Conditions: Dermatosis Papulosa Nigra
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 39
Healthy volunteers: no

Brief summary:
Evaluate the safety and efficacy of hydrogen peroxide, A-101 Solution 40% for the treatment of DPN lesions on subjects with a Fitzpatrick Skin Type of 5 or 6.

Detailed description:
The main objective of this study is to evaluate the safety and efficacy of hydrogen peroxide, A-101 Solution 40% for the treatment of DPN lesions on subjects with a Fitzpatrick Skin Type of 5 or 6.

The secondary objectives of this study include:

* Durability of response
* Safety

An exploratory objective of this study will evaluate the subject's assessment of the treatment of A-101 to DPN lesions using a Subject Self-Assessment Scale.

Arms:
arm 1: A-101 40% without medically abrading the identified DPN prior to treatment arm 2: A-101 40% with the identified DPN lesions medically abraded prior to treatment arm 3: A-101 40% without medically abrading the identified DPN prior to treatment

Interventions: intervention 1: A-101 Topical Solution 40%
Intervention descriptions: intervention 1: A-101 Topical Solution 40%

Protocol document:
Prot_000.pdf: 
Aclaris Therapeutics, Inc. 
Protocol Number: A-101-DPN-201 
Amendment 1 
Version 2.0:  28 MARCH 2018 
                                                                 Page 1 of 60 
CLINICAL STUDY PROTOCOL 
 
Protocol Number: A-101-DPN-201 
 
Version 2.0  
28 MARCH 2018 
 
A Phase 2 Open Label Study of A-101 Topical Solution in Subjects with Dermatosis 
Papulosa Nigra  
 
 
Sponsor 
Aclaris Therapeutics, Inc. 
640 Lee Road, Suite 200 
Wayne, PA 19087 
Telephone: (484) 324-7933 
Facsimile: (484) 320-2344 
 
Study Contact 
Judy Schnyder 
Aclaris Therapeutics, Inc. 
Telephone:  484-329-2144 
Email:  jschnyder@aclaristx.com 
 
Medical Monitor        
Stuart D. Shanler, MD 
Aclaris Therapeutics, Inc. 
Telephone:  484-321-5555 
Email:  sshanler@aclaristx.com 
 
Drug Safety Monitor 
Kenneth Kostenbader, MD 
Aclaris Therapeutics, Inc. 
Telephone:  484-329-2176 
Email:  kkostenbader@aclaristx.com 
 
Serious Adverse Event Facsimile:  484-324-2359 
 
 
 
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document constitutes an agreement by the recipient that no unpublished information contained herein will be used, 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: A101-DPN-201 
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                                                                Page 3 of 60 
INVESTIGATOR SIGNATURE PAGE 
Protocol Number: 
A-101-DPN-201 
 
Protocol Title:   
A Phase 2 Open Study of A-101 Topical Solution in Subjects with 
Dermatosis Papulosa Nigra  
 
Protocol Version  
Version 2.0 28 MARCH 2018 
 
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 material 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 patient or each prospective trial 
patient’s legal representative prior to conducting any protocol-specified procedures.  The Informed 
Consent Document used will have the approval of the IRB appropriate for each institution. 
 
I will maintain adequate source documents and record all observations, treatments and procedures 
pertinent to trial patients 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, 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 Name (print) 
________________________________________________ 
Investigator’s Signature 
Date:  _________________


Protocol: A101-DPN-201 
Amendment 1 
Version 2.0:  28 MARCH 2018 
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                                                                Page 4 of 60 
AMENDMENT HISTORY:   
This is the first amendment to the Original Protocol dated 05 MAY 2017. 
AMENDMENT RATIONALE:  
The rationale for Amendment 1 dated 28 MARCH 2018 is to add an additional cohort of subjects (up to an 
additional 24 subjects) in order to test a different treatment schedule of A-101 Topical Solution 40% for 
the treatment of DPN lesions.   
 
Protocol 
Version 
Date 
Section 
Revision 
Version 
1.0 
05 MAY 
2017 
NA 
NA 
Version 
2.0 
28 March 
2018 
Title Page 
Removed “Single Arm” from protocol 
title; Updated Sponsor Address; 
Added Kenneth Kostenbader, MD as 
the Aclaris Safety Monitor 
 
 
Protocol Signature Page and 
Investigator Signature Page 
Updated protocol title and version 
number. 
 
 
Synopsis 
Updated study design to add cohort 2 
as a 2- arm cohort.  Clarified the Visit 
days or cohort 2.  Treatment days in 
cohort 2 changed to Visit 2 (Day 1), 
Visit 3 (Day 15) and Visit 5 (Day 29).  
 
 
Section 3.2.2 Secondary 
Objective 
Corrected the secondary objective to 
remove safety as a secondary 
objective. Safety is already included 
in the primary objective of the study.   
 
 
Section 4 Study Design 
Study design revised to add cohort 2 
as a 2-arm cohort to test a different 
treatment schedule and to determine 
whether or not medically abrading the 
DPN lesion prior to treatment with A-
101 40 % Topical Solution affects the 
treatment outcome.   
 
 
Section 4.1 Number of Subjects 
and Study Centers 
Increased the number of subjects to be 
enrolled to the study with the addition 
of the second treatment cohort.   
 
 
Section 4.2 Duration of Study 
Revised the duration of the study to 
account for addition of 24 subjects 
being added to the study. 
 
 
Section 5.1 Inclusion Criteria 
Added an inclusion criteria to ensure 
that lesions that are identified for 
treatment are not inflamed or irritated 
prior to treatment.  Also removed the 
restriction of having the DPN lesions 
needing to be located in an 
inconspicuous area based on the 
safety results obtained from the first 
treatment cohort.   


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                                                                Page 5 of 60 
Protocol 
Version 
Date 
Section 
Revision 
 
 
Section 5.2 Exclusion Criteria 
Added an exclusion criteria to exclude 
subjects with a history of hypertrophic 
scars.  
 
 
Section 6 Study Procedures 
Added Table 2 which outlines the 
study assessment requirements for the 
cohort 2 subjects.   
 
 
Section 7.2 Subject 
Randomization 
Section updated to include 
randomization information for cohort 
2 subjects.  Subjects will be 
randomized to 1 of 2 treatment arms 
in a 1:2 ratio.   
 
 
Section 7.3 Study Medication 
Packaging, storage and 
dispensing 
The volume fill in the study 
medication applicator was corrected 
to reflect the correct volume of 1.5ml.   
 
 
Section 7.5 Study Medication 
Treatment; Section 7.8 Wound 
care; Section 8.1.1 Standardized 
Photography; Section 8.1.2 
Physician’s DPN Lesion 
Assessment; Section 8.1.3 
Lesion Dimensions; Section 8.2 
Subject Self-Assessment Scale; 
Section 9.1 Local Skin 
Reactions 
Updated section to include the 
treatment information for subjects 
randomized to the study in cohort 2 
[Visit 2 (Day 2), Visit 3 (Day 15) and 
Visit 5 (Visit 29)] if they meet the 
criteria for re-treatment.   
 
 
Section 9.5.2 Standardized 
Photography 
Deleted section; Section was repeated 
in Version 1.0 of the document.  
 
 
Section 10.2.2 Procedure for 
reporting a serious adverse event 
Updated section with Aclaris’s Drug 
safety monitor.   
 
 
Section 12.2 Statistical Analysis 
of Efficacy Data 
Statistical analysis of the efficacy data 
was updated to reflect how the data 
from cohort 2 would be analyzed.   
 
 
Appendix:  Subject Instructions 
Updated subject instructions to reflect 
the changes in the application of 
Aquaphor for subjects randomized to 
cohort 2.   
 


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Table of Contents 
1. 
SYNOPSIS .................................................................................................................................................... 9 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................................. 14 
2. 
INTRODUCTION ...................................................................................................................................... 16 
2.1. 
Summary ................................................................................................................................................... 16 
3. 
STUDY RATIONALE AND OBJECTIVES ....................................................................................... 20 
3.1. 
Rationale .................................................................................................................................................... 20 
3.2. 
Study Objectives ...................................................................................................................................... 20 
3.2.1. 
Primary Objective ................................................................................................................................ 20 
3.2.2. 
Secondary Objective ............................................................................................................................ 20 
3.2.3. 
Exploratory Objective ......................................................................................................................... 20 
4. 
STUDY DESIGN ........................................................................................................................................ 20 
4.1. 
Number of Subjects and Study Centers ............................................................................................. 22 
4.2. 
Duration of Study .................................................................................................................................... 22 
5. 
STUDY ENTRY CRITERIA .................................................................................................................. 22 
5.1. 
Inclusion Criteria .................................................................................................................................... 22 
5.2. 
Exclusion Criteria ................................................................................................................................... 23 
5.3. 
Removal of Patients from Study Therapy ......................................................................................... 23 
5.4. 
Withdrawal Procedures ......................................................................................................................... 24 
5.5. 
Subject Replacement .............................................................................................................................. 24 
5.6. 
Subject Identifier (SI) ............................................................................................................................. 24 
6. 
STUDY PROCEDURES ........................................................................................................................... 25 
7. 
STUDY TREATMENT............................................................................................................................. 30 
7.1. 
Investigational Study Medication ........................................................................................................ 30 
7.2. 
Subject randomization ........................................................................................................................... 30 
7.3. 
Study medication packaging, storage and dispensing .................................................................... 31 
7.4. 
Drug Accountability ................................................................................................................................ 31 
7.5. 
Study Medication Treatment ................................................................................................................ 31 
7.5.1. 
Preparing the Study Medication for Application ......................................................................... 32 
7.5.2. 
Applying Study Medication to the Face .......................................................................................... 34 
7.5.3. 
Applying Study Medication to the Neck ......................................................................................... 35 
7.6. 
Dose modification .................................................................................................................................... 36 


