure area with limited access under 
appropriately controlled and monitored storage conditions.  Study medication should be stored at 
controlled room temperature 59°F - 77°F (15°C – 25°C).  Subjects will be instructed to store the 
study medication in the original glass bottle (in the carton provided) at room temperature, away 
from heat, moisture, direct light, and to keep it from freezing and out of the reach of children. 
 
The study medication will be supplied in amber glass 120 mL bottles.  Disposable droppers with 
1 mL calibration mark will be provided in the study kits.  During the open-label portion of the 
study, applicators will also be provided for application of the ATI-50002 Topical Solution, 0.46% 
to the eyebrow(s).   
  
For the double-blind period, one Subject Kit box will contain 6 bottles in individual boxes and 
disposable droppers.  Each kit will be labelled with a two-part, three panel, double blind label.  
One part (one-panel) of the label remains attached to the Subject Kit, the other part (two-panel 
tear-off) is separated and attached to the subject’s study medication label page when the subject is 
randomized.  Each box and bottle will be labeled with a single panel label.   
 
For the open-label period, subjects will receive 1-3 bottles of ATI-50002 Topical Solution, 0.46% 
per month.  Each bottle is packaged in a carton and both the bottle and carton will be labelled with 
a single-panel label.   
 


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STUDY ASSESSMENTS 
The study assessments will be performed according to the schedules noted below by the 
investigator, an appropriately trained study staff member or the subject as noted for each 
assessment.  The SALT and ALODEX assessments should be performed by the same staff member 
for a given subject throughout the study.  If this is not possible, an appropriate designee with 
overlapping experience with the subject and study should perform the assessments.  Hair regrowth 
in subjects is not anticipated during the 28-day duration of the double-blind study medication 
application. 
9.1. 
Efficacy Assessments 
9.1.1. 
Severity Alopecia Tool (SALT) Score 
The SALT score is a measurement of the amount of scalp without any hair. The Investigator will 
assess the SALT score using an iPAD provided by Aclaris at Baseline (Visit 2), Day 29 (Visit 7), 
and as detailed in Section 7.3 for the subjects who continue in the open-label extension. Equipment, 
supplies, training and a detailed Reference Guide will be provided to the investigational site prior 
to the initiation of subject enrollment. 
 
9.1.2. 
Alopecia Density and Extent Score (ALODEX) 
The ALODEX score is a measurement of the amount of scalp with hair loss (Olsen, submitted).  
The Investigator will calculate the ALODEX score using the iPAD provided by Aclaris at Baseline 
(Visit 2), Day 29 (Visit 7) and as detailed in Section 7.3 for subjects who continue in the open-
label extension.  Equipment, supplies, training and a detailed Reference Guide will be provided to 
the investigational site prior to the initiation of subject enrollment. 
 
9.2. 
Pharmacodynamic (Biomarker) Assessment  
9.2.1. 
Scalp Biopsy (PD) 
A 4-mm punch biopsy of the scalp will be obtained on Baseline (Visit 2) just prior to the first 
application of study medication and at Day 29 (Visit 7) 24 hours (± 30 minutes) after the study 
medication application for histology and RNA sequencing (APPENDIX 5). At Visit 13, a 4-mm 
biopsy will be obtained approximately 24 hours ± 30 minutes after the morning dose on the day 
prior to the visit. 
 
9.2.2. 
Blood for Immunologic Evaluation (T-cells) 
The blood samples will be obtained on Day 1 (Visit 2) predose and on Day 29 (Visit 7) 24 hours 
(± 30 minutes) after the study medication application for measurement of the following tests 
including: 
• T, B, NK lymphocytes, CD4+, CD8+ T-cells 
• T-regulatory and T-cell subtypes 
• RNA seq 
• TCR seq 
At Visit 13, blood samples will be obtained approximately 24 hours ± 30 minutes after the morning 
dose on the day prior to the visit. 


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9.3. 
Pharmacokinetic Assessment 
9.3.1. 
Scalp Biopsy (PK) 
A 4-mm punch biopsy of the scalp will be obtained on Day 2 (Visit 3) and on Day 29 (Visit 7) 24 
hours (± 30 minutes) after the study medication application (on Day 1/Visit 2 and Day 28/Visit 6) 
to determine the concentration of ATI-50002 in the skin (APPENDIX 5).  The 
scalp 
biopsy 
should be obtained after the area of the scalp to be biopsied is tape stripped using 5 D-Squame 
circular discs. 
  
The bioanalytical lab will provide instructions on the collection and shipment of samples for 
analysis. 
9.3.2. 
Blood Samples (Double-blind Period)  
For the first six subjects enrolled into the study, blood samples for PK analysis of ATI-50002 will 
be collected by a qualified staff member.  On Baseline/ Day 1 (Visit 2) and Day 28 (Visit 6) blood 
samples will be collected at predose (0-hour) (just prior to study medication application in the 
morning) and then at the following times after study medication application: 
• 1 hour (±5 minutes) 
• 2 hours (±10 minutes) 
• 4 hours (±10 minutes) 
• 8 hours (±10 minutes) 
On Day 2 (Visit 3) and Day 29 (Visit 7) 
• 24 hours (±30 minutes) 
The bioanalytical laboratory will provide instructions on the collection and shipment of samples. 
 
9.4. 
Eyebrow Assessments (Open-Label Extension) 
Subjects with eyebrow loss in one or both eyebrows will be allowed to treat their affected 
eyebrow(s) during the open-label period of the study.  Both the investigator and subject will assess 
eyebrow loss at entry into the open-label extension and then monthly for the first 6 months, then 
at 9 and 12 months during the open-label treatment period.  The Investigator will document the 
affected areas of the eyebrow or brow(s) on the source document and eCRF.  
 
9.4.1. 
Clinician’s Eyebrow Assessment (CEA) (Open-Label Period) 
The CEA is the Investigator’s assessment of the affected eyebrow(s) at a particular point in time. 
The Investigator should NOT refer to any other assessments to assist with these assessments.  
 
At Visits 8 - 16, the Investigator will assess the affected eyebrow(s) using the scale below and report 
the one integer that best describes the amount of eyebrow hair present.  If both eyebrows are 
affected, each eyebrow will be assessed separately. 
 
 
 


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Clinician’s Eyebrow Assessment 
 
Grade Descriptor 
0 
No eyebrow hair: No terminal hairs are visible in the affected area(s)  
1 
A little eyebrow hair: Occasional terminal hairs are visible in the affected area(s) 
2 
Some eyebrow hair: Numerous terminal hairs are visible in the affected area(s) 
3 
Most eyebrow hair: Mostly complete eyebrow regrowth with terminal hair in the 
affected area(s) 
4 
Full eyebrow hair: Complete eyebrow regrowth with terminal hair in the affected 
area (s) 
 
9.4.2. 
Subject’s Eyebrow Assessment (SEA) (Open-Label Period): 
The SEA is the subject’s assessment of the appearance of eyebrow hair present on the affected 
eyebrow(s) at a particular point in time. The subject should NOT refer to any other assessments to 
assist with these assessments.  
 
At Visits 8-16, the subject will assess the affected eyebrow(s) using the scale below and report the 
one integer that best describes the amount of eyebrow hair present.  If both eyebrows are affected, 
each eyebrow will be assessed separately. 
 
Subject’s Eyebrow Assessment 
Grade Descriptor 
0 
No eyebrow hair:  No thick, coarse hairs are visible in the affected area(s) 
1 
A little eyebrow hair: A few thick, coarse hairs are visible in the affected area(s) 
2 
Some eyebrow hair: Numerous thick, coarse hairs are visible in the affected area(s) 
3 
Most eyebrow hair: The majority of the affected area(s) of the eyebrow is covered 
in thick, coarse hairs 
4 
Full eyebrow hair:  The affected area(s) of the eyebrow is fully covered in thick, 
coarse hairs 
 
An investigational staff member will identify the eyebrow to be evaluated by the subject, educate the 
subject on the SEA scale before each evaluation and direct the subject to assess the eyebrow, one 
eyebrow at a time. The staff member should not influence the subject’s assessment. 
 
The study staff member will report the SEA grade the subject indicates in the source document for 
the affected eyebrow(s). Both the subject and the study staff member must sign/initial the source 
document to indicate the subject performed the SEA as instructed. 
 
9.5. 
Assessment of Safety 
Safety will be assessed throughout the study by the investigator or a designated and appropriately 
trained staff member. 
 


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9.5.1. 
Vital signs 
Vital signs will be measured at each visit during the study. The following items will be measured: 
• Body temperature 
• Pulse rate 
• Respiration rate 
• Blood pressure (systolic and diastolic) after the subject sits quietly for at least 5 minutes 
• Height and Weight (at Visit 2 only). 
 
Any measure that is, in the opinion of the investigator, abnormal AND clinically significant (CS) 
must be recorded as medical history if found prior to the first study medication application, or as 
an AE if found after the first study medication treatment begins.  
 
A systolic blood pressure >140mm Hg or a diastolic blood pressure >90 mmHg is considered 
abnormal and therefore must be defined as CS or not clinically significant (NCS) on the eCRF.   A 
weight >300 lbs. is considered abnormal and therefore must be defined as CS or NCS on the eCRF.  
 
9.5.2. 
Physical Examination 
The investigator or designee will perform a physical examination for all body systems (general 
appearance, examination of head, eyes, ears, nose and throat, respiratory, cardiovascular, 
abdominal, extremities, neurological, musculoskeletal, lymphatic and skin assessment) at 
Screening (Visit 1) and Day 29 (Visit 7). For subjects who are enrolled in the Open-label extension, 
a physical examination will also be performed at Week 56 (Visit 16). 
 
9.5.3. 
Clinical Laboratory Assessments 
A qualified staff member will collect non-fasting samples for clinical laboratory analysis at the 
times in the visit schedule in Section 7.3. Samples will be sent to a central laboratory for analysis.  
Refer to the study specific laboratory manual for handling and shipping instructions. 
 
The following tests will be conducted: 
Chemistry Panel 
Complete Blood Count 
Albumin 
Hematocrit 
Alkaline phosphatase 
Hemoglobin 
Alanine aminotransferase (ALT) 
Platelet count 
Aspartate aminotransferase (AST) 
Red blood cell morphology 
Blood urea nitrogen (BUN) 
Red blood cell count 
Bicarbonate 
White blood cell count 
Calcium 
White blood cell differential 
Chloride 
    % & absolute 
Creatinine 
    Basophils 
Glucose 
    Eosinophils 
Lactate dehydrogenase (LDH) 
    Lymphocytes 
Phosphorus 
    Monocytes 
Potassium 
    Neutrophils 
Sodium 
 
Total bilirubin 
Urinalysis 


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Chemistry Panel 
Complete Blood Count 
Total protein 
 
Uric acid 
HDL, LDL, Total cholesterol, 
Triglycerides 
 
Screening Tests Only 
Hep B, HCV, HIV 
Quantiferon Gold 
Total Iron Binding Capacity (TIBC) 
Serum iron 
Serum Ferritin 
T3/T4, TSH 
Serum Pregnancy 
 
 
The results of the clinical laboratory tests will be reported on the central laboratory’s standard 
reports. The investigator must note NCS or CS to define the clinical relevance of any result that is 
outside the normal range for the laboratory. The investigator must date and initial every laboratory 
report.  
 
The investigator or subinvestigator must review all the Screening (Visit 1) laboratory test results 
against the study entry criteria for each subject prior to Baseline (Visit 2). The investigator must 
report all laboratory results that are BOTH outside the normal range for the laboratory AND, in 
the opinion of the investigator, CS as medical history if found prior to the first study medication 
treatment or as an AE if found after the first study medication treatment begins. The investigator 
must review all laboratory reports in a timely manner. 
9.5.4. 
Pregnancy tests 
Subjects who are WOCBP must have a negative serum pregnancy test result at Screening (Visit 1) 
to continue in the study, a negative UPT at Baseline (Visit 2) prior to randomization and prior 
to study medication application at Day 28 (Visit 6). WOCBP who are enrolled in the open label 
period will have UPT at the visits detailed in Section 7.3 during the treatment period.  The UPT 
kits provided by Aclaris Therapeutics, Inc. have a minimum sensitivity of 25-mIU ß-
HCG/milliliter (mL) of urine. If the result of any post-treatment UPT is positive, the subject will 
be withdrawn from the study and the subject’s pregnancy documented and followed. 
 
9.5.5. 
ECGs 
Standard 12-lead ECGs will be performed by a qualified staff member at Screening (Visit 1), 
Baseline (Visit 2), Day 15 (Visit 5), Day 29 (Visit 7) and the visits outlined in Section 7.3.  The 
ECGs must be obtained using a standard 12-lead ECG with a 10mm/mV amplitude, at 25mm/sec 
and a 5-10-second duration. To ensure a steady heart rate the subject must rest quietly in the supine 
position for at least 5 minutes prior to performing the ECG.  
 
A central lab, eResearchTechnology, Inc. (ERT), will provide equipment, supplies and site 
training.  In addition, ERT will process ECGs received by the sites and report results via a secure 
study portal. The ECG results will be interpreted by a qualified health professional (evaluator) and 


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the interpretation reported either directly on the tracing or in a separate report.   The evaluator will 
interpret the results of every ECG and define the ECG as “normal” or “abnormal”.  Variations 
such as minor ST changes (i.e., <0.5mm depression) and early re-polarization are considered 
normal.  
 
The investigator must review the evaluator’s interpretation of each subject’s screening ECG prior 
to Baseline (Visit 2). The investigator will review the evaluator’s interpretation of all ECG reports 
in a timely manner and comment on the clinical relevance of any result that is defined by the 
evaluator as abnormal.  
 
Any abnormalities that are, in the opinion of the investigator, clinically significant, must be 
reported as medical history if found prior to the start of the first study medication application or as 
an AE if found after the start of the first study medication application (see Section 10.1.1). 
 
9.6. 
Other Assessments 
9.6.1. 
Demographics, Medical History and Alopecia Areata History 
During the Screening visit, the investigator or designee will interview each subject to obtain 
demographic information including date of birth, sex at birth, Fitzpatrick Skin Type, race and, if 
appropriate, ethnicity. The investigator or designee will interview each subject to obtain medical 
history information related to all medical conditions, surgeries and disease states that, at Screening 
(Visit 1): are ongoing, require concomitant therapy or are, in the opinion of the investigator, 
relevant to the subject’s study participation.  In addition, the medical history of women who are 
not of childbearing potential should reflect the reason e.g. post-menopausal for 1 year or greater, 
bilateral tubal ligation, or hysterectomy.  The investigator or designee will also obtain an extensive 
AA history at Screening (Visit 1) (APPENDIX 3). 
 
9.6.2. 
Photographic Assessment 
A qualified investigational staff member will take standardized photographs of the scalp at 
Baseline (Visit 2), prior to study medication application, Visit 7 (Day 29) prior to the scalp biopsy 
and if enrolled in the open-label extension at the visits detailed in Section 7.3.  The photographs 
are to document the baseline hair loss and any early signs of hair growth during treatment.  
Equipment, supplies, training and detailed instructions for obtaining and managing photographs 
will be provided to the investigational center prior to the initiation of subject enrollment. 
 
 
ADVERSE EVENTS 
Adverse events will be monitored throughout the study and reported on the appropriate Aclaris 
Therapeutics, Inc. AE eCRF.   
 
10.1. 
Definitions 
10.1.1. 
Adverse Events (AE) 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a study medication(s) and which does not necessarily have a causal relationship with 


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the study medication.  An AE can therefore be any unfavorable and unintended sign or symptom 
associated with the use of a study medication (including an abnormal laboratory finding), whether 
or not related to the study medication.  
 
Thus, any new, clinically significant worsening of an existing sign, symptom or disease, should be 
considered an AE.  
 
Every new episode or clinically significant worsening of a chronic condition (e.g., headaches, 
seasonal allergies, depression, or hypertension) should be reported as a separate AE, even if the 
condition is reported in the subject’s medical history. 
 
The investigator should, when certain, report a diagnosis rather than the signs, symptoms or 
clinically significant abnormal laboratory values associated with the AE. Otherwise, signs, 
symptoms or abnormal laboratory values may be used to describe the AE. 
 
Any CS abnormality discovered prior to the first study medication treatment should be reported as 
medical history, not as an AE. 
 
10.1.2. 
Serious Adverse Event (SAE) 
A Serious Adverse Event is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect 
• Is an important medical event 
 
The term “life threatening” refers to an event in which the subject was at risk of death at the time 
of event; it does not refer to an event that hypothetically might have caused death if it were more 
severe. 
Inpatient hospitalization is considered to have occurred if the subject is admitted to the hospital on 
an in-patient basis, even if released the same day. Prolongation of hospitalization is defined as an 
additional night stay in the hospital. Hospitalization for a diagnostic test (even if related to an AE) 
or elective hospitalization that was planned before study enrollment (signing the ICF) are not 
themselves reasons for an event to be defined as a SAE. 
 
Important medical events are those that may not be immediately life threatening, result in death or 
hospitalization, but are clearly of major clinical significance and may jeopardize the subject or 
require intervention to prevent one of the outcomes listed in the SAE definition above. These 
should also usually be considered serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasia or convulsions that do not 
result in hospitalization. 
 


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10.1.3. 
Unexpected Adverse Event 
An AE is considered unexpected if it is not listed in the Investigator Brochure or is not listed at 
the specificity or severity that has been observed. 
 
10.1.4. 
Adverse Event Reporting Period 
The investigator must start reporting non-serious AEs with the subject’s first study medication 
application and continue reporting until the end of the subject’s last study visit. Reporting for SAEs 
must start when the subject signs the ICF and continue until the end of the subject’s last visit. 
 
10.1.5. 
Severity 
The investigator is to define the severity of each AE using the following definitions as a guideline. 
The investigator will consider the range of the possible severity of the event and identify the 
severity that is the most appropriate according to her/his medical judgment. 
 
Mild – Awareness of signs or symptom, but easily tolerated. 
Moderate – Discomfort, enough to cause interference with usual activity. 
Severe – Incapacitating with inability to perform usual activity. 
10.1.6. 
Relationship to Study Medication 
The investigator will determine if there is a reasonable causal relationship between the study 
medication and an AE or not. The investigator will use her/his best medical judgment and consider 
all relevant factors (e.g., temporal relationship, location of the event, the subject’s relevant medical 
history, concomitant therapies and concurrent conditions) to determine the relationship of the AE 
to the study medication. The investigator will define the relationship of an AE to the study 
medication by selecting one of the following categories: 
 
Related – There is a reasonable causal relationship between the study medication and the 
AE. 
 
Not Related – There is not a reasonable causal relationship between the study medication 
and the AE. 
 
The expression “reasonable causal relationship” is meant to convey in general that there are facts 
(evidence) or arguments to suggest a causal relationship (International Conference on 
Harmonization [ICH] E2A). 
 
10.2. 
Reporting Procedures 
10.2.1. 
Procedures for Reporting Adverse Events 
At each post-enrollment visit, the investigator will question the subject to elicit AEs using a non-
directive question such as “Has there been any change in your health since the previous study 
visit?”  If appropriate, based on the subject’s response to non-directed questioning to elicit AEs, 
the investigator will follow-up with directed questions and appropriate evaluations.  


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Any AE noted during the reporting period must be reported in the source documents and on the 
appropriate AE eCRF. AEs that are defined as “Not Related” to the study medications will be 
followed until they are resolved or until the subject’s last study visit. AEs that are defined as 
“Related” to the study medications will be followed until they are resolved or, if not resolved after 
the subject’s last study visit, until in the opinion of the investigator, the AE reaches a clinically 
stable outcome with or without sequelae. 
 
10.2.2. 
Procedure for Reporting a Serious Adverse Event 
Upon becoming aware of a SAE occurring during the AE reporting period, whether or not related 
to the study medications, the investigator must: 
 
1. 
Take the appropriate medical action to ensure the subject’s safety. 
Immediately (within 24 hours) inform the Medical Monitor of the SAE by telephone: 
Terrence Chew, MD, RAC 
Aclaris Therapeutics, Inc. 
640 Lee Rd 
Suite 200 
Wayne, PA 19087 
Office Telephone: 858-922-6307   
SAE facsimile 484-324-2359 
E-mail: tgchew@icloud.com 
2. 
Within 24-hours complete, as fully as possible, an AE eCRF and an SAE form; fax or e-mail 
the forms and any other relevant information (e.g., concomitant medication eCRF, medical 
history eCRF, laboratory test results) to the Aclaris Therapeutics, Inc. Medical Monitor. 
3. 
Monitor and document the progress of the SAE until it resolves or, if not resolved after the 
subject’s last study visit, until in the opinion of the investigator the AE reaches a clinically 
stable outcome with or without sequelae AND the investigator and Aclaris Therapeutics, Inc.  
Medical Monitor agree that the SAE is satisfactorily resolved. 
4. 
Inform the Aclaris Therapeutics, Inc. Medical Monitor of SAE updates by telephone 
followed by an SAE form update sent by e-mail. 
5. 
Comply with the appropriate regulatory requirements and Aclaris Therapeutics, Inc. 
instructions regarding reporting of the SAE to the responsible Institutional Review Board 
(IRB) or Ethics Committee (EC). 
 
10.2.3. 
Safety Monitoring ECG Discontinuation Criteria 
Any subject who develops any of the following ECG criteria during the active treatment phase will 
be instructed to stop study medication and will be withdrawn from the study: 
• A post-study medication ECG result where the evaluator’s interpretation shows any of the 
following: 
➢ Clinically significant rhythm disturbance other than sinus rhythm or ectopic 
supraventricular rhythm (ectopic atrial rhythm) 


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➢ Clinically significant conduction disturbance including PR >240msec, pre-
excitation (delta wave and PR <120msec), second degree or higher AV block  
➢ New finding of QRS>120ms (if not present at screen. For example, subjects with 
Right Bundle Branch Block at screening would not need to be withdrawn from the 
study if their subsequent ECGs remained unchanged). 
➢ Evidence of QT-interval prolongation, defined as an increase in the QTcF interval 
>60ms from Visit 1 
➢ New QTcF > 500 ms 
➢ Acute signs of ischemia or infarction 
➢ Any ECG abnormality which may, in the opinion of the investigator, represent a 
new medical issue of concern 
 
10.2.4. 
Study Medication Interruption and Discontinuation 
10.2.4.1 
Study Medication Interruption 
Treatment with ATI-50002 Topical Solution should be temporarily interrupted in the event of 
severe adverse events considered related to ATI-50002, or in the event of one or more of the 
abnormal laboratory values in Table 2. 
 