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7.7. 
Previous and Concomitant Therapies ................................................................................................ 36 
7.7.1. 
Previous therapies ................................................................................................................................ 36 
7.7.2. 
Concomitant therapies ........................................................................................................................ 36 
7.7.3. 
Prohibited therapies ............................................................................................................................. 37 
7.8. 
Wound Care .............................................................................................................................................. 37 
8. 
ASSESSMENTS OF CLINICAL EFFICACY .................................................................................... 37 
8.1. 
Target Lesion Identification ................................................................................................................. 37 
8.1.1. 
Standardized photography ................................................................................................................. 38 
8.1.2. 
Physician’s DPN Lesion Assessment ................................................................................................ 39 
8.1.3. 
Lesion Dimensions ................................................................................................................................ 39 
8.2. 
Subject Self-Assessment Scale .............................................................................................................. 40 
8.3. 
Subject Instructions ................................................................................................................................ 41 
8.4. 
Other Study Supplies .............................................................................................................................. 41 
9. 
ASSESSMENT OF SAFETY .................................................................................................................. 42 
9.1. 
Local Skin Reactions (LSR) .................................................................................................................. 42 
9.2. 
Vital signs .................................................................................................................................................. 43 
9.3. 
Clinical laboratory sampling ................................................................................................................ 44 
9.4. 
Urine pregnancy tests ............................................................................................................................. 45 
9.5. 
Other Evaluations ................................................................................................................................... 45 
9.5.1. 
Demographics and medical history .................................................................................................. 45 
10. 
ADVERSE EVENTS ................................................................................................................................ 46 
10.1. 
Definitions ................................................................................................................................................. 46 
10.1.1. 
Adverse events (AE) ............................................................................................................................. 46 
10.1.2. 
Serious adverse event (SAE) .............................................................................................................. 47 
10.1.3. 
Adverse event reporting period ......................................................................................................... 47 
10.1.4. 
Severity .................................................................................................................................................... 48 
10.1.5. 
Relationship to study medication ...................................................................................................... 48 
10.2. 
Reporting Procedures ............................................................................................................................. 48 
10.2.1. 
Procedures for reporting adverse events ........................................................................................ 48 
10.2.2. 
Procedure for reporting a serious adverse event .......................................................................... 49 
10.2.3. 
Withdrawal Due to an Adverse Event ............................................................................................. 49 
11. 
PREGNANCY ............................................................................................................................................. 50 
12. 
STATISTICAL CONSIDERATIONS .................................................................................................. 51 
12.1. 
Sample Size and Power Considerations ............................................................................................. 51 


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12.2. 
Statistical Analysis of Efficacy Data ................................................................................................... 51 
12.3. 
Exploratory Analysis .............................................................................................................................. 51 
12.4. 
Statistical Analysis of Safety Data ....................................................................................................... 51 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................. 52 
13.1. 
Protocol Amendments ............................................................................................................................ 52 
13.2. 
Protocol Deviations, Violations and Exceptions ............................................................................... 52 
13.3. 
Training ..................................................................................................................................................... 52 
13.4. 
Monitoring ................................................................................................................................................ 53 
13.5. 
Data Management ................................................................................................................................... 53 
13.6. 
Quality Assurance ................................................................................................................................... 54 
13.7. 
Record Retention ..................................................................................................................................... 54 
14. 
ETHICS AND GENERAL STUDY CONDUCT CONSIDERATIONS ................................. 55 
14.1. 
Institutional Review Board (IRB)/Ethics Committee (EC)...................................................... 55 
14.2. 
Ethical Conduct of the Study ............................................................................................................ 56 
14.3. 
Regulatory Documents ........................................................................................................................... 56 
14.4. 
Contractual Requirements .................................................................................................................... 57 
15. 
Appendices ................................................................................................................................................... 58 
15.1. 
Subject Instructions ................................................................................................................................ 58 
16. 
References .................................................................................................................................................... 60 
 
 
 


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1. 
SYNOPSIS 
Protocol Number: A-101-DPN-201 Synopsis 
Protocol Title:   
 
A Phase 2 Open Label Study of A-101 Topical Solution in Subjects with 
Dermatosis Papulosa Nigra 
Protocol Number: 
 
 
A-101-201-DPN 
Sponsor 
Aclaris 
Phase of Development 
Phase 2  
Study Drug Description: 
 
A-101 Solution 40% is hydrogen peroxide that will be supplied in a glass ampule with an applicator to 
be applied to a dermatosis papulosa nigra (DPN) lesion on subjects with a Fitzpatrick Skin Type of 5 or 
6.     
 
The study drug, A-101 Solution 40% is a colorless solution that must be stored at room temperature 
(20-25º C or 68 -77 º F), protected from light. 
 
Study Objectives: 
 
The main objective of this study is to evaluate the safety and efficacy of hydrogen peroxide, A-101 
Solution 40% for the treatment of DPN lesions on subjects with a Fitzpatrick Skin Type of 5 or 6.   
 
Study Design:   
 
This is a phase 2 open label study to evaluate the safety of A-101 40% Solution in subjects with DPN.  
Subjects will be required to have up to four DPN lesions located on the subject’s face or neck.   
 
The first cohort of the study will enroll a total of 12 subjects (6 subjects with a Fitzpatrick Skin Type of 
5 and 6 subjects with a Fitzpatrick Skin Type of 6) will be enrolled to the study.   
The second cohort of the study a total of 24 subjects will be a randomized to a two-arm cohort. 
Subjects will be randomized to one of the following 2 treatment arms: 
• 
A-101 40% without medically abrading the identified DPN prior to treatment 
• 
A-101 40% with the identified DPN lesions medically abraded prior to treatment 
 
All enrolled/randomized subjects will receive at least one application of A-101 40% solution on up to 
four target DPN lesions on the subject’s face or neck.  Subjects in cohort 1 may receive a second 
application of A-101 40% Solution if the lesions meet the criteria for retreatment at Visit 4 (Day 22).  
Subjects in cohort 2 may receive up to 3 treatment applications if the lesions meet the criteria for 
retreatment at Visit 3 (Day 15) and Visit 5 (Day 29).  All subjects will be followed on study protocol 
until Visit 8 (Day 106).     
 
Safety will be evaluated based on clinical laboratory studies (hematology and clinical chemistry), vital 
signs, urine pregnancy tests, assessment of local skin reactions (LSRs), assessment of adverse events 
(AEs), and concomitant medication review.   
 


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                                                                Page 10 of 60 
Efficacy will be evaluated based on assessment of each treated Target DPN Lesion based on a four- 
point Physician’s DPN Lesion Assessment Scale.  Sites will be required to take standardized color 
photographs of each of the identified Target DPN Lesions to assist with the documentation of the 
location of each of the DPN Lesions throughout the study.   
 
Number of Patients to be Enrolled: 
 
A total of 36 subjects will be enrolled to the study.  Twelve evaluable subjects will be enrolled to the 
first cohort (6 subjects with a Fitzpatrick Skin Type of 5 and 6 subjects with a Fitzpatrick Skin Type of 
6) and a total of 24 subjects will be randomized to the study in cohort 2.     
Number of Study Sites: 
 
This study will be conducted at up to 2 US clinical treatment site.     
Inclusion Criteria: 
Subjects must meet all of the following criteria to be considered for participation in this study.   
1. Provisions of written informed consent for participation in this study. 
2. Male or female ≥ 18 years old. 
3. Subject has a clinical diagnosis of dermatosis papulosa nigra (DPN). 
4. Subject has a Fitzpatrick Skin Type of 5 or 6. 
5. Subject has up to 4 Target DPN Lesions located in an area that has not been previously treated 
and meets the following requirements as defined below: 
a. Have a clinically typical appearance 
b. Diameter that is between 2mm and less than 5mm 
c. Height that is ≤ 2mm 
d. Have a Physician’s DPN Lesion Assessment Score of ≥ 2 
e. Be a discrete lesion 
f. Not be covered with hair which, in the investigator’s opinion, would interfere with the 
study medication treatment or the study evaluations 
g. Not be in an intertriginous fold 
h. Not be on the eyelids 
i. 
Not be within 5mm of the orbital rim 
j. 
Not be pedunculated.  
k. Not be inflamed, irritated, or excoriated.  
6. Subject chemistry and complete blood count results are within normal limits for the central 
laboratory.  If any of the laboratory values are outside normal limits, the treating investigator 
must assess the value/s as not clinically significant and document this in the patient’s source 
documents.   
7. Woman of childbearing potential must have a negative urine pregnancy test within 14 days of 
the first application of study drug and agree to use an active method of birth control for the 
duration of the study 
8. Subject is non-pregnant and non-lactating. 
9. Subject is in good general health and free of any known disease state or physical condition 
which, in the investigator’s opinion, might impair the evaluation of any of the Target DPN 
Lesions or which exposes the subject to an unacceptable risk by study participation.   
10. Subject is willing and able to follow all study instructions and to attend all study visits.  
 
Exclusion Criteria: 
Subjects are excluded from this study if any 1 or more of the following criteria is met: 
1. Subject has clinically atypical and /or rapidly growing DPN lesion. 
2. Subject has current systemic malignancy. 