Table 2:  Study Medication Interruption Criteria 
Laboratory Test 
Hold Study Medication if: 
Resume Study Medication if: 
WBC count 
< 2 x 109/L 
≥ 2.5 x 109/L 
ANC 
< 1 x 109/L 
≥ 1.5 x 109/L 
Lymphocyte count < 0.5 x 109/L 
≥ 0.75 x 109/L  
Platelet count 
< 75 x 109/L 
≥ 100 x 109/L 
Hemoglobin 
< 8 g/dL or decrease > 2 g/dL 
≥ 10 g/dL 
AST or ALT 
> 3 x ULN 
< 2 x ULN or within 20% of baseline values 
Serum creatinine 
>2 x ULN 
<1.5 x ULN or within 10% of baseline value 
 
If a subject has one or more of the abnormal laboratory values noted in Table 2, the investigator 
or designee upon receipt and review of the central laboratory report should instruct the subject to 
interrupt study medication applications. The investigator or designee should ask the subject 
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 SAEs considered 
related to study medication or laboratory abnormalities noted in Table 2. 
  
If the retest confirms the abnormal laboratory value, then the study medication interruption should 
continue, followed by repeat testing once a week or sooner at the discretion of the investigator.  
The subject should be followed until the laboratory abnormality(s) return to normal or to baseline 
values.  Study medication can be resumed after the abnormal lab value returns to normal or 
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10.2.4.2 
Study Medication Discontinuation 
Study medication should be permanently discontinued in the event of any of the following: 
• Severe infection requiring parenteral antimicrobial therapy or hospitalization 
• Symptomatic herpes zoster 
• Malignancy – except for non-melanoma skin cancer (e.g. squamous or basal cell 
carcinoma) not in or near the treatment area 
• Anaphylactic or severe allergic reaction 
• WBC Count: < 1 x 109/L or second occurrence of < 2 x 109/L 
• ANC:< 0.5 x 109/L or second occurrence of < 1 x 109/L 
• Lymphocyte count:< 0.3 x 109/L or second occurrence of < 0.5 x 109/L  
• Platelet count: < 50 x 109/L or second event of < 75 x 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: 
➢ > 5 x ULN persisting for 1 week of study medication interruption or second event 
of > 5 x ULN 
➢ > 3 x ULN with total bilirubin >2 x ULN or symptoms of hepatocellular  
injury (fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash and/ or eosinophilia (>5%). 
• Serum creatinine: > 2 x ULN persisting for >2 weeks of treatment discontinuation or 
second occurrence of > 2 x ULN 
The continued treatment of subjects who experience other serious or severe adverse events 
considered related to study treatment should be discussed with the Sponsor’s medical monitor. 
 
PREGNANCY 
11.1. 
Definition of Women of Child Bearing Potential (WOCBP) 
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 (Visit 1) and a negative UPT at Baseline (Visit 2) prior to randomization. 
11.2. 
Highly Effective Methods of Birth Control 
The Investigator or subinvestigator will discuss the potential risk factors associated with pregnancy 
and the importance of maintaining a highly effective method of contraception throughout the study 
with all WOCBP (for example, those which result in a low failure rate - i.e., less than 1% per year- 
when used consistently and correctly).  All WOCBP must use a highly effective method of birth 
control during the study and for 30 days after the final application of study medication in a manner 
such that risk of failure is minimized.   
 
Highly effective methods include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 


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o oral 
o intravaginal 
o transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o oral 
o injectable 
o implantable 
• intrauterine device (IUD) 
• Obstruction of fallopian tubes via medical device (Essure™) 
• intrauterine hormone-releasing system (IUS) 
• vasectomized partner1 
• sexual abstinence2 
1Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner 
of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the surgical 
success.  
2 Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatments (study duration and 30 days after 
the last study medication application). The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject. 
 
WOCBP must be on a highly effective method of birth control for the following timeframes prior 
to study entry:  
• Implants (on a stable dose for ≥90 days) 
• Injectables (on a stable dose for ≥90 days) 
• Patches (on a stable dose for ≥90 days) 
• Combined oral contraceptives (on a stable dose for ≥90 days) 
• Intrauterine devices (inserted for ≥30 days) 
 
Prior to trial enrollment, WOCBP must be advised of the importance of avoiding pregnancy during 
trial participation and of the potential risk factors associated with pregnancy while in study.  The 
subject must sign an informed consent form documenting this discussion.  During the trial, all 
WOCBP will be instructed to contact the investigator immediately if they suspect they might be 
pregnant (e.g., missed or late menstrual period). 
If a subject or investigator suspects that the subject may be pregnant prior to study medication 
administration, the study medication must be withheld until the results of a pregnancy test are 
available.  If pregnancy is confirmed, the subject must not receive study medication and must be 
discharged from the study.  
 
If, following study medication administration, it is determined that the subject may have been or 
was pregnant at the time of study medication exposure (including at least 2 days after study 
medication administration) the investigator must immediately notify the Aclaris Therapeutics, Inc. 
Medical Monitor and record the event on a pregnancy surveillance form. While not an AE or SAE, 
the investigator must report every pregnancy using a pregnancy surveillance form and follow the 
reporting procedures described for SAE reporting. 
 
Protocol-required procedures for trial discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate pregnancy 


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follow-up procedures should be considered if indicated. In addition, the investigator must report 
to Aclaris Therapeutics, Inc.’s Medical Monitor on the pregnancy surveillance form, follow-up 
information regarding the course of the pregnancy, including perinatal and neonatal outcome. 
Infants should be followed for a minimum of six weeks.  
 
 
STATISTICAL ANALYSES   
12.1. 
Sample Size and Power Calculations 
The planned sample size is 12 subjects.  This is the first multicenter study evaluating the effect of 
ATI-50002 Topical Solution in subjects with stable alopecia universalis and alopecia totalis. No 
formal power calculations will be performed.   
 
12.2. 
Analysis Populations 
Pharmacokinetic and Pharmacodynamic study populations will be described in a Statistical 
Analysis Plan and finalized prior to database lock. 
 
12.3. 
Demographic and Baseline Characteristics 
Subject demographic and baseline characteristics, including medical and alopecia history, prior 
medications and therapies and physical examination findings will be summarized using descriptive 
statistics. 
 
For continuous variables, descriptive statistics (number, mean, standard deviation, standard error, 
median, minimum, and maximum) will be provided.  For categorical variables, subject counts 
and percentages will be provided.  Categories for missing data will be presented, if necessary. 
 
12.4. 
Pharmacokinetic Analyses 
Blood Samples 
Blood samples for analysis of the concentration of ATI-50002will be taken from the first 6 subjects 
enrolled into the study on Baseline/Day 1 (Visit 2) and Day 29 (Visit 7) at predose (0 hr), and 1, 
2, 4, 8 hours after study medication application and on Day 2 (Visit 3) and Day 29 (Visit 7), 24 
hours post dose.  For each subject, standard PK parameters (Cmax, Tmax, AUC0-t, AUC0-∞, t1/2) will 
be calculated, as a minimum and whenever possible, based on the plasma concentrations of ATI-
50002.   
 
Scalp Biopsy 
The concentration of ATI-50002 in skin will be determined in a 4-mm punch biopsy of the scalp 
taken on Day 2 (Visit 3) and Day 29 (Visit 7) 24 hours post study medication application in the 
office on Day 1(Visit 2) and Day 28 (Visit 6).    
  
12.5. 
Pharmacodynamic (Biomarker) Analyses 
12.5.1. 
ALADIN Scores               
The cytotoxic T-lymphocyte infiltration (CTL), Interferon (IFN-gamma), and hair keratin (KRT) 
ALADIN scores will be calculated for each scalp biopsy sample as previously described in (Xing 


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et al, 2014, Jabbari 2016).  Change in ALADIN scores within individual subjects will be 
assessed between Baseline/ Day 1 (Visit 2), Day 29 (Visit 7) and Week 28 (Visit 13) for subjects 
enrolled in the open-label extension.   
12.5.2. 
Histology 
Scalp punch-biopsies will be formalin-fixed and paraffin-embedded and will be sectioned both 
vertically and horizontally by a qualified dermatopathologist.  Specimens will be stained with 
hematoxylin and eosin (H&E) for “routine” histopathologic evaluation that will include (but is not 
limited to) diagnosis and evaluation of the presence, quantity, location, and quality of any hair, 
hair follicles, and inflammatory infiltrate present.  Additionally, immunohistochemical (IHC) 
stains will be employed to identify immune cell populations (e.g., Lymphocytes, cytotoxic T-
lymphocytes (CTLs)), and hair-specific keratins.  IHC stains to assess inflammatory responses will 
include but not be limited to, CD8, HLA-DR and ICAM-1.  Data will be presented as percent 
change from baseline in the number of cells/ high power field in regions of interest (peribulbar 
areas) and in percent change from baseline in the number of cells/mm2. 
 
12.5.3. 
Blood for Immunology 
Blood samples will be stained with cell surface antibodies for fluorescence acquisition cell sorting 
(FAC) analysis.  FACS experiments will allow for assessment of the subset and activation status 
of immune cells involved in AA. 
 
12.5.4. 
Secondary Analyses 
Summary descriptive statistics (N, mean, median, SD) by visit will be provided for all efficacy 
parameters.  Secondary efficacy parameters are described below: 
 
The secondary efficacy endpoints include mean change from baseline in the SALT score at Week 
28 (Visit 13), Week 40 (Visit 14) and Week 52 (Visit 15).   
 
The percentage hair growth will be calculated as the mean change from Baseline (Visit 2) scores 
compared to end of treatment Week 28 (Visit 13), Week 40 (Visit 14) and Week 52 (Visit 15).   
 
Mean change from baseline in the ALODEX score, proportion of subjects achieving a ≥ 50% hair 
growth compared with baseline.   
 
Treatment satisfaction will be summarized.  
 
The ALODEX score analysis will use the same methodology as specified for SALT score analysis.  
Other parameters will be analyzed as detailed in the statistical analysis plan.  
 
Mean change from baseline in eyebrow growth will be calculated as the mean change in the 
Clinician’s Eyebrow Assessment (CEA) from entry into the long-term, open-label extension 
compared to Week 28(Visit 13), Week 40 (Visit 14) and Week 52 (Visit 15).  The CEA evaluates 
eyebrows on a scale from “No eyebrow hair” (Grade 0) to “Full eyebrow hair” (Grade 4).     
 


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Mean change from baseline in the Subject’s Eyebrow Assessment (SEA) will be calculated from 
entry into the long-term open label extension to Week 28 (Visit 13), Week 40 (Visit 14) and Week 
52 (Visit 15).  The SEA evaluates eyebrows on a scale from “No eyebrow hair” (Grade 0) to “Full 
eyebrow hair” (Grade 4).     
 
12.6. 
Safety Analyses 
Safety analyses will include descriptive statistics calculated on the safety parameters using the 
safety population. The proportion of subjects with treatment-emergent adverse events will be 
tabulated and presented by treatment and Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class. Vital signs and clinically significant abnormal laboratory 
results will also be tabulated and presented by treatment group. Overall incidence of adverse 
events will be compared between groups using a chi-square test. 
Data from all randomized subjects will be presented and summarized. Safety summaries by study 
treatment group will include listings by study medication of adverse events incidences within 
each MedDRA System Organ Class, and changes from pre-application values in vital signs. 
Adverse event summaries will be presented by study medication showing the proportion of 
subjects experiencing adverse events, both overall and by MedDRA System Organ Class. 
 
 
TRAINING, MONITORING, DATA MANAGEMENT AND QUALITY 
ASSURANCE 
13.1. 
Training 
For each investigational center, there will be an initiation visit prior to enrolling any study subjects. 
 
It is strongly recommended that all investigators, other evaluators, study nurses, study coordinators 
or other applicable personnel attend this visit.  During this visit, participants will be trained to the 
protocol, study specific procedures, and the eCRFs.  Those unable to attend the initiation visit must 
receive on-site training from an appropriately trained individual prior to participating in any of the 
procedures and evaluations in this study.  
 
Clinical Research Associates (CRAs) and other applicable personnel will be trained prior to study 
initiation to familiarize CRAs with the disease, the Standard Operating Procedures (SOPs), the 
protocol and other study specific items.  Team organization, communication and operational issues 
will also be discussed.  Aclaris Therapeutics, Inc. will provide an investigational center file to each 
center. 
 
13.2. 
Monitoring 
The conduct of the study will be closely monitored by representatives of Aclaris Therapeutics, Inc. 
to verify adherence to ICH Good Clinical Practice (GCP) guidelines, and applicable SOPs.  
Reports of these verifications will be archived with the study report.  The investigator will allow 
the Aclaris Therapeutics, Inc. representative’s designee and/or any regulatory agency to have 
direct access to all study records, eCRFs, corresponding subject medical records, study 
medication-dispensing records and study medication storage area, and any other documents 


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considered source documentation.  The investigator also agrees to assist the representative, if 
required. 
 
13.3. 
Data Management 
Data-management activities of this study will be subcontracted.  Edit checks and review processes 
will be performed by the sub-contractor until all data clarifications are resolved. The data will be 
exported to be stored in SAS datasets (or equivalent) by the sub-contractor. After all data 
clarifications are resolved and subject’s evaluability is determined, the database will be locked. 
 
13.4. 
Quality Assurance 
The study is conducted under the sponsorship of Aclaris Therapeutics, Inc. in compliance with the 
applicable regulatory requirements as well as applicable ICH guidelines, Declaration of Helsinki, 
and in respect of the Aclaris Therapeutics, Inc. and/or sub-contractor SOPs for study conduct and 
monitoring. 
 
Audits may be carried out by Aclaris Therapeutics, Inc. or Aclaris Therapeutics, Inc.’s 
representatives, and inspections may be performed by regulatory authorities or IRB/ECs before, 
during or after the study.  The investigator will provide the auditing/inspecting group direct access 
to all study records (e.g., eCRFs, subject medical records, study medication dispensing records) 
and the investigational center study facilities. The investigator and study staff will be available and 
will assist the auditing/inspecting groups as appropriate.  
 
 
ETHICS AND GENERAL STUDY CONDUCT CONSIDERATIONS 
14.1. 
Institutional Review Board (IRB)/Ethics Committee (EC) 
This protocol, informed consent form, any information provided to subjects, subject-recruiting 
advertisements, and any amendments to these items will receive IRB/EC approval prior to use. 
The IRB/EC must receive a copy of the Investigator’s Brochure, all protocol amendments, safety 
reports and other study related information as required by regulation or the IRB/EC procedures. 
 
14.2. 
Ethical Conduct of the Study 
The rights, safety and well-being of the subjects are the most important considerations in this study 
and take priority over the interests of society and science.  
 
This study will be conducted in accordance with the ethical principles originating from the 
Declaration of Helsinki, the current ICH E6 GCP guideline, local regulatory requirements and, at 
US investigational centers, in compliance with the HIPAA. The study will be conducted in 
compliance with the IRB/EC approved version of the protocol and any applicable amendments. 
 
Subjects will provide voluntary informed consent prior to initiation of any study related 
procedures. 
 


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14.3. 
Subject Information and Consent 
All subjects who participate in this study must be fully informed about the study in accordance 
with the GCPs, federal regulations, local regulations and, at US investigational centers, with 
HIPAA.  The ICF will contain all the required elements in compliance with the current ICH E6 
GCP guideline and local regulatory requirements.  
 
The investigator must have a defined process for obtaining voluntary informed consent from every 
subject.  The ICF, approved by an IRB/EC, will be fully explained to the subject.  Prior to any 
study related procedures, including washout from therapies, the subject will voluntarily sign and 
date the ICF. The investigator must maintain each subject’s ICF in the investigational center’s 
study file and must provide each subject with a copy of the signed and dated ICF. 
 
14.4. 
Study Conduct and Protocol Amendments 
With the exception of eliminating an immediate hazard to a subject, the investigator should not 
deviate from the protocol or implement any changes without prior written approval from the 
Aclaris Therapeutics, Inc.’s representative or designee and prior review and documented approval 
from the IRB/EC. 
 
The investigator should document and explain any deviation from the protocol. Changes that 
involve only logistical or administrative changes are allowed.  The investigator should document 
and explain any deviation from the protocol.  A protocol deviation is a non-adherence to protocol-
specific study procedures or schedules that does not increase the risk to a study subject and does 
not affect the scientific integrity of the study.   
 
A protocol violation is defined as any divergence from the protocol-specific study procedures or 
schedules that may result in an increased risk to a study subject or that affect the scientific integrity 
of the study.  All protocol violations must be reviewed by the Medical Monitor and reported to the 
IRB by the Investigator, as directed by the IRB-specific procedures. 
 
14.5. 
Regulatory Documents 
The investigator must maintain a study file containing current and complete regulatory 
documentation in compliance with the current ICH E6 GCP guideline. This file will be reviewed 
as part of the routine monitoring for this study. 
 
14.6. 
Contractual Requirements 
A contractual agreement will be signed between Aclaris Therapeutics, Inc. and each investigator.  
This document will contain supplemental information, including financial terms, confidentiality, 
study schedule, third party responsibility, and publication rights. 
 


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14.7. 
Data Collection and Archiving 
14.7.1. 
Data collection  
 
The Investigator must maintain required records for all study subjects.  Data for this study will be 
recorded in the subject's source document and on the eCRFs.  All data on these eCRFs should be 
recorded completely and promptly.  A copy of the completed eCRFs for each subject will be 
retained by the investigational center. 
 
Records of the subject’s participation in this study will be held confidential except as disclosure is 
required by law. The study doctor, the sponsor, persons working on behalf of the sponsor, and 
under certain circumstances, the United States Food and Drug Administration and the Institutional 
Review Board will be able to inspect and copy confidential study-related records that identify 
subjects by name. Therefore, absolute subject confidentiality cannot be guaranteed. If the results 
of this study are published or presented at meetings, the subject’s identity will not be revealed. 
 
14.7.2. 
Source documentation 
Investigators must keep accurate separate records (other than the eCRFs) of all subjects' visits that 
include all pertinent study related information.  A statement should be made indicating that the 
subjects have been enrolled in this clinical study and have provided written informed consent.  Any 
AEs must be completely documented. Source documentation includes results of any diagnostic 
tests conducted during the study.   
 
14.7.3. 
Archiving 
All pertinent data, samples, photographs, correspondence, original or amended protocol, reports 
and all other material relating to the study will be maintained securely in Aclaris Therapeutics, Inc. 
/contract research organization/investigator archives for the legally required duration for archiving. 
 
The investigator should maintain the essential study documents as specified in ICH GCP, and in 
compliance with all regulatory requirements. The investigator should ensure these documents are 
protected from accidental destruction or disposal.  If the Investigator needs to re-assign 
responsibility for maintaining these documents (e.g., due to retirement) it must be transferred to a 
person willing to accept this responsibility.  The investigator must notify Aclaris Therapeutics, 
Inc., in writing, of the name and address of the new individual. 
 


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REFERENCES 
Alkhalifah A, Alsantali A, Wang E, McElwee KJ, Shapiro J. Alopecia areata update: Part II. 
Treatment. J Am Acad Dermatol. 2010;62(2):191-202. 
Arca E, Muşabak U, Akar A, Erbil AH, Taştan HB. Interferon-gamma in alopecia 
areata. Eur J Dermatol. 2004 Jan-Feb;14(1):33-6.  
Barahmani N, Schabath MB, Duvic M; National Alopecia Areata Registry. History  
of atopy or autoimmunity increases risk of alopecia areata. J Am Acad Dermatol. 
2009 Oct;61(4):581-91.  
Bilgiç Ö, Bilgiç A, Bahalı K, Bahali AG, Gürkan A, Yılmaz S. Psychiatric symptomatology and 
health-related quality of life in children and adolescents with alopecia areata. J Eu Acad 
Dermatol Venereol. 2014;28(11):1463-1468. 
Christiano, A.  2016.  Data on File.  
Craiglow BG, King BA. Killing Two Birds with One Stone: Oral Tofacitinib Reverses Alopecia 
Universalis in a Patient with Plaque Psoriasis. J Invest Dermatol. 2014;134(12):2988-2990. 
Craiglow BG, Liu LY, and King BA. Tofacitinib for the treatment of alopecia areata and variants in 
adolescents. J Am Acad Dermatol. 2017;76(1):29-32.  
Delamere FM, Sladden MJ, Dobbins HM, Leonardi-Bee J. Interventions for alopecia areata. 
Cochrane Database Syst Rev. 2008;16(2). 
Gilhar A, Kam Y, Assy B, Kalish RS. Alopecia areata induced in C3H/HeJ mice by 
interferon-gamma: evidence for loss of immune privilege. J Invest Dermatol. 2005;124(1):288-9.  
Gupta AK. Efficacy of tofacitinib in treatment of alopecia universalis in two patients. J Eur Acad 
Dermatol Venereol. 2016;30(8):1373-1378. 
Hirota R, Tajima S, Yoneda Y, Okada M, Tashiro J, Ueda K, Kubota T, Yoshida R. 
Induction of hair regrowth in the alopecia site of IFN-gamma knockout mice by 
allografting and IFN-gamma injection into the transplantation site. J Interferon  
Cytokine Res. 2003 Aug;23(8):433-9. 
Hordinsky MK. Current Treatments for Alopecia Areata. J Investig Dermatol Symp Proc. 
2015;17(2):44-46. 
Ito, T., Ito, N., Saatoff, M., Hashizume, H., Fukamizu, H., et al. Maintenance of hair 
follicle immune privilege is linked to prevention of NK cell attack. J. Investig Dermatol. 
2008:128; 1196–1206. 
Jabbari A, Dai Z, Xing L, et al. Reversal of Alopecia Areata Following Treatment With the JAK1/2 
Inhibitor Baricitinib. EBioMedicine. 2015;2(4):351-355. 
Jabbari A, Cerise JE, Chen JC, Mackay-Wiggan J, Duvic M, Price V, Hordinsky M, Norris D, 
Clynes R, Christiano AM. Molecular signatures define alopecia areata 
subtypes and transcriptional biomarkers. EBioMedicine. 2016 May;7:240-7. 
Kim BY and Kim HS. Successful hair growth in a Korean patient with alopecia universalis 
following tofacitinib treatment. Singapore Med. J., 2017 May; 58(5): 279-280. 
Kuwano Y, Fujimoto M, Watanabe R, Ishiura N, Nakashima H, Ohno Y, Yano S, 
Yazawa N, Okochi H, Tamaki K. Serum chemokine profiles in patients with alopecia  
areata. Br J Dermatol. 2007:157(3):466-73.  
Olsen EA.  Investigative guidelines for alopecia areata.  Dermatol Ther. 2011:24;311-319. 
Olsen EA, Green C, Hordinsky M, Bergfeld W, McMichael A, Callender V, Washenik K, 
Cotsarelis G, Shapiro J, Roberts J, Wolfe S, Cherill D, Canfield D.  Alopecia Density and Extent 
(ALODEX):  A new method for assessing severity of hair loss in alopecia areata.  Submitted for 
publication. 