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3. Subject has a history of hypertrophic scars or keloids 
4. Subject has a history of post inflammatory hyperpigmentation lasting longer than 1 year. 
5. Subject has used any of the following systemic therapies within the specified period prior to 
Visit 1: 
• 
Retinoids; 180 days 
• 
Corticosteroids; 28 days 
• 
Antimetabolites (e.g., methotrexate); 28 days 
6. Subject has used any of the following topical therapies within the specified period prior to Visit 
1 on, or in a proximity to any Target DPN Lesion, that in the investigator’s opinion interferes 
with the study medication treatment or the study assessments: 
• 
LASER, light or other energy-based therapy (e.g., intense pulsed light [IPL], photo-
dynamic therapy [PDT]; 180 days 
• 
Liquid nitrogen, electrodesiccation, curettage, imiquimod, 5-flurouracil (5FU), or 
ingenol mebutate; 60 days 
• 
Retinoids; 28 days 
• 
Microdermabrasion or superficial chemical peels; 14 days 
• 
Corticosteroids or antibiotics; 14 days. 
7. Subject currently has or has had any of the following within the specified period prior to Visit 
1 on or in a proximity to any Target DPN Lesion that, in the investigator’s opinion, interferes 
with the study medication treatment or the study assessments: 
• 
Cutaneous malignancy; 180 days 
• 
Sunburn; currently 
• 
Pre-malignancy (e.g. actinic keratosis); currently 
• 
Body art (e.g. tattoos, piercing, etc.); currently 
• 
Excessive tan.  The use of self-tanning lotions/sprays are prohibited. 
8. Subject has a history of sensitivity to any of the ingredients in the study medications. 
9. Subject has any current skin disease (e.g., psoriasis, atopic dermatitis, eczema, sun damage), or 
condition (e.g. sunburn, excessive hair, open wounds) that, in the opinion of the investigator, 
might put the subject at undue risk by study participation or interfere with the study conduct or 
evaluations.  
10. Participation in another therapeutic investigational drug trial in which administration of an 
investigational study medication occurred with 30 days prior to Visit 1.  
Duration of Treatment 
The duration of the study participation is anticipated to be a maximum of 127 days per subject.  The 
final visit (Visit 8) has a maximum allowable visit window of 7 days:  Study visits for cohort 1 are: 
• 
Visit 1 (Day -13 to 0) screening 
• 
Visit 2 (Day 1) enrollment and study medication treatment 
• 
Visit 3 (Day 8) follow up visit  
• 
Visit 4 (Day 22) follow up visit and second application of study medication if DPN target 
lesions meets criteria for retreatment 
• 
Visit 5 (Day 29) follow up visit 
• 
Visit 6 (Day 50) follow up visit 
• 
Visit 7 (Day 78) follow up visit 
• 
Visit 8 (Day 106) follow up visit; end of study 
 
Study visits for cohort 2 are: 
The protocol defined study visits for cohort 2 are: 
• Visit 1 (Day -13 to 0) screening 


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• Visit 2 (Day 1) randomization and study medication treatment 
• Visit 3 (Day 15) follow up visit and second application of study medication if DPN 
target lesions meet criteria for retreatment 
• Visit 4 (Day 22) follow up visit  
• Visit 5 (Day 29) follow up visit and third application of study medication if DPN target 
lesions meet criteria for retreatment 
• Visit 6 (Day 50) follow up visit 
• Visit 7 (Day 78) follow up visit;  
• Visit 8 (Day 106) follow up visit; end of study 
 
 
Criteria for Evaluation 
Efficacy: 
The investigator will evaluate each treated Target DPN Lesion based on a 4- point Physician’s DPN 
Lesion Assessment Scale.  Subjects will also evaluate each DPN lesion using a Subject Self-
Assessment Scale.   
 
Safety: 
Safety will be evaluated based on clinical laboratory studies (hematology and clinical chemistry), vital 
signs, urine pregnancy tests, assessment of local skin reactions (LSRs), assessment of adverse events 
(AEs), and concomitant medication review.   
 
 
Study Drug Administration 
 
A-101 Study medication will be applied to the identified Target DPN lesions during Visit 2 by a 
member of the investigational site staff.   In cohort 1, Target DPN lesions that have not cleared at Visit 
4 (Day 22) may be re-treated.  In cohort 2, Target DPN lesions may be treated up to 3 times if they 
meet the criteria for retreatment [Visit 3 (Day 15) and Visit 5 (Day 29)].  Subjects randomized to ARM 
B in cohort 2 will have their Target DPN Lesions medically abraded prior to treatment with A-101 
study medication.   
 
The A-101 40% Solution will be applied to each of the Target DPN Lesions for approximately 15 
seconds.  Each DPN lesion will be treated up to 3 times while waiting approximately 60 seconds 
between each application.   
 
 
Statistical Methods 
 
Efficacy Analysis 
Efficacy endpoints will include summary statistics (frequency distributions, proportions, means, 
medians and standard deviations, as appropriate) by visit for the following parameters: Physician’s 
DPN Lesion Assessment scale results per treated lesion, subject responders defined by Physician’s 
DPN Lesion Assessment scale outcome, and changes from baseline Target lesion diameter.  Summaries 
will also be presented by subject Fitzpatrick Skin Type.  
 
Exploratory Analysis 


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Exploratory efficacy endpoints will include summary statistics (frequency distributions, proportions, 
means, medians and standard deviations, as appropriate) by visit for the following parameters: Subject 
Self-Assessment scale results per treated lesion, and subject responders defined by Subject Self-
Assessment scale outcome.  Summaries will also be presented by subject Fitzpatrick Skin Type. 
 
Safety Analysis 
Safety endpoints for adverse events (AEs) include the following:  incidences of all treatment-emergent 
AEs (TEAEs) and all serious AEs (SAEs); by severity, by relationship to study drug and 
discontinuation of patients from study due to AEs.  Safety endpoints for AEs, clinical laboratory tests, 
vital signs, and physical examinations and local skin reactions will be specified in the statistical 
analysis plan (SAP).  All safety endpoints will be summarized using descriptive statistics.   
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE  
Adverse Event 
ANCOVA 
Analysis of Covariance 
°C 
Degrees Centigrade 
CBC 
Complete Blood Count 
CMH 
Cochran-Mantel-Haenszel 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CS 
Clinically Significant 
DPN 
Dermatosis Papulosa Nigra 
e.g.  
for example (Latin; exempla gratia) 
EC 
Ethics Committee 
°F 
Degrees Fahrenheit 
FDA 
Food and Drug Administration 
5FU 
5 Fluorouracil 
G 
Gram 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
H2O2 
Hydrogen Peroxide 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
i.e.  
that is (Latin; id est) 
IPL 
Intense Pulsed Laser 
IRB 
Institutional Review Board 
ITT 
Intent To Treat 
LOCF 
Last Observation Carried Forward 
LSR 
Local Skin Reactions 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Milliliter 


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Abbreviation 
Term 
Mm 
Millimeter 
NCS 
Not Clinically Significant 
OTC 
Over-The-Counter 
PDT 
Photodynamic Therapy 
PLA 
Physician’s Lesion Assessment 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SI 
Subject Identifier 
SK 
Seborrheic Keratosis 
SOP 
Standard Operation Procedure 
US 
United States 
WOCBP 
Women of childbearing potential 


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2. 
INTRODUCTION 
2.1. 
Summary 
Seborrheic keratosis (SK) is one of the most common skin tumors in man. These benign epithelial 
skin tumors are most commonly seen in older individuals, increasing in prevalence with increasing 
age, and affect men and women roughly equally. While the growths may be solitary, they often 
occur in large numbers and typically present as well demarcated, elevated or “stuck-on” appearing 
papules or plaques that may vary from flesh-colored, to shades of yellow, gray, brown, or black.  
 
Dermatosis Papulosa Nigra (DPN) is a clinical variant of SK primarily affecting individuals of 
higher Fitzpatrick Skin Types (e.g. Fitzpatrick Type 5 or 6) and is seen in up to 35% of African 
Americans (Hairston, 1961).  Like clinically typical larger SKs, each DPN lesion is a benign 
epithelial tumor, and histologically, the lesions are indistinguishable from larger SKs.  DPN lesions 
are characterized by small brown or black “spots” typically appearing around the malar and 
periorbital regions but can also appear on other areas of the face, neck and chest (Kundu, 2017).  
The lesions can vary in size and number, though typically they begin as minute papules that 
increase in size to from 1 to 5 mm (or more) and they become more and more numerous over time.  
DPN does affect women more commonly than men, and, like clinically typical larger SKs, do not 
spontaneously resolve.   
 
Treatment options for the removal of DPN lesions include scissor excision, shave excision, 
cryosurgery, electrodesiccation, curettage, dermabrasion, and laser removal.  However, with these 
treatments comes the risk of potential scarring and changes in pigmentation (Kundu, 2017).   
 
While there are existing methods for treating DPN lesions, many require specialized training and 
the use of expensive equipment, they are often quite painful and may require anesthesia and/or 
analgesia, and they are often complicated by significant adverse cosmetic outcomes.  Both 
hypopigmentation and hyperpigmentation, which may be transient but is often permanent, are 
common, particularly when cryosurgery is employed and particularly in individuals of the darker 
skin types prone to develop DPN. The potential for scarring at the treatment site, particularly with 
the surgical treatment options, and the typical post-surgical risks of bleeding and infection increase 
the risk that the sequela from the treatment of these benign, but cosmetically disturbing, lesions 
may be worse than the lesions themselves.  There is a great unmet need for a safe, effective, 
standardized and less painful treatment for this extremely common condition in patients of darker 
skin types. 
 
Hydrogen peroxide (H2O2) is a compound that is ubiquitous in the environment. It is the simplest 
peroxide and a potent oxidizing agent commonly used in innumerable household goods including 
chlorine-free bleaches, general-purpose cleaning products, and disinfectants. Additionally, H2O2 
has been employed as the oxidizing component in hair dyes and has been used in oral hygiene 
products and tooth-whitening systems for many years. In industry, it is employed in the treatment 
of wastewater. In high concentrations, it is used in bleaching paper, pulp, and textiles. Clinically, 
in addition to its use as an oral topical agent noted above, H2O2 is widely employed at low 
concentrations (e.g., 3%-6%) as a wound irrigant and topical antiseptic/disinfectant and has been 
in use medicinally since its introduction into clinical practice by Richardson in 1858.  


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H2O2 is an important oxidizing agent in biological systems. The local deleterious effects of reactive 
oxygen species on the skin are mitigated by the presence of a complex antioxidant defense system 
that includes, enzymes such as catalase, glutathione peroxidase, superoxide dismutase, thioredoxin 
reductase, lipoamine, lipid peroxidase and others, as well as non-enzymatic components including 
ascorbic acid, urates and uric acid, tocopherol, glutathione, ubiquinones, ubiquinol and other 
water-soluble groups.  The local application of supra-physiologic concentrations of H2O2 may 
overwhelm the antioxidant defense systems in the skin, allowing H2O2 to act not only through its 
direct oxidation of organic tissues, generation of reactive oxygen species, and local lipid 
peroxidation, but also by the generation of local concentrations of O2 that are toxic to the abnormal 
lesional (seborrheic keratosis) cells. 
 
A-101 (hydrogen peroxide) Solution has been tested in three phase 2 clinical programs and three 
phase 3 clinical programs in which over 1000 subjects with SK lesions were treated.  Data from 
these studies demonstrated that A-101 Solution has the potential to safely and effectively resolve 
SK lesions without the need for analgesia and/or anesthesia, and with a minimal risk of 
hypopigmentation, hyperpigmentation, or scarring. Refer to Table 1 for a complete list of 
completed A-101 clinical trials for the treatment of SK lesions.   
 


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Table 1  Summary of Previous Clinical Trials with A-101 Solution in Seborrheic Keratosis 
Clinical Study 
Report 
Study 
Phase 
Study Population 
Countries 
Total Randomized 
or Enrolled/ 
Completed 
Study Design 
Treatment Duration 
Dose 
A-101-SEBK-
201 
2 
At least 4 SK target 
lesions on the back 
US 
35/34 
Single-center, 
randomized, double-
blind, vehicle-
controlled, within-
subject comparison 
Application on Day 1, target 
lesions meeting criteria were 
to be retreated on Day 22 
(end of study on Day 78) 
A-101 solution 25%, 
32.5%, 40%, and 
vehicle 
A-101-SEBK-
202 
2 
At least 4 SK target 
lesions on the trunk/ 
extremities 
US 
172/169 
Multicenter, 
randomized, double-
blind, vehicle-
controlled, parallel-
group 
Application on Day 1, target 
lesions meeting criteria were 
to be retreated on Day 22 
(end of study on Day 106) 
A-101 solution 
32.5%, 40%, and 
vehicle 
A-101-SEBK-
203 
2 
1 SK target lesion on 
the face 
US 
119/116 
Multicenter, 
randomized, double-
blind, vehicle-
controlled, parallel-
group 
Application on Day 1, target 
lesions meeting criteria were 
to be retreated on Day 22 
(end of study on Day 106) 
A-101 solution 
32.5%, 40%, and 
vehicle 
A-101-SEBK-
301 
3 
4 SK target lesions, 
including at least 1 on 
the face and at least 1 
on the trunk or 
extremities 
US 
450/446 
Multicenter, 
randomized, double-
blind, vehicle-
controlled, parallel-
group 
Application on Day 1, target 
lesions meeting criteria were 
to be retreated on Day 22 
(end of study on Day 106) 
A-101 solution 40% 
and vehicle 
A-101-SEBK-
302 
3 
4 SK target lesions, 
including at least 1 on 
the face and at least 1 
on the trunk or 
extremities 
US 
487/479 
Multicenter, 
randomized, double-
blind, vehicle-
controlled, parallel-
group 
Application on Day 1, target 
lesions meeting criteria were 
to be retreated on Day 22 
(end of study on Day 106) 
A-101 solution 40% 
and vehicle 


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Clinical Study 
Report 
Study 
Phase 
Study Population 
Countries 
Total Randomized 
or Enrolled/ 
Completed 
Study Design 
Treatment Duration 
Dose 
A-101-SEBK-
303 
3 
4 SK target lesions on 
trunk, extremities, 
and face 
US 
147/139 
Open-label 
Application on Day 1, target 
lesions meeting criteria were 
to be retreated on Days 22, 
43, and 64 (end of study on 
Day 148) 
A-101 solution 40% 
 


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3. 
STUDY RATIONALE AND OBJECTIVES 
3.1. 
Rationale 
The rationale for this study is to assess safety and efficacy of A-101 Solution 40% when applied 
to up to 4 DPN Target Lesions in subjects with Fitzpatrick Skin Type 5 or 6.   
 
Aclaris recently completed three phase clinical studies (301, 302, and 303) that demonstrated that 
A-101 40% Solution is both safe and effective in treating subjects with seborrheic keratosis lesions 
on the face, trunk and extremities.  Based on this data and the classification of DPN lesions as a 
clinical variant of seborrheic keratosis, a study of A-101 in darker skin type subjects with DPN 
lesions is warranted.   
3.2. 
Study Objectives 
3.2.1. 
Primary Objective 
The main objective of this study is to evaluate the safety and efficacy of hydrogen peroxide, A-
101 Solution 40% for the treatment of DPN lesions on subjects with a Fitzpatrick Skin Type of 5 
or 6.   
 
3.2.2. 
Secondary Objective 
The secondary objective of this study is to assess durability of response. 
 
3.2.3. 
Exploratory Objective 
An exploratory objective of this study is to evaluate the subject’s assessment of the treatment with 
A-101 to DPN lesions using a Subject Self-Assessment Scale.   
4. 
STUDY DESIGN 
This is a phase 2 open label study with an initial single arm safety cohort evaluating A-101 40% 
Topical Solution in subjects with DPN lesions.  A second cohort will randomize subjects to two 
different treatment arms to evaluate different treatment schedules using A-101 40% Topical 
Solution. Refer to Figure 1:  A-101-DPN-201 Study Design.  Subjects may have up to 4 Target 
DPN lesions treated.  Lesions that are selected for treatment must be on the subject’s face or neck. 
Subjects will be required to complete a total of 8 study visits.   
 
 
 
 
 
 
 
 
 
Cohort 1 
A-101 40% Solution  
12 Subjects 
Treatment Days 1 and 22 


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Figure 1:  A-101-DPN-201 Study Design 
 
The protocol defined study visits for cohort 1 are: 
• Visit 1 (Day -13 to 0) screening 
• Visit 2 (Day 1) enrollment and study medication treatment 
• Visit 3 (Day 8) follow up visit  
• Visit 4 (Day 22) follow up visit and second application of study medication if DPN target 
lesions meet criteria for retreatment 
• Visit 5 (Day 29) follow up visit 
• Visit 6 (Day 50) follow up visit 
• Visit 7 (Day 78) follow up visit;  
• Visit 8 (Day 106) follow up visit; end of study 
 
The protocol defined study visits for cohort 2 are: 
• Visit 1 (Day -13 to 0) screening 
• Visit 2 (Day 1) randomization and study medication treatment 
• Visit 3 (Day 15) follow up visit and second application of study medication if DPN target 
lesions meet criteria for retreatment 
• Visit 4 (Day 22) follow up visit  
• Visit 5 (Day 29) follow up visit and third application of study medication if DPN target 
lesions meet criteria for retreatment 
• Visit 6 (Day 50) follow up visit 
Cohort 2 
ARM A 
A-101 40% Solution; No medical 
abrasion to the Target DPN 
Lesions 
Treatment Days 1, 15 and Day 29 
ARM B 
A-101 40% Solution applied after 
abrading the Target DPN Lesions 
on Days 1, Day 15 and Day 29 
 


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• Visit 7 (Day 78) follow up visit;  
• Visit 8 (Day 106) follow up visit; end of study 
 
 
Refer to Section 6 for a complete list of protocol required study assessments.   
4.1. 
Number of Subjects and Study Centers 
Approximately 36 evaluable subjects will be enrolled at up to 2 investigational centers in the US. 
4.2. 
Duration of Study 
 The duration of study participation is anticipated to be a maximum of 127 days per subject. 
Subjects will have a total of 8 study visits.   
The maximum anticipated duration for the study is 18 months.  
 
5. 
STUDY ENTRY CRITERIA 
5.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be considered for participation in this study.   
1. Provisions of written informed consent for participation in this study. 
2. Male or female ≥ 18 years old. 
3. Subject has a clinical diagnosis of dermatosis papulosa nigra. 
4. Subject has a Fitzpatrick Skin Type of 5 or 6. 
5. Subject has up to 4 Target DPN Lesions located on the subject’s face or neck that has not been 
previously treated and meets the requirements as defined below: 
a. Have a clinically typical appearance 
b. Diameter that is between 2mm and less than 5mm 
c. Height that is ≤ 2mm 
d. Have a Physician’s DPN Lesion Assessment Score of ≥ 2 
e. Be a discrete lesion 
f. Not be covered with hair which, in the investigator’s opinion, would interfere with the 
study medication treatment or the study evaluations 
g. Not be in an intertriginous fold 
h. Not be on the eyelids 
i. 
Not be within 5mm of the orbital rim 
j. 
Not be pedunculated. 
k. Not be inflamed, irritated or excoriated.   
6. Subject chemistry and complete blood count results are within normal limits for the central 
laboratory.  If any of the laboratory values are outside normal limits, the treating investigator 
must assess the value/s as not clinically significant and document this in the patient’s source 
documents.   
7. Woman of childbearing potential must have a negative urine pregnancy test within 14 
days of the first application of study drug and agree to use an active method of birth 
control for the duration of the study 
8. Subject is non-pregnant and non-lactating. 
9. Subject is in good general health and free of any known disease state or physical condition which, 
in the investigator’s opinion, might impair the evaluation of any Target DPN Lesions or which 
exposes the subject to an unacceptable risk by study participation.   


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10. Subject is willing and able to follow all study instructions and to attend all study visits.  
 