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Petukhova, L., Duvic, M., Hordinsky, M., Norris, D., Price, V., et al.  Genome-wide association 
study in alopecia areata implicates both innate and adaptive immunity. Nature.2008:466, 113–
117.  
Pieri L, Guglielmelli P, Vannucchi AM. Ruxolitinib-induced reversal of alopecia universalis in a 
patient with essential thrombocythemia. Am J Hematol. 2015;90(1):82-83. 
Price VH. Treatment of Hair Loss. N Eng J Med. 1999;341(13):964-973. 
Price VH, Hordinsky MK, Olsen EA, et al. Subcutaneous efalizumab is not effective in the 
treatment of alopecia areata. J Am Acad Dermatol. 2008;58(3):395-402. 
Ruiz-Doblado S, Carrizosa A, García-Hernández MJ. Alopecia areata: psychiatric comorbidity and 
adjustment to illness. Int J Dermatol. 2003;42(6):434-437. 
Safavi KH, Muller SA, Suman VJ, Moshell AN, Melton Iii LJ. Incidence of Alopecia Areata in 
Olmsted County, Minnesota, 1975 Through 1989. Mayo Clinic Proc. 1995;70(7):628-633. 
Scheinberg M, and Ferreira SB. Reversal of Alopecia Universalis by Tofacinitinib: A Case Report; 
Ann Intern Med.; 2016 Nov 15; 165(10): 750-751. doi: 10.7326/L16-0125. 
Strober BE, Siu K, Alexis AF, et al. Etanercept does not effectively treat moderate to severe 
alopecia areata: An open-label study. J Am Acad of Dermatol. 2005;52(6):1082-1084. 
Tosti A, Bellavista S, Iorizzo M. Alopecia areata: a long term follow-up study of 191 patients. J Am 
Acad Dermatol. 2006;55(3):438-441. 
Weise K, Kretzschmar L, John SM, Hamm H. Topical Immunotherapy in Alopecia areata: 
Anamnestic and Clinical Criteria of Prognostic Significance. Dermatology. 1996;192(2):129-
133. 
Whiting, D.A., 2003. Histopathologic features of alopecia areata: a new look. Arch. 
Dermatol. 139, 1555–1559.  
Xing L, Dai Z, Jabbari A, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is 
reversed by JAK inhibition. Nat Med. 2014;20(9):1043-1049. 
 
 
 
 
 
 


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:  Subject Instructions for Study Medication Application to the Scalp 
Preparation and General Instructions:  
1. Gather a clean, dry washcloth and towel, the study medication bottle and disposable 
droppers. 
2. Scalp should be clean (free of any products applied to the scalp), and dry before applying 
study medication.  A clean scalp will allow the study medication to penetrate down into 
the scalp to ensure you are getting the best application. You should wash your scalp at 
least an hour prior to study medication application, at least once a day to prevent 
accumulation of study medication on your skin.  
3. Wash your hands thoroughly with soap and water before and after using this study 
medication.  
4. You will apply a thin layer (a minimum of 1.5 up to a maximum of 4 mL) of study 
medication to the entire scalp twice-a day approximately every 12 hours, as instructed by 
the study doctor or the study staff.  On the first and last days of study medication dosing, 
you will apply study medication once-a-day only.  Once you apply study medication, do 
not wash your scalp or participate in strenuous exercise that would cause profuse sweating 
for at least 6 hours. 
5. Avoid study medication contact with the eye.  If the study medication gets on any part of 
your body other than your scalp, rinse the area well with water.  
6. Avoid exposing your scalp to excessive natural or artificial ultraviolet radiation (e.g., 
sunlight, tanning beds) and wear a hat or use sunscreen on your scalp, if excessive sun 
exposure cannot be avoided. 
7. Remember to bring your study medication bottles (both used and unused) to each study 
visit. 
8. Apply your study medication in the evening before Day 28 (Visit 6) and note the time.  
Do not apply your morning dose of study medication on your Day 28 (Visit 6) visit. 
9. Do not apply study medication to the area where the biopsy was performed until the 
study doctor indicates you are allowed. 
 
Study Medication Application: 
1. Remove the cap from the bottle.  Squeeze the rubber bulb of the dropper and insert the 
dropper into the bottle.  Release the bulb, allowing the dropper to fill with the solution to 
the 1 mL line.  If the level of the solution is above the 1 mL line, squeeze the extra 
amount back into the bottle.  The study medication level should be in line with the 1mL 
mark on the dropper.  
2. During study medication application, keep your head tilted back to avoid any study 
medication running into your eyes.  
3. Start to slowly deposit drops of study medication on the left side of your scalp from the 
front to the back.  Gently rub the solution into your scalp as you go, to avoid the 
medication from running off of your scalp.  
4. Draw up the next dropper of study medication and repeat the process.  Work from the left 
to the right side of your scalp until   your entire scalp is covered with a thin film of study 
medication.  The total amount of study medication you should apply per application is 
_____ mL. 
5. Replace the screw top cap and make sure it is closed tightly.  Dispose of the used 
dropper. 


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6. Wash your hands thoroughly after using the study medication to prevent any residue 
being left on your hands. 
7. Allow the study medication to dry for at least 20 minutes (or until completely dry) before 
you cover your head with a hat, wig, or scarf to avoid transfer of study medication.   
8. If you missed any applications of study medication, be sure to inform the study staff at 
your next visit. 
9. Do not wash your scalp or participate in strenuous exercise that would cause profuse 
sweating for at least 6 hours after applying study medication.  
Wigs and Hairpieces 
1. Wigs and hairpieces may be worn while participating in the study but must be 
appropriately managed. 
2. Wigs or hairpieces should not be worn until the study medication is completely dry on 
the scalp.  Thus, wigs or hairpieces should not be reapplied for at least 20 minutes after 
the study drug has been applied.  
3. Wigs and hairpieces will need to be removed at each study visit to allow the study doctor 
to evaluate your scalp and hair loss.  Any hairpieces that may be difficult to remove will 
prevent you from participating in the study.  Do not have semi permanent or difficult to 
remove hairpieces applied during the study.  Hair “weaves” that only involve areas of the 
scalp that continue to have hair may be accepted on a case by case basis. 
4. If scalp irritation develops during the study, it may be necessary to temporarily stop 
wearing of a hairpiece or wig.  The study doctor will discuss this with you should scalp 
irritation develop. 
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, note this missed dose, inform the 
study staff at your next visit 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 out of the reach of children. 
 
 


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:  Subject Instructions for Study Medication Application to the Eyebrow(s) 
General Instructions: 
1. Before application of study medication, your face and eyebrow area should be clean (free 
of any makeup, moisturizers, sunscreen, etc.), and dry. This will allow the study 
medication to penetrate down into the skin to ensure you are getting the best application. 
2. The study doctor will instruct you to apply study medication to one or both eyebrows. 
You will apply the study medication to the entire eyebrow area, both with and without 
eyebrow hair.   
3. You will be asked to apply a thin layer of study medication to the affected eyebrow with 
an applicator as instructed by the study doctor or the study staff. Keep applying study 
medication to the affected eyebrow(s) throughout the study, even if hair is re-growing in 
these areas. 
4. You will want the tip of your applicator to be saturated, but not too much as to cause 
dripping.  An applicator should only be dipped in the bottle once and then disposed of. 
5. Keep the study medication out of your eyes.  If the study medication gets in your eyes, 
rinse the area well with water for up to 15 minutes.  Contact the study doctor for further 
advice on managing the eye exposure. 
6. You will apply study medication twice-a-day, approximately 12 hours apart.  Once you 
apply study medication, do not wash your face and eyebrow area or participate in 
strenuous exercise that would cause profuse sweating for at least 6 hours. 
7. Remember to bring your study medication bottles, both used and unused, to each study 
visit. 
8. Avoid exposing your face to excessive natural or artificial ultraviolet radiation (e.g., 
sunlight, tanning beds) and use sunscreen on the face including the eyebrows, if 
excessive sun exposure cannot be avoided. 
9. Remove any products applied to the eyebrow area at least 1 hour before study visits.  Do 
not apply study medication less than 6 hours before a study visit. If your visit is in the 
morning you should wait until after the visit to apply your study medication. 
10. Each bottle of study medication should be used for 14 days only, even if there is 
remaining study medication.  
 
Preparation for Study Medication Application 
1. Gather a clean, dry washcloth or towel, the study medication bottle, disposable 
applicators and a mirror. 
2. Wash your hands with soap and water before and after using this study medication. 
3. Gently wash your face, ensuring your eyebrow areas are clean. Use your normal 
cleansing regime as approved by your study doctor.  Do not use abrasive cleansers or 
materials on your face and eyebrow area.  
4. Pat your face dry with a clean towel and then let it air dry until it is completely dry to the 
touch. 
 
 
 


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Study Medication Application: 
1. Unscrew the cap from the bottle.  Place the open bottle on a stable, level surface.   
2. Dip a disposable applicator into the bottle of study medication for about 2 seconds. Tap 
the tip of the applicator twice inside the edge of the bottle to remove any excess study 
medication.  The applicator should be saturated, but not dripping.   
3. Tilt your head back and place a clean, dry washcloth over one eye. Swipe the applicator 
across your affected eyebrow ridge above the covered eye, applying a thin layer of study 
medication over the entire affected eyebrow area.  Your eyebrow area should be wet, but 
not dripping wet.  Dispose of the applicator.  Do not dip the same applicator in the 
study medication bottle more than once. 
4. If you need additional study medication to cover your entire affected eyebrow, use a new 
applicator and repeat the application process as described in #2 and #3.  
5. If you are instructed by the study doctor to treat both eyebrows, apply study medication 
to your other eyebrow following instructions in #2, #3, and #4. 
 
After Study Medication Application 
1. Securely close the study medication bottle and dispose of any used applicators.   
2. Wash your hands after using this product. 
3. Allow the study medication to completely dry for at least 10 minutes. 
4. Do not apply any products (moisturizers, sunscreens, cosmetics, etc.) to your eyebrow 
area until the study medication has completely dried, at least 30 minutes after applying 
study medication. 
5. Do not wash your face and eyebrow areas or participate in strenuous exercise that would 
cause profuse sweating for at least 6 hours after applying the study medication. 
 