5.2. 
Exclusion Criteria 
Subjects are excluded from this study if any 1 or more of the following criteria is met: 
1. Subject has clinically atypical and /or rapidly growing DPN lesion. 
2. Subject has current systemic malignancy. 
3. Subject has a history of hypertrophic scars or keloids 
4. Subject has a history of post inflammatory hyperpigmentation lasting longer than 1 year. 
5. Subject has used any of the following systemic therapies within the specified period prior 
to Visit 1: 
• Retinoids; 180 days 
• Corticosteroids; 28 days 
• Antimetabolites (e.g., methotrexate); 28 days 
6. Subject has used any of the following topical therapies within the specified period prior to 
Visit 1 on, or in a proximity to any Target DPN Lesion, that in the investigator’s opinion 
interferes with the study medication treatment or the study assessments: 
• LASER, light or other energy-based therapy (e.g., intense pulsed light [IPL], photo-
dynamic therapy [PDT]; 180 days 
• Liquid nitrogen, electrodesiccation, curettage, imiquimod, 5-flurouracil (5FU), or 
ingenol mebutate; 60 days 
• Retinoids; 28 days 
• Microdermabrasion or superficial chemical peels; 14 days 
• Corticosteroids or antibiotics; 14 days. 
7. Subject currently has or has had any of the following within the specified period prior to 
Visit 1 on or in a proximity to any Target DPN Lesion that, in the investigator’s opinion, 
interferes with the study medication treatment or the study assessments: 
• Cutaneous malignancy; 180 days 
• Sunburn; currently 
• Pre-malignancy (e.g. actinic keratosis); currently 
• Body art (e.g. tattoos, piercing, etc.); currently 
• Excessive tan.  The use of self-tanning lotions/sprays are prohibited. 
8. Subject has a history of sensitivity to any of the ingredients in the study medications. 
9. Subject has any current skin disease (e.g. psoriasis, atopic dermatitis, eczema, sun damage), 
or condition (e.g. sunburn, excessive hair, open wounds) that, in the opinion of the 
investigator, might put the subject at undue risk by study participation or interfere with the 
study conduct or evaluations.  
10. Participation in another therapeutic investigational drug trial in which administration of an 
investigational study medication occurred with 30 days prior to Visit 1.  
 
5.3. 
Removal of Patients from Study Therapy 
A subject may be removed from the study therapy for a variety of reasons, including: 
• Unacceptable adverse event 


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• Subject unwilling or refusal to continue with the protocol defined study visits and/or 
consent withdrawal for study participation 
• Change in compliance with an inclusion/exclusion criteria 
• Pregnancy 
• General or specific changes in the subject’s condition that render the subject unacceptable 
for further treatment in this study in the judgement of the investigator. 
 
If a subject is to be withdrawn from the study, the Aclaris Therapeutics, Inc. study monitor or 
designee must be informed of the decision to remove the subject from the study.   
 
The study may be discontinued at the discretion of Aclaris Therapeutics, Inc. Some examples 
of reasons for discontinuation are the occurrence of the following:   
• Increased frequency, severity or duration of known AEs 
• Medical, regulatory or ethical reasons affecting the continued performance of the 
study 
• Difficulties in the recruitment of subjects. 
   
5.4. 
Withdrawal Procedures 
 
If a subject withdraws from the study prior to Visit 8, the reason for and the date of withdrawal 
from the study must be recorded on the eCRF.  If the reason for withdrawal is an adverse event or 
a clinically significant abnormal laboratory test result, monitoring of the subject will continue until 
the event has resolved or stabilized, until the patient is referred to the care of a local health care 
professional, or until a determination of a cause unrelated to the study drug or study procedure is 
made.   
5.5. 
Subject Replacement 
If a subject is enrolled to the study but does not receive a dose of study drug, then the subject will 
be replaced.   
5.6. 
Subject Identifier (SI) 
The investigator or designee will assign a unique five-digit subject identifier (SI) to each subject 
at Visit 1.  
 
The SI format will be NN-NNN where the first 2 digits are the investigational center site number 
(using leading zeroes, as appropriate). The final 3 digits are the subject number and must be 
assigned in ascending numerical order, without omitting or repeating any number, starting with 
001 at each investigational center. For example, the SI for the second subject that signs an informed 
consent at site number 04 would be 04-002.  
 
The subject will be identified using the SI in all study documentation for the duration of the study. 
 


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6. 
STUDY PROCEDURES 
The schedule of study activities (including assessments, tests, exams, disease assessments, and 
study drug administration) beginning with screening and continuing through the end of study are 
outlined in Table 2.  A written, signed informed consent form (ICF) must be obtained from each 
subject prior to performing any study related procedure (i.e., vital signs, clinical laboratory 
sampling, urine pregnancy test or photography).   


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Table 2: 
 Study Procedures for Cohort 1 Subjects 
Visit  
V1 
Screening 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Treatment Day 
-13 to 0 
1 
8 
22 
29 
50 
78 
106 
Treatment Window 
N/A 
N/A 
+ 7 days 
+ 4 days 
+7 days 
± 7days 
± 7 days 
± 7 days 
Study Procedures 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion Criteria/Exclusion 
Criteria 
X 
X1 
 
 
 
 
 
 
Subject Identifier 
X2 
 
 
 
 
 
 
 
Medical history/demographics 
X 
 
 
 
 
 
 
 
Fitzpatrick Skin Type Assessment 
X3 
 
 
 
 
 
 
 
Vital Signs 
X 
X4 
 
X 
 
 
 
X 
Prior Medications/Therapies 
X5 
 
 
 
 
 
 
 
Clinical Chemistry and CBC6 
X 
 
 
 
 
 
 
X 
Urine Pregnancy Test7 
X 
X 
 
 
 
 
 
X 
Target Lesion Identification8 
X 
 
 
 
 
 
 
 
Physician’s DPN Lesion 
Assessment9 
X 
X 
 
X 
 
X 
X 
X 
Subject Self-Assessment Scale10 
X 
X 
 
X 
 
X 
X 
X 
Lesion Dimensions11 
X 
X 
 
X 
 
X 
X 
X 
Standardized Photography12 
X 
X 
 
X 
 
X 
X 
X 
Subject Enrollment 
 
X13 
 
 
 
 
 
 
Local Skin Reactions 
 
X14 
X 
X14 
X 
X 
X 
X 
Study Medication Application 
 
X15 
 
X15 
 
 
 
 
Wound Care16 
 
X 
 
X 
 
 
 
 
Subject Instructions 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapies17 
 
X 
X 
X 
X 
X 
X 
X 
Adverse Events18 
 
X 
X 
X 
X 
X 
 
 
1Subject inclusion/exclusion criteria will be re-assessed prior to study enrollment during Visit 2.  
2Investigational sites will assign a unique five-digit subject identifier to each subject at Visit 1. This subject identifier will be used in all study documentation for 
the duration of the study.   
3Each subject’s skin must be assessed during Visit 1 using the Fitzpatrick Skin Type Assessment. Refer to Section 9.5.1 for the scale.  
4Vital signs [including temperature, pulse, respiratory rate, blood pressure, and weight (Visit 1 only)] will be measured by a qualified staff member at Visit 1, Visit 
2 prior to study enrollment, and at Visit 8.   
5Prior medications/therapies will be collected for a time-period of 13 days prior to Visit 2.  Refer to Section 7.7 for a list of permitted and restricted concomitant 
medications.    


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6A complete blood count (including hematocrit, hemoglobin, platelet count, red blood cell count, white blood cell count and differential (absolute and %) including 
basophils, eosinophils, lymphocytes, monocytes and neutrophils and a clinical chemistry panel including albumin, alkaline phosphatase, alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), bicarbonate, calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), 
phosphorus, potassium, sodium, total bilirubin, total protein, and uric acid.   
7 Woman of child bearing potential will be required to have a urine pregnancy test at Visit 1, at Visit 2 prior to enrollment and at Visit 8. 
8The treating investigator will identify up to 4 Target DPN Lesions.  Each lesion that is identified to be treated must be in an inconspicuous area.     
9 The investigator will assess each DPN target lesion based on a 4- point Physician’s DPN Lesion Assessment Scale.  In order to be eligible for enrollment at Visit 
2, the subject must have at least one DPN lesion that is between 2mm and 5 mm in diameter. At Visit 2 and if applicable at Visit 4, the investigator must assess 
each DPN lesion that is to be treated prior to application of the study medication.   
10 Subjects will use a Subject Self-Assessment Scale to assess each Target DPN Lesion at Screening Visit 1, at Visit 2 prior to application of the study medication, 
at Visit 4 (prior to study medication, if applicable), at Visit 6, Visit 7 and Visit 8.   
11The investigator will measure the diameter and thickness of each identified Target DPN Lesions at Visit 1 and prior to enrollment. at Visit 2.  At Visit 4 prior to 
retreatment (if applicable, at Visit 6, Visit 7 and at Visit 8 the investigator will only measure the diameter of each Target DPN Lesion.   
12 At Visits 1, Visit 2 (prior to study medication application), Visit 4 prior to study medication application if applicable, Visit 6, Visit 7, and at Visit 8, a qualified 
investigational center staff member will take a photograph of each DPN lesion that has been treated using the Aclaris supplied camera.  All photographs will be 
sent to a central imaging laboratory.   
13 Subjects will be enrolled to the study at Visit 2 prior to application of study medication.  Investigational study staff will re-confirm subject eligibility prior to 
study enrollment.   
14 Both the investigator and the subject will assess each Target DPN Lesion for symptoms associated with irritation.  At Visit 2 and Visit 4, the investigator will 
assess the Target DPN Lesions prior to application of the study medication and 20 (± 4) minutes after treatment with the study medication. At Visit 2 and Visit 4, 
the subject will assess the Target DPN Lesions prior to application of the study medication and 10 (±4) minutes after the treatment of the study medication.    
15 A-101 study medication will be applied by the treating physician.  All Target DPN Lesions will be treated with study medication following enrollment at Visit 
2.  If a Target DPN Lesion meets the criteria for re-treatment as defined in Section 7.5, the lesion will be re-treated at Visit 4.  Following application of study 
medication, subjects must NOT wash/submerge the Target DPN Lesions for at least 6 hours and they must NOT apply any topical products to the Target DPN 
Lesions for at least 6 hours.   
16All subjects will be required to apply Aquaphor to all Target DPN Lesions the morning after study medication application.  Sites will be provided supplies of 
Aquaphor by the Sponsor.   
17All concomitant therapies including (topical and oral) prescription medications, over the counter medications and natural supplements and non-drug therapies 
including chiropractic, physical therapy, and energy-based therapy must be documented in the subject CRF.  Subjects must not apply any topical products (e.g. 
moisturizers, sunscreen, etc.) to their Target Lesions within 12 hours prior to any study visit.   
18The reporting period for Serious Adverse Events (SAEs) begins when the subject signs the informed consent.  Refer to Section 10 for instructions on the reporting 
of SAEs.  Non-serious clinical adverse events will be collected following the application of the study medication at Visit 2. Non-serious adverse events that occur 
between the time of consent and study medication application will be documented as medical history.   All safety reporting (AEs and SAEs) will conclude at Visit 
5 (approximately 21 days after last study medication application) except for clinical adverse events related to local skin reactions.  These events will be collected 
through V8.     
 