Missed Doses 
If you miss a dose of this study medication, 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.  Tell 
the study staff about any missed doses at your next study visit. 
 
Storage 
Store the study medication in the original glass bottle at room temperature, away from heat, 
moisture, and direct light. Do not refrigerate or freeze. Keep out of reach of children. 
 


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: Alopecia Areata History  
The following AA history will be obtained: 
 
1. Onset date of alopecia 
 
2. Onset date of current episode of AU or AT 
 
3. Did the subject use previous therapies for Patchy AU or AT? 
 
a. If Yes, indicate which therapies 
1. Topical immunotherapy 
2. Glucocorticosteroids 
3. Systemic Steroids 
4. DMARDS 
5. Biologics or immunosuppressants 
6. Plaquenil 
7. PDT 
8. Janus kinase inhibitors 
9. Phototherapy 
10. Laser therapy 
11. Narrow-band UVB 
12. Other 
 
 


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:  Fitzpatrick’s Skin Type Chart 
Fitzpatrick Skin Type 
Description (Sunburn & Tanning History According to Skin Type) 
Skin Type 
Always Burns; never tans (pale white skin) 
I 
Burns easily; tans minimally (white skin) 
II 
Burns moderately; tans uniformly (light brown skin) 
III 
Burns minimally; always tans (moderate brown skin) 
IV 
Rarely burns; tans profusely (dark brown skin)  
V 
Never burns; deeply pigmented (dark black Skin) 
VI 
 


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:  Scalp Biopsy 
All scalp punch biopsies will be performed by the investigator according to the Schedule of Events 
in Section 7.3. Note:  The scalp biopsy for pharmacokinetic analysis performed on Day 2 and 
Day 29 should be obtained after the area of the scalp to be biopsied is tape stripped using 5 
D-Squame circular discs.  
 
The biopsy site will be anesthetized with an injection of 1% lidocaine with epinephrine. The 
lidocaine with epinephrine may be neutralized with bicarbonate to prevent stinging.  After 
approximately 1 minute, the physician will apply pressure to the biopsy site using a 4mm diameter 
skin punch (a sterile cylindrical tube with a sharp edge). The punch is twisted until the blade of the 
skin punch has pierced the epidermis and dermis of the skin and enters the subcutaneous fat. 
Depending on the thickness of the skin in the area being biopsied, the cylindrical blade may be 
buried to the hub (approximately 6mm in depth). After the blade has sufficiently cored or carved 
out a cylinder of skin, the skin punch is removed. Nontraumatic forceps are used to gently grasp 
the cored skin, pulling upward to remove the core and reveal the subcutaneous fat. Scissors are 
used to cut the cored tissue free from the underlying subcutaneous fat. Care should be taken to 
ensure that the specimen is cut well below the level of the hair follicle.  The specimen is placed 
immediately into the appropriate media. Once the specimen has been removed, pressure is applied 
to the biopsy site with a sterile 2 x 2 gauze. The biopsy site is then closed with several simple 
interrupted sutures. Either an absorbable or nonabsorbable suture may be used at the investigator’s 
discretion. Antibiotic ointment is applied, and the area is covered with a standard Band-Aid or 
sterile gauze and paper tape. If the presence of adjacent hair makes adhesion of a bandage difficult, 
antibiotic ointment will be used without a covering. When necessary, a small pressure dressing 
may be applied. Subjects will be instructed in wound care, to avoid applying study medication to 
the biopsy site until the sutures are removed and will be advised to call the research unit if they 
have any concerning signs or symptoms during healing.  A follow-up visit will be scheduled 
approximately 2 weeks later, to remove sutures, if necessary, and examine the healing process of 
the biopsy site to ensure it is healing appropriately. 
 
 

SAP_001.pdf: 


Aclaris Therapeutics Inc. 
10 December 2018 
Protocol: ATI-50002-AA-202 
Statistical Analysis Plan 
 
Page 2 of 15 
 
TABLE OF CONTENTS 
1. 
STUDY OBJECTIVES .................................................................................. 4 
1.1 Primary Objective ............................................................................................. 4 
1.2 Secondary Objectives ........................................................................................ 4 
2. 
STUDY DESIGN ........................................................................................... 4 
3. 
SCHEDULE OF ASSESSMENTS ................................................................ 5 
4. 
STATISTICAL METHODS ......................................................................... 10 
4.1 Study Populations, Disposition, Baseline Characteristics, 
Medical History Concomitant Medications, Exposure and 
Protocol Violations .................................................................................... 10 
4.1.1 
Analysis Populations .................................................................... 10 
4.1.2 
Patient Disposition ....................................................................... 10 
4.1.3 
Demographic and Baseline Characteristics .................................. 11 
4.1.4 
History of Alopecia ...................................................................... 11 
4.1.5 
Prior and Concomitant Medications, Therapies and 
Procedures .................................................................................... 11 
4.1.6 
Exposure to Study Medication and Study Medication 
Administration .............................................................................. 11 
4.1.7 
Major Protocol Violations ............................................................ 11 
4.2 Pharmacokinetic Endpoints ............................................................................. 12 
4.2.1 
Blood Levels of ATI-50002 .......................................................... 12 
4.2.2 
Scalp Biopsy Levels of ATI-50002 .............................................. 12 
4.3 Pharmacodynamic Endpoints .......................................................................... 12 
4.3.1 
SALT and ALODEX Scores ......................................................... 12 
4.3.1 
ALADIN Scores ........................................................................... 12 
4.3.2 
Eyebrow Assessments during Open-Label ................................... 12 
4.3.3 
Subject Global Impression of Treatment Satisfaction 
(SGIS) ........................................................................................... 12 
4.4 Safety Analyses ............................................................................................... 13 
4.4.1 
Adverse Events ............................................................................. 13 
4.4.2 
Physical Examinations ................................................................. 14 
4.4.3 
Vital Signs .................................................................................... 14 
4.4.4 
ECG assessments .......................................................................... 14 
4.4.5 
Laboratory Evaluations ................................................................ 14 
4.5 Pharmacokinetic Analyses ............................................................................... 14 
4.6 Interim Analyses .............................................................................................. 14 
4.7 Sample Size ..................................................................................................... 15 
4.8 Changes in/ Clarifications to the Conduct of the Study or 
Planned Analysis ....................................................................................... 15 


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5. 
STATISTICAL SOFTWARE ....................................................................... 15 
 


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INTRODUCTION 
 
The purpose of this statistical analysis plan (SAP) is to provide a description of the 
statistical analyses performed for the Phase 2 protocol, ATI-50002-AA-202, V2.0 
(14Aug2018). 
1. 
STUDY OBJECTIVES 
1.1 Primary Objective 
To assess safety, tolerability, pharmacokinetics and pharmacodynamics of ATI-50002 
Topical Solution, 0.46% compared to vehicle in subjects with alopecia universalis (AU) 
and alopecia totalis (AT). 
1.2 Secondary Objectives 
To assess the efficacy of ATI-50002 Topical Solution, 0.46% for the treatment of scalp hair 
loss and eyebrow in subjects with AU or AT. 
To assess subject satisfaction following treatment with ATI-50002 Topical Solution, 0.46% 
for the treatment of scalp hair loss in subjects with AU or AT. 
2. 
STUDY DESIGN 
 In the double-blind period, this Phase 2, multicenter, randomized study is designed to 
evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of ATI-50002 
Topical Solution in subjects with AU and AT.  Subjects will be required to have a clinical 
diagnosis of stable, clinically typical AU or AT for a duration of at least six months up to 
and including seven years.  A total of 12 subjects will be randomized.   
 
During the screening period, subjects will be assessed for eligibility into the study.  
Subjects who meet all the entry criteria will be randomized 2:1 to ATI-50002 Topical 
Solution, 0.46% or Vehicle Topical Solution and will apply a minimum of 1.5 mLs up to 
a maximum of 4 mLs of study medication to the entire scalp twice-a-day for 28 days. On 
Day 1 (Visit 2) and Day 28 (Visit 6), and Day 196 (1 day prior to Visit 13), subjects will 
apply study medication once-a-day. 
 
Blood samples for concentrations of ATI-50002will be collected from the first 6 subjects 
enrolled into the study on Day 1 (Visit 2), and Day 28 (Visit 6) at pre-application and 1, 
2, 4, 8 hours post application and on Day 2 (Visit 3) and Day 29 (Visit 7), 24 hours post-
application.  Blood samples for immunology will be collected on Day 1 (Visit 2) before 
study medication application, and on Day 29 (Visit 7), 24 hours after study medication 
application on Day 28 (Visit 6).  A 4-mm punch biopsy of the scalp will be obtained to 
determine the concentration of ATI-50002 in the scalp skin on Day 2 (Visit 3) 24 hours 
after study medication application on Day 1 (Visit 2) and on Day 29 (Visit 7), 24 hours 


Aclaris Therapeutics Inc. 
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Statistical Analysis Plan 
 
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after study medication application on Day 28 (Visit 6).  A 4-mm punch biopsy will be 
obtained to determine histology and immunology prior to study medication application 
on Day 1 (Visit 2) and on Day 29 (Visit 7) and Day 197 (Visit 13), 24 hours after study 
medication application on Day 28 (Visit 6) and Day 196.  Safety and tolerability will be 
evaluated at each study visit by assessment of adverse events and vital signs, and at select 
visits, ECGs and clinical laboratory tests will be completed. 
 
On Day 29 (Visit 7) subjects who complete Visit 7, continue to meet the entry criteria and 
have no clinically significant AEs or tolerability issues will be eligible to enter a 12-
month open-label extension.  In the open-label extension, safety, tolerability and efficacy 
will be assessed.  All subjects enrolled in the open-label extension will apply ATI-50002 
Topical Solution, 0.46% to the entire scalp, twice daily for 52 weeks (12 months).  In 
addition, subjects with eyebrow loss may apply a thin film of study medication to the 
affected eyebrow(s) twice-daily for 52 weeks (12 months).  Subjects will be followed 
monthly for safety, tolerability and efficacy as detailed in Section 7.3.  Subjects who 
decline or are not eligible for the open-label extension should be seen for suture removal, 
if applicable per Section 7.3 and Visit 16 (Post-treatment) 30 days ± 3 days following the 
Day 28 (Visit 6).  Subjects enrolled in the initial 6-month Open Label Extension outlined 
by Protocol Amendment 1 (dated 06Feb2018) must be re-consented under Protocol 
Amendment 2 (dated 14AUG2018) in order to continue for an additional 6 months of 
Open Label treatment. 
3. 
SCHEDULE OF ASSESSMENTS 
The study schedule of assessments can be found in Table 1.A. 


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Statistical Analysis Plan 
 
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Schedule of Assessments 
 
Screening 
Baseline 
 Double Blind Treatment 
Visit  
1 
Visit  
2 
 
Visit 3 Visit 4 Visit 5 
 
Call Visit 6 
 
Visit 7 
Optional  
Visit 
(Suture Removal) 
Week 
 
0 
0 
1 
2 
4 
4 
4 
6 
Treatment Day 
-30 to 0 
1 
2 
8 
15 
27 
28 
29 
43 
Treatment Window(days) 
N/A 
N/A 
 
± 3 
± 3 
-3 
-3 
-3 
± 3 
Informed consent1 
X 
 
 
 
 
 
 
X17 
 
Inclusion/exclusion criteria  
X 
X 
 
 
 
 
 
 
 
Physical exam2 
X 
 
 
 
 
 
 
X 
 
Demographics & medical history 
X 
 
 
 
 
 
 
 
 
Alopecia Areata History  
X 
 
 
 
 
 
 
 
 
Vital signs3  
X 
X 
X 
X 
X 
 
X 
X 
X 
Clinical laboratory sampling4: CBC, Chemistry with lipids, Virology, Serum Pregnancy, 
Urinalysis  
X4 
X 
 
 
X 
 
 
X 
 
Urine pregnancy test (WOCBP)5 
 
X 
 
 
 
 
X 
 
 
ECG  
X 
X 
 
 
X 
 
 
X 
 
SALT Score (prior to ALODEX)6 
 
X 
 
 
 
 
 
X 
 
ALODEX Score (after SALT)7 
 
X 
 
 
 
 
 
X 
 
Clinician Eyebrow Assessment 
 
 
 
 
 
 
 
X18 
 
Subject Eyebrow Assessment 
 
 
 
 
 
 
 
X18 
 
Subject Global Impression of Treatment Satisfaction (SGIS) 
 
 
 
 
 
 
 
 
 
Photography8 
 
X 
 
 
 
 
 
X 
 
Subject randomization 
 
X 
 
 
 
 
 
 
 
Subject instructions9 
 
X 
X 
X 
X 
X 
X 
X17 
 
Biopsy for PK10 
 
 
X 
 
 
 
 
X 
 
Biopsy for PD11 
 
X 
 
 
 
 
 
X 
 
Blood sample for PK12 
 
X 
X 
 
 
 
X 
X 
 
Blood for immunologic studies13 
 
X 
 
 
 
 
 
X 
 
Dispense, collect, weigh study medication bottles14 
 
X 
X 
X 
X 
 
X 
X17 
 
In office study medication application9,14 
 
X 
 
 
 
 
X 
 
 
Suture removal, if applicable15 
 
 
 
 
X 
 
 
 
X 
Telephone Call16 
 
 
 
 
 
X 
 
 
 
Concomitant therapies 
 
X 
 
X 
X 
X 
X 
X 
X 
Adverse events  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Open-Label Treatment 
Post-
Treatment17 


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Statistical Analysis Plan 
 
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Visit 8 
Visit 9 
Visit 10 
Visit 11 
Visit 12 
Call 
Visit 13 
Optional Visit 
(Suture Removal) 
Visit  
14 
Visit  
15 
Visit  
16 
Week 
8 
12 
16 
20 
24 
28 
28 
30 
40 
52 
56 
Treatment Day17 
57 
(OLE 28) 
85 
(OLE 56) 
113 
(OLE 84) 
141 
(OLE 112) 
169 
(OLE 140) 
196 
(OLE 167) 
197 
(OLE 168) 
211 
(OLE 182) 
281 
(OLE 252) 
365 
(OLE 336) 
59/ 393 
(OLE 364) 
Treatment Window(days) 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
+7 
± 3/± 7 
Informed consent1 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
 
 
 
 
 
 
 
 
 
 
 
Physical exam2 
 
 
 
 
 
 
 
 
 
 
X 
Demographics & medical 
history 
 
 
 
 
 
 
 
 
 
 
 
Alopecia Areata History  
 
 
 
 
 
 
 
 
 
 
 
Vital signs3  
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Clinical laboratory 
sampling4: 
CBC, Chemistry with 
lipids, Virology, Serum 
Pregnancy, Urinalysis  
 
X 
 
 
 
 
X 
 
X 
X 
X 
Urine pregnancy test 
(WOCBP)5 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
ECG  
 
X 
 
 
 
 
X 
 
 
 
X 
SALT Score (prior to 
ALODEX)6 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
ALODEX Score (after 
SALT)7 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Clinician Eyebrow 
Assessment 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Subject Eyebrow 
Assessment 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Subject Global Impression 
of Treatment Satisfaction 
(SGIS) 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Photography8 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Subject randomization 
 
 
 
 
 
 
 
 
 
 
 
Subject instructions9 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Biopsy for PD11 
 
 
 
 
 
 
X 
 
 
 
 
Blood for immunologic 
studies13 
 
 
 
 
 
 
X 
 
 
 
 
 
 


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Open-Label Treatment 
Post-
Treatment17 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Visit 12 
Call 
Visit 13 
Optional Visit 
(Suture Removal) 
Visit  
14 
Visit  
15 
Visit  
16 
Week 
8 
12 
16 
20 
24 
28 
28 
30 
40 
52 
56 
Treatment Day17 
57 
(OLE 28) 
85 
(OLE 56) 
113 
(OLE 84) 
141 
(OLE 112) 
169 
(OLE 140) 
196 
(OLE 167) 
197 
(OLE 168) 
211 
(OLE 182) 
281 
(OLE 252) 
365 
(OLE 336) 
59/ 393 
(OLE 364) 
Treatment Window(days) 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
+7 
± 3/± 7 
Dispense, collect, weigh 
study medication bottles14 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
In office study medication 
application9,14 
 
X 
 
 
 
 
 
 
 
 
 
Suture removal, if 
applicable15 
 
 
 
 
 
 
 
X 
 
X 
 
Telephone Call16 
 
 
 
 
 
X 
 
 
 
 
 
Concomitant therapies 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1A written signed ICF must be obtained from each subject prior to performing any study related procedure (i.e., prior to performing vital signs, standardized photography, biopsies, clinical 
laboratory sampling, or UPT). 
2A physical exam includes:  General appearance, examination of head, eyes, ears, nose and throat, respiratory, cardiovascular, abdominal, neurological, musculoskeletal, lymphatic and skin 
assessment. 
3 Vital signs include oral or ear temperature, blood pressure, heart rate, respiration rate (height and weight at Baseline only). 
4 Clinical laboratory sampling includes: CBC, Chemistry with lipids, Urinalysis, at each visit and At Screening only:  Quantiferon Gold, TIBC, Serum iron, Serum Ferritin, Serum pregnancy, 
T3, T4, and TSH. 
5 UPT must be performed prior to randomization at Visit 2 and prior to study medication application at Day 28 (Visit 6) and at each OLE visit. UPT must be negative for the subject to continue 
in the study.  WOCBP must have a negative serum pregnancy test at screening and a negative UPT at baseline prior to randomization. 
6SALT is performed prior to ALODEX score using device provided. 
7 ALODEX is performed after SALT score using device provided. 
8 Photography should be performed on Day 1 (prior to application of study medication application) and on Day 29 & Day 197 prior to the scalp biopsy.   
9Subjects must be instructed to apply the study medication according to the instructions in Appendix 1.  Subjects will apply the first dose of study medication on the morning of Day 1 (Visit 2) 
and the last application of study medication on the morning of Day 28 (Visit 6), under the instruction and supervision of the study staff.  Study medication at these visits should be applied in 
the morning to allow the 8-hour post dose assessments to occur at a reasonable time. On Day 1 (Visit 2) and Day 29 (Visit 7) subjects will only apply study medication once-a-day in the 
office. 
10 PK: A 4mm punch biopsy must be obtained on Day 2 (Visit 3) and Day 29 (Visit 7) 24 hours (± 30 minutes) after study medication application on Day 1 (Visit 2) and Day 28 (Visit 6). 
11 PD:  A 4mm punch biopsy must be obtained on Day 1 (Visit 2) before application of first dose of study medication and Day 29 (Visit 7) 24 hours (± 30 minutes) after study medication 
application.  Subjects that choose to continue in to open-label extension treatment will also have a 4mm punch biopsy collected on Day 197 (Visit 13). 


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Statistical Analysis Plan 
 
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Open-Label Treatment 
Post-
Treatment17 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Visit 12 
Call 
Visit 13 
Optional Visit 
(Suture Removal) 
Visit  
14 
Visit  
15 
Visit  
16 
Week 
8 
12 
16 
20 
24 
28 
28 
30 
40 
52 
56 
Treatment Day17 
57 
(OLE 28) 
85 
(OLE 56) 
113 
(OLE 84) 
141 
(OLE 112) 
169 
(OLE 140) 
196 
(OLE 167) 
197 
(OLE 168) 
211 
(OLE 182) 
281 
(OLE 252) 
365 
(OLE 336) 
59/ 393 
(OLE 364) 
Treatment Window(days) 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
+7 
± 3/± 7 
12PK: The first 6 subjects enrolled in the study will have the blood PK testing performed.  Blood for PK sampling will be obtained on Day 1 (Visit 2) and Day 28 (Visit 6), just prior to study 
medication application (predose), and 1, 2, 4, 8 hours post dose and on Day 2 (Visit 3) and Day 29 (Visit 7), 24 hours after study mediation application (on Day 1 (Visit 2) and Day 28 (Visit 
6). See Section 9.3.2 for PK sample draw time windows. 
13 Blood for immunology will be obtained prior to administration of study medication on Day 1 (Visit 2) and on Day 29 (Visit 7) 24 hours (± 30 min) after study medication application on Day 
28 (Visit 6).  Subjects that choose to continue in to open-label extension treatment will also have blood for immunology collected on Day 197 (Visit 13). 
14 On Day 1 (Visit 2) and Day 28 (Visit 6) the study medication bottle should be weighed and then dispensed to the subject for the initial application under the supervision of study staff in the 
office.  After the initial application on Day 1, the study medication bottle should be collected, weighed and dispensed to the subject after the 24-hour post-dose blood draw on Day 2 (Visit 3).  
For Visits 3 -6, each study medication bottle (with the cap) must be weighed before dispensing to the subject and at the time of return using the scale provided by Aclaris.  On Day 28 (Visit 6), 
the study medication bottle should be weighed after subject applies the study medication in the office and not redispensed. 
15 The investigator or designee will remove the sutures approximately 14 days after scalp biopsy, unless an absorbable suture is used. 
16 On Day 27 or the day prior to Day 28 (Visit 6), the study staff will call the subject to remind them not to apply study medication on the morning of Day 28 (Visit 6) and to bring both used 
and unused study medication bottles to the visit.  Study medication will be applied in the office under the supervision of the study staff.  On Day 196 or the day prior to Week 28 (Visit 13) the 
study staff will call the subject to remind them not to apply study medication in that evening and on the morning of Week 28 (Visit 13), and to bring both used and unused study medication 
bottles to the visit.  The scalp biopsy at Week 38 (Visit 13) should be performed 24 hours (±30 minutes) post the last study medication application. 
17On Day 29 (Visit 7) subject may be given the option to move into open-label extension treatment.   
• 
If the subject declines the open-label extension, she/he should be seen for the Visit 16 (Post-treatment) assessments 30 days following the date of Day 29 (Visit 7). 
• 
If the subject chooses to continue in to the open-label extension, she/he must sign an ICF prior to being dispensed open-label drug and receiving continued study medication 
application instructions.  
• 
If the subject enrolls in open-label treatment after Day 29 (Visit 7), an unscheduled visit will be conducted in order to obtain consent, review drug application instructions, and 
dispense drug.  This will be considered the official date that the subject initiated open-label extension treatment and the scheduling of subsequent visits 8-16 should be based off 
of this date as referenced by (OLE xxx) in the treatment day schedule header above. 
 