 


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Table 3:  Study Procedures for Cohort 2 Subjects 
Visit  
V1 
Screening 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Treatment Day 
-13 to 0 
1 
15 
22 
29 
50 
78 
106 
Treatment Window 
N/A 
N/A 
+ 4 days 
+ 2 days 
+4 days 
± 7days 
± 7 days 
± 7 days 
Study Procedures 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion Criteria/Exclusion 
Criteria 
X 
X1 
 
 
 
 
 
 
Subject Identifier 
X2 
 
 
 
 
 
 
 
Medical history/demographics 
X 
 
 
 
 
 
 
 
Fitzpatrick Skin Type Assessment 
X3 
 
 
 
 
 
 
 
Vital Signs 
X 
X4 
 
 
 
 
 
X 
Prior Medications/Therapies 
X5 
 
 
 
 
 
 
 
Clinical Chemistry and CBC6 
X 
 
 
 
 
 
 
X 
Urine Pregnancy Test7 
X 
X 
 
 
 
 
 
X 
Target Lesion Identification8 
X 
 
 
 
 
 
 
 
Physician’s DPN Lesion 
Assessment9 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Self-Assessment Scale10 
X 
X 
X 
X 
X 
X 
X 
X 
Lesion Dimensions11 
X 
X 
X 
X 
X 
X 
X 
X 
Standardized Photography12 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Randomization 
 
X13 
 
 
 
 
 
 
Local Skin Reactions 
 
X14 
X14 
X 
X14 
X 
X 
X 
Study Medication Application 
 
X15 
X15 
 
X15 
 
 
 
Wound Care16 
 
X 
X 
 
X 
 
 
 
Subject Instructions 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapies17 
 
X 
X 
X 
X 
X 
X 
X 
Adverse Events18 
 
X 
X 
X 
X 
X 
 
 
1Subject inclusion/exclusion criteria will be re-assessed prior to study enrollment during Visit 2.  
2Investigational sites will assign a unique five-digit subject identifier to each subject at Visit 1. This subject identifier will be used in all study documentation for 
the duration of the study.   
3Each subject’s skin must be assessed during Visit 1 using the Fitzpatrick Skin Type Assessment. Refer to Section 9.5.1 for the scale.  
4Vital signs [including temperature, pulse, respiratory rate, blood pressure, and weight (Visit 1 only)] will be measured by a qualified staff member at Visit 1, Visit 
2 prior to study enrollment, and at Visit 8.   
5Prior medications/therapies will be collected for a time-period of 13 days prior to Visit 2.  Refer to Section 7.7 for a list of permitted and restricted concomitant 
medications.    


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6A complete blood count (including hematocrit, hemoglobin, platelet count, red blood cell count, white blood cell count and differential (absolute and %) including 
basophils, eosinophils, lymphocytes, monocytes and neutrophils and a clinical chemistry panel including albumin, alkaline phosphatase, alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), bicarbonate, calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), 
phosphorus, potassium, sodium, total bilirubin, total protein, and uric acid.   
7 Woman of child bearing potential will be required to have a urine pregnancy test at Visit 1, at Visit 2 prior to enrollment and at Visit 8. 
8The treating investigator will identify up to 4 Target DPN Lesions.       
9 The investigator will assess each DPN target lesion based on a 4-point Physician’s DPN Lesion Assessment Scale.  In order to be eligible for enrollment at Visit 
2, the subject must have at least one DPN lesion that is between 2mm and 5 mm in diameter. The investigator must assess each DPN lesion that is to be treated 
prior to application of the study medication at Visit 2, if applicable at Visit 3 and Visit 5.   
10 Subjects will use a Subject Self-Assessment Scale to assess each Target DPN Lesion at Screening Visit 1, Visit 2 (prior to application of the study medication), 
Visit 3 (prior to study medication, if applicable), Visit 4, Visit 5 (prior to study medication, if applicable), Visit 6, Visit 7 and Visit 8.   
11The investigator will measure the diameter and thickness of each identified Target DPN Lesions at Visit 1 and prior to enrollment. at Visit 2.  At Visit 3 (prior to 
treatment, if applicable), Visit 4, Visit 5 (prior to retreatment if applicable), Visit 6, Visit 7 and Visit 8 the investigator will only measure the diameter of each 
Target DPN Lesion.   
12 At Visits 1, Visit 2 (prior to study medication application) Visit 3 (prior to study medication application, if applicable), Visit 4, Visit 5 (prior to study medication 
application if applicable), Visit 6, Visit 7, and Visit 8, a qualified investigational center staff member will take a photograph of each DPN lesion that has been 
treated using the Aclaris supplied camera.  All photographs will be sent to a central imaging laboratory.   
13 Subjects will be enrolled to the study at Visit 2 prior to application of study medication.  Investigational study staff will re-confirm subject eligibility prior to 
study enrollment.   
14 Both the investigator and the subject will assess each Target DPN Lesion for symptoms associated with irritation.  At Visit 2, Visit 3 and Visit 5, the investigator 
will assess the Target DPN Lesions prior to application of the study medication and 20 (± 4) minutes after treatment with the study medication, if applicable. At 
Visit 2, Visit 3, and Visit 5, the subject will assess the Target DPN Lesions prior to application of the study medication and 10 (±4) minutes after the treatment of 
the study medication, if applicable.    
15 A-101 study medication will be applied by the treating physician.  All Target DPN Lesions will be treated with study medication following enrollment at Visit 
2.  Subjects randomized to ARM B will be required to have their Target DPN Lesions medically abraded prior to treatment with A-101 study medication.  If a 
Target DPN Lesion meets the criteria for re-treatment as defined in Section 7.5, the lesion will be re-treated at Visit 3, and Visit 5.  Following application of study 
medication, subjects must NOT wash/submerge the Target DPN Lesions for at least 6 hours and they must NOT apply any topical products to the Target DPN 
Lesions for at least 6 hours.   
16All subjects will be required to apply Aquaphor to all Target DPN Lesions the morning after study medication application.  Sites will be provided supplies of 
Aquaphor by the Sponsor.   
17All concomitant therapies including (topical and oral) prescription medications, over the counter medications and natural supplements and non-drug therapies 
including chiropractic, physical therapy, and energy-based therapy must be documented in the subject CRF.  Subjects must not apply any topical products (e.g. 
moisturizers, sunscreen, etc.) to their Target Lesions within 12 hours prior to any study visit.   
18The reporting period for Serious Adverse Events (SAEs) begins when the subject signs the informed consent.  Refer to Section 10 for instructions on the reporting 
of SAEs.  Non-serious clinical adverse events will be collected following the application of the study medication at Visit 2. Non-serious adverse events that occur 
between the time of consent and study medication application will be documented as medical history.   All safety reporting (AEs and SAEs) will conclude at Visit 
5 (approximately 21 days after last study medication application) except for clinical adverse events related to local skin reactions.  These events will be collected 
through V8.     
 


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7. 
STUDY TREATMENT 
7.1. 
Investigational Study Medication 
The study medication for this study is A-101 Solution 40%. The study medication solution is clear 
and colorless solution.   
 
Table 4 
Study Medication Information 
Study Medication 
Name 
A-101 Solution 40% 
Manufacturer 
James Alexander Corporation, Blairstown NJ 
A-101 concentration 
(%) 
40 
Pharmaceutical Form 
Solution 
Storage Conditions 
59ºF to 77ºF (15ºC to 25ºC) protected from excessive heat, open flame 
and combustibles, out of direct sunlight and in a well-ventilated, dry 
area 
Route 
Topical 
Application  
Safety glasses and nitrile or vinyl examination gloves must be worn 
during the application process.  Latex gloves are prohibited.   
Duration of 
Administration 
Apply study medication to each Target Lesion for approximately 15 
seconds.  Allow each Target Lesion to remain undisturbed for 
approximately 60 seconds.  Repeat the application/waiting cycle until 
the study medication has been applied to each Target Lesion up to 3 
times.   
 
 
7.2. 
Subject randomization  
Cohort 1 of this study is an open label study. Subject randomization is not applicable for this part 
of the study.   
 
Subjects that are determined to be eligible for treatment in Cohort 2 will be randomized in a 1:2 
ratio to one of the following treatment arms. 
 
• ARM A:  A-101 40% Solution; No medical abrasion to the Target DPN Lesions 
Treatment Days 1, 15 and 29 
• ARM B:  A-101 40% Solution applied after medically abrading the Target DPN Lesions; 
Treatment Days 1, 15 and 29 
 
 


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7.3. 
Study medication packaging, storage and dispensing 
A-101 Solution 40% will be provided by Aclaris Therapeutics, Inc. and labelled according to the 
local law and legislation.   
 
The study medication will be packaged in single use applicators.  Each single-use applicator 
consists of a crushable glass ampoule that contains 1.5 milliliters (mL) of study medication.  The 
ampoule is provided inside a sealed polyethylene tube with a flocked, doe foot applicator on one 
end.   
 
The investigational site will be supplied with a lot of A-101 Solution 40% labelled appropriately 
for the study.  Investigational sites will be required to maintain full drug accountability for all 
applicators that are received at the site.    
 
A-101 study medication must be stored in a location where there is limited access to the 
investigational study medication at 59ºF to 77ºF (15ºC to 25ºC) protected from excessive heat, 
open flame and combustibles, out of direct sunlight and in a well-ventilated, dry area.   
 
Investigational study medication supplies are only to be used for subjects properly consented and 
enrolled to this study.   
 