18Subjects who are eligible and consent to enter the open-label extension will have a baseline CEA and SEA completed at Visit 7 or the unscheduled Visit. 


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Statistical Analysis Plan 
 
 
 
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4. 
STATISTICAL METHODS  
In general summaries will be presented according to double-blind treatment group and 
additionally for the subset of patients entering open-label.  Other than baseline data (ie data 
collected prior to the first application of double-blind medication), the data summarized 
corresponds to the period of collection (ie during double-blind or during open-label).  For 
those entering open-label, the open label period begins at the application of open-label 
medication.  Additional details are provided in the data handling and programming 
specifications document.    No imputation of missing data was performed other than 
completely or partially missing dates as described in the Data Handling and Programming 
Specifications document.  
All Data listings are sorted by double-blind treatment group and patient ID. 
4.1 Study Populations, Disposition, Baseline Characteristics, Medical History 
Concomitant Medications, Exposure and Protocol Violations 
4.1.1 Analysis Populations 
The efficacy and safety populations will be defined as follows: 
• As-Treated population (AS): This population includes all patients with at least 
one application of study treatment.  This population will be used for 
pharmacodynamics and safety analyses.  All analyses using this population will 
be based on the treatment actually received. 
• Blood Pharmacokinetic (PK1) population:  This population includes patients 
participating in the PK assessment who had evaluable blood plasma 
measurements with no significant protocol deviations that may impact the data. 
• Scalp Pharmacokinetic (PK2) population:  This population includes patients 
participating in the PK assessment who had evaluable scalp biopsy measurements 
with no significant protocol deviations that may impact the data. 
• Pharmacodynamic (PD) population:  This population includes all randomized 
patients who had at least 1 evaluable pharmacodynamic measurement. 
4.1.2 Patient Disposition 
The number of patients in each population is presented together with the study completion 
status and the reasons for discontinuation. Patents entering open-label are considered to 
have completed the study with regard to double-blind medication. 


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4.1.3 Demographic and Baseline Characteristics 
Demographic and baseline characteristics are presented in the data listings.  Descriptive 
summary statistics (n, mean, standard deviation, median, minimum, and maximum) and/or 
frequency distributions, as appropriate, are generated for the AS population.   
4.1.4 History of Alopecia 
The type of Alopecia (AT or AU) and prior therapies for alopecia will be summarized by 
frequency distributions. The time since onset of the current episode of alopecia at entry 
will be summarized using descriptive statistics (n, mean, standard deviation, median, 
minimum, and maximum).  Summaries will be generated for the AS population.   
Histological/Cytologic information will be tabulated.  
4.1.5 Prior and Concomitant Medications, Therapies and Procedures 
Medications are coded using the WHO Drug Reference.  Prior and concomitant 
medications are listed only.  The period(s) in which the medications were administered are 
flagged. 
4.1.6 Exposure to Study Medication and Study Medication 
Administration 
Exposure will be summarized and listed for the AS population with separate summaries 
from double-blind and open-label periods.  Additionally, the combined exposure to ATI-
50002 from the double-blind and open-label periods will be tabulated. 
The duration of treatment, total weight, total volume, and average volume per application 
will be summarized using descriptive statistics (n, mean, SD, median, minimum and 
maximum).  
4.1.7 Major Protocol Violations 
Protocol violations will be identified  to measure adherence to key aspects the protocol.  
Prior to unblinding the sponsor will assess the data and identify all major and minor 
protocol deviations.  Specific data fields that will be examined to identify protocol 
deviations include entrance inclusion/exclusion criteria and prohibited prior and 
concomitant medications as well as all deviations identified by the investigator. All 
protocol violations will be listed, and major protocol violations will be summarized (n and 
percent) by randomized treatment group for all violations during the double-blind period. 


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4.2 Pharmacokinetic Endpoints 
4.2.1 Blood Levels of ATI-50002 
The blood levels of ATI-5002 will be listed only. 
4.2.2 Scalp Biopsy Levels of ATI-50002 
Scalp biopsy levels of ATI-50002 will summarized with descriptive statistics for each 
schedule collection visit.  Levels that are BLQ will not be included but will be accounted 
for categorically. 
4.3 Pharmacodynamic Endpoints 
The baseline scores for SALT and ALODEX will be the last non-missing value collected ≤ 
the date of the first application of double-blind study medication. This baseline will be used 
also for calculating changes during open-label for these variables.  For the eyebrow 
assessments (CEA and SEA), the value collected at V7 will be used as the baseline for 
calculating changes during subsequent visits.  
4.3.1 SALT and ALODEX Scores 
For both SALT and ALODEX the mean and mean change from baseline will be tabulated 
by visit and treatment group.  Change will be assessed both as an absolute percentage 
difference (timepoint percentage score – baseline percentage score) as well as relative 
percent regrowth (absolute percentage difference divided by baseline percentage * -1).  In 
addition, the proportion of patients that have ≥25%, ≥50% and ≥75% regrowth will be 
tabulated for both SALT and ALODEX.  
4.3.1 ALADIN Scores 
The analysis of ALADIN scores will be detailed in a separate document. 
4.3.2 Eyebrow Assessments during Open-Label 
For patients entering open-label, mean Percent hair loss, CEA and SEA scores mean and 
mean change from baseline will be provided by visit. At entry into open-label, V7, 
summary statistics will be provided by double-blind treatment group as well as for all 
patients entering open-label. Where applicable, each patient’s scores for the left and right 
eyebrows will be averaged prior to summarization.  Individual scores for the left and right 
eyebrows will be provided in the data listings.  
4.3.3 Subject Global Impression of Treatment Satisfaction (SGIS) 
For patients entering open-label, descriptive statistics (N, mean, SD, median, minimum 


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and maximum) of the SGIS will be provided by visit.  Additionally, the number of 
percentage of patents recording each of the 7 possible SGIS scores will be provided 
categorically.  
4.4 Safety Analyses 
The comprehensive safety analysis is based on all patients in the AS population.  
The following sections detail the summaries performed on the safety data. Additional data 
handling rules including those for imputation of partially missing dates are provided in a 
separate SAP document pertaining to data handling and programming specifications. 
The baseline scores for vital signs, laboratory assessments and ECGs will be the last non-
missing value collected ≤ the date of the first application of double-blind study medication. 
This baseline will be used also for calculating changes during open-label for these variables.     
4.4.1 Adverse Events 
Adverse events are coded using the MedDRA dictionary and are categorized by system 
organ class (SOC) and preferred term (PT).  Only treatment emergent adverse events are 
included in summary tabulations and include the following groupings:  Double-Blind ATI-
5002, Double-Blind Placebo, Open-Label ATI-5002 and Total ATI-50002 (Double-Blind + 
Open-Label). All adverse events are included in the data listings including those that are 
not considered treatment emergent.   
To allow differentiation as to which study period an Adverse Event occurred, four 
categories are defined based upon onset date. Adverse Events that had onset dates prior to 
the first application of study medication are considered "prior”. Adverse events with 
onset dates on or after the first application of double-blind study medication, prior to 
entry into open label (first application of open-label study medication) and within 30 days 
following the last application of study medication are considered "on double-blind 
therapy" or equivalently “treatment emergent”.  Events with onset dates on or after the 
first application of open-label study medication and within 30 days of the last application 
of study medication are consider “on-open-label therapy” and also considered “treatment 
emergent”. Events with onset dates more than 30 days after the last application of study 
medication, be it double-blind or open label, are considered as "post-therapy".   
   
Frequency tabulations are presented by MedDRA SOC and preferred term, for all adverse 
events; study treatment-related, adverse events resulting in discontinuation of study 
treatment, serious adverse events and adverse events by maximum severity. Adverse events 
resulting in discontinuation are those with ‘action taken’ recorded as ‘drug withdrawn’. 


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4.4.2 Physical Examinations 
Physical examination findings will be listed for each patient. 
4.4.3 Vital Signs 
Systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate and 
temperature are summarized using descriptive statistics for each visit. Both actual values 
and changes from baseline are summarized. 
4.4.4 ECG assessments 
The core laboratory’s interpretation of the ECGs are summarized as “shift” from baseline 
to “worst” overall interpretation recorded after baseline where the order of severity of the 
interpretations from best to worst are “Normal”, “Abnormal, NCS” and “Abnormal, CS”. 
Separate summaries are used for post baseline data collected during double-blind and 
during open-label.  If applicable, follow-up visits are included in the post-baseline data 
dependent upon entry into open-label (ie included in double-blind assessment if a patient 
did not enter open-label and in open-label assessment if they did).  
4.4.5 Laboratory Evaluations 
Shift tables showing changes in relationship to the normal reference range grade from 
baseline to the “worst” relationship recorded post-baseline are tabulated.  In the event a 
patient had both “low” and “high” post-baseline values the patient will be counted under 
both “low” and “high”.  As such the percentages of the cells in the shift table may add to 
more than 100%.   
Chemistry and Hematology parameters are summarized using descriptive statistics for each 
visit. Both actual values and changes from baseline are summarized. 
The number and percentage of patients meeting criteria for hepatobiliary abnormalities and 
for potential renal impairment are provided for Double-Blind ATI-50002, Double-Blind 
Placebo, Open-Label ATI-50002 and Total ATI-50002 (Double-Blind + Open-Label). 
4.5 Pharmacokinetic Analyses 
Levels of ATI-50002 in the scalp biopsy is summarized for V3 (Day 2) and V7 (Day 29) 
using simple descriptive statistics. Only values that are quantifiable are included in the 
mean, SD, etc.; however, a separate summary of the number and percentage of patients 
with value that were BLQ (below limit of quantification) is provided. 
4.6 Interim Analyses 
An interim assessment of blood and scalp PK was performed in the first N=6 patients.  For 
this analysis, the following steps were taken to ensure that unblinded review of PK / PD 


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parameters did not affect the blinded creation, collection, review or verification of any 
clinical study data. No PK / PD unblinded reviews were undertaken until all relevant 
subjects have had all data through Visit 7 verified by source document review and were 
determined to have all data complete and accurate. Additionally, data from visits through 
Visit 7 were locked in the EDC system by CRAs, to prevent any changes without 
permission from the Sponsor. As such, the EDC system audit trail will capture all data 
activity before and after this Visit 7 lock.  All clinical evaluations through Visit 7 for the 
applicable subjects were done without knowledge of treatment group assignment. 
 
4.7 Sample Size 
Since this is the first multicenter study of ATI-50002 Topical Solution in subjects with 
stable alopecia universalis and alopecia totalis, sample size considerations were based upon 
feasibility factors and not on a formal power computation. 
4.8 Changes in/ Clarifications to the Conduct of the Study or Planned Analysis 
The Chi-square statistic was not created to compare the incidence of adverse events    
Details of analyses of ALADIN scores and immunologic evaluation of blood T-cells will 
be provided in a separate document.  
Scalp biopsy histology will not be analyzed due to limited samples.  
5. 
STATISTICAL SOFTWARE 
All data summaries and listings will be performed using SAS Version 9.2 or higher, under 
Windows operating system.