7.4. 
Drug Accountability  
The investigator or designee will maintain an accurate record of the receipt of the study 
medications as shipped by Aclaris Therapeutics, Inc. (or designee), including the date received and 
the condition of the study medications. One copy of this receipt will be returned to Aclaris 
Therapeutics, Inc. (or designee) when the contents of the study medication shipment have been 
verified and one copy maintained in the study file. In addition, an accurate study medication 
disposition record will be kept, specifying the amount dispensed for each subject and the date of 
dispensing. This inventory record will be available for inspection at any time. At the completion 
of the study, the original inventory record will be available for review by Aclaris Therapeutics, 
Inc. upon request. 
 
Final drug accountability will be completed by the study monitor at the completion of the study 
and all unused study medication will be returned to Aclaris Therapeutics, Inc. drug depot for 
disposal per Aclaris Therapeutics, Inc. (or designee’s) written instructions. 
 
7.5. 
Study Medication Treatment 
The study medications are for external, topical use on the DPN Target Lesions on the appropriate 
study subject only.  
 
The treating investigator performing the study medication treatments must comply with the study 
medication handling warnings.  In cohort 1, the treating physician will apply the A-101 Solution 
40% to each DPN Target Lesion at Visit 2 and at Visit 4, if applicable.   
 


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At Visit 4, any Target Lesion that has a Physician DPN Lesion Assessment grade of >0 and ONLY 
DPN Target Lesions that have a Physician DPN Lesion Assessment grade of >0, must receive 
study medication treatment UNLESS either of the following criteria apply to the DPN Target 
Lesion: 
• The DPN Target Lesion has a Visit 4 pre-treatment LSR grade of 3 (severe) for any sign 
or symptom AND the grade has increased compared to the Visit 3 
• The DPN Target Lesion is, in the investigator’s opinion, not appropriate for a 
retreatment (the investigator must note the reason on the subject’s Comments CRF 
page). 
 
In cohort 2, for those subjects randomized to ARM B, the treating physician will medically 
abrade the Target DPN Lesion prior to apply the A-101 study medication.  All subjects in cohort 
2 will be allowed to have up to 3 treatment applications of the A-101 study medication.  If 
subjects meet the criteria as outlined above, subjects in cohort 2 may receive 2 additional study 
medication applications at Visit 3 (Day 15) and Visit 5 (Day 29).   
 
7.5.1. 
Preparing the Study Medication for Application 
To perform a study medication treatment for a DPN Target Lesion a staff member will select the 
appropriate study medication applicator. Then follow these instructions:  
• Prepare for the treatment: 
o Wash your hands prior to, and after completing the study medication treatments  
o Wear safety glasses and nitrile or vinyl examination gloves during the treatment; 
latex gloves are prohibited 
o Visually inspect the applicator for damage: 
 If the applicator appears damaged do not use it for the treatment, contact 
the study monitor for disposal instructions and select an unused applicator 
with the next highest number for the treatment 
 If the applicator is intact, proceed with the treatment process. 
• Activate and prime the applicator: 
o Hold the applicator horizontally with the tip/cap end pointing away from the 
subject and any staff; ensure the applicator tip protective cap is firmly attached 
o Place the thumbs and forefingers of both hands on the applicator tube at the point 
on the applicator where indicated 
o Gently but firmly squeeze the applicator tube with your fingers until the glass 
ampoule is crushed, you should hear an audible “SNAP”  
o Repeatedly squeeze the applicator tube moving your finger location up and down 
the tube to the tip and back again 2 or 3 times to ensure the glass ampoule 
containing the study medication has been completely crushed 
o Examine the applicator tube and tip for any wetness or leaking (if the applicator 
is damaged do not use it for the treatment, contact the study monitor for disposal 
instructions and select an unused applicator with the next highest number for the 
treatment) 
o Hold the applicator in one hand and orient it vertically with the TIP FACING 
DOWN 


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o With your other hand, gently flick or tap the applicator tube to ensure any air 
bubbles have been displaced and the study medication flows downward toward 
the tip 
o Remove the applicator tip protective cap 
o Hold the applicator with one hand over a disposable paper free absorbent material 
(e.g., gauze pad), place your thumb and forefinger approximately 0.5 inch above 
top of the finger grip on the applicator tube and gently and repeatedly squeeze the 
applicator tube until you see a drop of study medication visible in the opening of 
the holed applicator tip. The flow of study medication may be controlled by gently 
squeezing to apply pressure to the sides of the applicator tube to express more 
study medication, and by releasing pressure on the tube slow or stop the delivery 
of the study medication 
o The applicator is now ready to use in a treatment.  Refer to Figure 2 for a visual 
diagram of the steps needed to prepare the A-101 study medication applicator.   
 
 


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Figure 2:  Diagram Showing the Process for Preparing the A-101 study medication 
applicator 
7.5.2. 
Applying Study Medication to the Face 
To apply the study medication to Target Lesions on the FACE the staff member will follow these 
treatment instructions: 
• Do not apply the study medications to eyes, mouth, mucous membranes, open wounds 
• Do not apply the study medication to the eyelids or within 5 mm of the orbital rim 
• If, in the investigator’s opinion it is needed to ensure no study medication enters the eye: 
o Position the subject in the supine position with the head slightly elevated and 
angled such that any excess study medication will flow away from the eye. 
o Aclaris Therapeutics will supply sites supplies of white petrolatum (100%) United 
States Pharmacopeia (USP) that is to be applied along the orbital rim and at the 
medial and lateral canthi; gently stretch the periorbital skin between the thumb 
and forefinger at the time of petrolatum application to distend any periorbital 
rhytides (e.g., “crow’s feet”) and ensure full coverage of the skin at the base of 
the rhytides to decrease the likelihood of tracking of the study medication towards 
the eye 
o Have the subject hold an absorbent pad in the appropriate area of the eye to absorb 
any excess study medication that might track away from the Target Lesion 


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o Instruct the subject to keep both eyes closed during the entire study medication 
treatment procedure 
• After the subject is properly prepared and positioned, thoroughly cleanse the Target 
Lesion by firmly rubbing with a swab/wipe wetted with 70% isopropyl alcohol 
• **Subjects randomized to ARM B of cohort 2 will have their DPN lesions medically 
abraded prior to the application of the A-101 study medication.   
• Using firm pressure, while avoiding squeezing the applicator barrel, apply one drop of 
study medication onto the DPN lesion and then move applicator around in a circular 
motion to fully saturate the lesion.  Using the smaller Q-tip applicator that is supplied 
massage the A-101 study medication into the DPN lesion for approximately 15 seconds. 
• Minimize exposure to the surrounding normal skin 
• During the treatment process remove excess study medication from the surrounding skin 
using a clean absorbent wipe 
• Ensure the DPN Target Lesion is wet with study medication at the end of the ~15 second 
application 
• Allow the DPN Target Lesion to remain undisturbed for ~60 seconds 
• After ~60 seconds repeat the ~15 second application process 
• Repeat the application/waiting cycle until the study medication has been applied to the 
DPN Target Lesion up to 3 times. 
 
Record the number of times each Target DPN Lesion is treated during a treatment visit and record 
the time the final treatment is completed for the last treated Target DPN Lesion as the Treatment 
Completion Time. 
  
It is acceptable to treat multiple Target DPN Lesions at the same time if, in the investigator’s 
opinion, it is practical without exposing non-lesional skin to the study medication. 
 
After completing the study medication treatment to the Target DPN Lesion do not disturb the DPN 
Target Lesion until just prior to the subject’s post-treatment LSR evaluation.   
 
Just prior to the subject’s post-treatment LSR evaluation absorb any remaining study medication 
and gently dab or otherwise dry the Target DPN Lesion with an absorbent pad or dry gauze without 
wiping or rubbing.   
 
7.5.3. 
Applying Study Medication to the Neck  
To apply the study medication to a Target DPN Lesion on the neck the staff member will follow 
these treatment instructions:  
• Do not apply the study medications to eyes, nose, mouth, mucous membranes, or open 
wounds 
• Position the subject with the plane of the Target DPN Lesion to minimize exposure of the 
skin surrounding the Target Lesion to the study medication  
• Thoroughly cleanse the Target Lesion by firmly rubbing with a swab/wipe wetted with 
70% isopropyl alcohol 


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• **Subjects randomized to ARM B of cohort 2 will have their DPN lesions medically 
abraded prior to the application of the A-101 study medication.   
• Using firm pressure, squeezing in the middle of the applicator, apply one drop of study 
medication onto the DPN lesion and then move applicator around in a circular motion to 
fully saturate the lesion.  Using the smaller Q-tip applicator that is supplied massage the 
A-101 study medication into the DPN lesion for approximately 15 seconds. 
• Minimize exposure to the surrounding normal skin 
• During the treatment process remove excess study medication from the surrounding skin 
using a clean absorbent wipe 
• Ensure the Target DPN Lesion is fully saturated with study medication at the end of the 
~15 second application 
• Allow the Target DPN Lesion to remain undisturbed for ~60 seconds 
• After ~60 seconds repeat the ~15 second application process 
• Repeat the application/waiting cycle until the study medication has been applied to the 
Target DPN Lesion up to 3 times. 
 
7.6. 
Dose modification 
If a subject refuses to allow a study medication initial treatment or retreatment the investigator 
must report the visit number, visit date, Target Lesion number(s) the subject refused to allow 
treatment for and the reason for the refusal in the subject’s CRF.  
 
If the subject’s refusal is associated with an AE, the investigator must also report the event on the 
appropriate CRF.  
 
The subject must have the Visit 2 initial study medication treatment to all Target Lesions to remain 
in the study.  
 
The subject does not need to be removed from the study based solely on her/his refusal to have a 
study medication retreatment at Visit 4.  
 
7.7. 
Previous and Concomitant Therapies 
7.7.1. 
Previous therapies 
During Visit 1, the investigator or designee will question the subject to ensure they have not used 
any excluded therapies. 
 
7.7.2. 
Concomitant therapies 
Concomitant therapies are any new or existing therapy received from Visit 1 until discharge from 
the study.  
 


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Concomitant therapies include drug (e.g., prescription, over-the-counter [OTC]) and non-drug 
(e.g., chiropractic, physical therapy, energy-based treatments) therapies. Subjects will refrain from 
receipt of any therapy in compliance with the inclusion/exclusion criteria. Subjects should refrain 
from changing the use of any concomitant therapies during the study.  
 
All new or modified concomitant therapies used during the study must be recorded in the subject 
CRF. 
 
7.7.3. 
Prohibited therapies 
During the course of this study, subjects are prohibited from using the following treatment 
therapies to treat any of the Target Lesions: 
 
• Retinoids (systemic or topical) 
• Corticosteroids (systemic or topical)  
• Antimetabolites 
• LASER, light or other energy-based therapy 
• Liquid nitrogen, electrodesiccation, curettage, imiquimod, ingenol mebutate 
• Microdermabrasion or superficial chemical peels 
• Antibiotics (topical)    
• Self-tanner lotions and sprays 
  
The investigator should notify the Medical Monitor immediately if any prohibited therapies are 
required to ensure subject safety. 
 
Starting with Visit 2, subjects must not apply any topical products (e.g., moisturizers, sunscreens, 
etc.) to their Target Lesions within 12 hours prior to any study visit (Note: routine cleansing 
products are allowed). 
 
After the completion of any study visit where a study medication treatment was performed subjects 
must NOT wash/submerge the Target Lesions for at least 6 hours and must not apply any topical 
products to the Target Lesions for at least 6 hours. 
 
7.8. 
Wound Care 
All subjects will be required to apply Aquaphor to the treated Target DPN Lesions beginning the 
morning after the application of study medication.  Sites will be provided with supplies of 
Aquaphor that may be dispensed to subjects enrolled to the study. Subjects will be instructed to 
apply a thin layer of Aquaphor 2x’s per day, as needed. Subjects will be instructed to stop applying 
the Aquaphor 12 hours prior Visit 4 (treatment visit, cohort 1 subjects) or 12 hours prior to Visit 3 
and Visit 5 for cohort 2 subjects.  
8. 
ASSESSMENTS OF CLINICAL EFFICACY 
8.1. 
Target Lesion Identification 
At Visit 1, the investigator will identify up to 4 Target DPN Lesions located on the subject’s body. 


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At Visit 1, each Target Lesion must: 
• Have a clinically typical appearance    
• Have a Physician’s DPN Lesion Assessment score of ≥ 2  
• Have a diameter that is between 2 mm and less than 5 mm 
• Have a height or thickness that is ≤2mm      
• Be a discrete lesion    
• Not be covered with hair which, in the investigator’s opinion, would interfere with the 
study medication treatment or the study evaluations  
• Not be in an intertriginous fold    
• Not be on the eyelids 
• Not be within 5mm of the orbital rim 
• Not be pedunculated. 
• Not be inflamed, irritated, or excoriated. 
 
 
Record the approximate location of each Target DPN Lesion on the appropriate body chart in the 
CRFs. Also, identify the body area (i.e., face, neck) for each Target DPN Lesion in the CRFs. 
Number the Target DPN Lesions starting with 1 and proceeding up to 4 with no number omitted 
or reused. 
 
Aclaris Therapeutics will provide the investigational site with standard circular templates to 
identify the Target DPN Lesions.   
 
8.1.1. 
Standardized photography 
At Visits 1, 2, 3 (prior to retreatment, if applicable for cohort 2 subjects ONLY), 4 (prior to 
retreatment, if applicable for cohort 1 subjects ONLY), 5 (prior to retreatment, if applicable for 
cohort 2 subjects ONLY), 6, 7 and 8 qualified investigational center staff member will take 
standardized color photographs of each Target Lesion.  
 
The photographs are to document the location of the Target DPN Lesion and to assist with 
relocating the Target DPN Lesion and the Target DPN Lesion ID stickers must be visible in the 
photographs. The subject’s identity will not be revealed in the study photographs. 
 
At Visit 2, the photographs must be taken prior to the study medication treatment. 
Care must be taken to ensure the same lighting, background, subject positioning relative to the 
camera and camera settings are used for each photograph.  
 
Sites will be provided with photography equipment and supplies necessary for obtaining the Target 
Lesion photographs.  Detailed instructions for obtaining and managing the photographs will be 
documented in the study specific Photography Manual and provided to the site at the study 
initiation visit.    


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8.1.2. 
Physician’s DPN Lesion Assessment  
The Physician’s DPN Lesion Assessment is the investigator’s assessment of the severity of the 
Target DPN Lesion at a particular time point. The investigator should NOT refer to any other 
assessments to assist with these assessments.  
 
 
At Visits 1, 2, 3 (cohort 2 ONLY), 4 (cohort 1 ONLY), 5 (cohort 2 ONLY), 6, 7 and 8, the investigator 
will assess the Target DPN Lesion using the scale below and report the one integer that best describes 
the severity of the Target DPN Lesion. At Visit 2, and if appropriate at Visit 4 for cohort 1 subjects 
or Visit 3 and Visit 5 for cohort 2 subjects, the investigator must complete the Physician’s DPN 
Lesion Assessment prior to the study medication treatment. 
 
Table 5:   Physician’s DPN Lesion Assessment Definitions 
 
Physician’s DPN Lesion Assessment 
Grade 
Descriptor 
0 
Clear:  no visible DPN lesion;  
1 
Near Clear:  a slightly visible DPN lesion; lesion may be macular 
2 
Small:  a visible DPN lesion with a diameter of less than 3 mm 
3 
Large:  a visible DPN lesion that is elevated with a diameter of ≥3 mm 
 
At Visit 1 and Visit 2, for the subject to be eligible for enrollment to the study the identified DPN 
lesions must have a Physician’s Lesion Assessment of grade ≥ 2. 
 
8.1.3. 
Lesion Dimensions 
At Visit 1 and at Visit 2 prior to enrollment the Investigator will be required to measure the 
diameter and thickness of each Target DPN Lesion.  For subjects enrolled to cohort 1 the 
investigator will measure the diameter of each Target DPN Lesion using the ruler at Visit 4 (prior 
to retreatment, if applicable), Visit 6, Visit 7 and Visit 8.  For subjects randomized to cohort 2, the 
investigator will measure the diameter of each Target DPN Lesion t Visit 3 (prior to retreatment if 
applicable), Visit 4, Visit 5 (prior to retreatment if applicable) Visit 6, Visit 7 and Visit 8.  
 
At Visit 1 for the subject to be enrolled and at Visit 2 for the subject to be enrolled each Target DPN 
Lesion must have: 
• A diameter that is between 2 mm and less than 5 mm. 
• A height or thickness that is ≤ 2 mm.   
 


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8.2. 
Subject Self-Assessment Scale 
For subjects enrolled to cohort 1, each subject will use the Subject Self-Assessment Scale to assess 
each Target DPN Lesions at the following visits:   Visit 1, Visit 2 (prior to treatment), Visit 4 (prior 
to treatment), Visit 6, Visit 7 and Visit 8. For subjects randomized to cohort 2, each subject will use 
the Subject Self-Assessment Scale to assess each Target DPN Lesion at the following visits:  Visit 1, 
Visit 2 (prior to treatment), Visit 3 (prior to retreatment, if applicable), Visit 4, Visit 5 (prior to 
retreatment, if applicable) Visit 6, Visit 7 and Visit 8. 
 
 


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Subject Self-Assessment Scale 
Grade Descriptor 
0 
No Visible DPN Lesion 
1 
Mild; Slightly raised DPN lesion 
2 
Moderate; Obviously raised DPN lesion 
3 
Severe; Prominent DPN lesion 
 
8.3. 
Subject Instructions 
An investigational center staff member will dispense a Subject Instruction Sheet to each subject at 
Visit 1 (Refer to Appendix 15.1). 
 
Throughout the study, the subjects should: 
• Continue their routine cleansing regimen except they should avoid vigorous scrubbing of 
the Target DPN Lesions (e.g., loofah, back brushes, scrubbing straps, abrasive washcloths, 
sponges and cleansing pads, etc.) 
• Continue their routine cosmetics and skin care products 
• Avoid exposing the Target DPN Lesions to excessive natural or artificial ultraviolet 
radiation (e.g., sunlight, tanning beds) and use sunscreen on the Target DPN Lesions, if 
excessive exposure cannot be avoided 
• Bring the subject instruction sheet with them to each visit. 
 
On study visit days, the subjects should: 
• When appropriate for the Target DPN Lesion location wear loose fitting clothing to the 
visit (Note: clothing that comes in contact with the study medication may be bleached) 
• Starting with Visit 2, not apply any topical products to the Target DPN Lesions within 12 
hours prior to the visit (Note: routine cleansing products are allowed) 
• After the completion of any study visit where a study medication treatment was performed 
DO NOT: 
o Wash/submerge the DPN Target Lesions for at least 6 hours 
o Apply any topical products to the Target Lesions for at least 6 hours. 
• Apply Aquaphor to the Target DPN Lesions the morning after the treatment visits (Visit 2 
and Visit 4, cohort 1, or Visit 2, Visit 3 and Visit 5, cohort 2 
 
8.4. 
Other Study Supplies 
Aclaris Therapeutics, Inc. will provide: 
• An appropriate ruler, or other instrument, for measuring the thickness of the Target Lesions 
and the Lesion Dimensions 
• 70% isopropyl alcohol for cleansing the Target DPN Lesion during the study medication 
treatment process 
• White Petrolatum USP for protecting sensitive areas during study medication treatments 
for Target Lesions on the face 
• Individual subject supplies of Aquaphor for Wound Care.  


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• Templates for use when identifying Target Lesions 
• Supplies and instructions for collecting, labeling, shipping and result reporting for the 
clinical laboratory tests and urine pregnancy tests from a third party 
• Equipment, supplies and training for taking standardized photographs 
• Small Q-tip applicators 
• Eyewash kits. 
9. 
ASSESSMENT OF SAFETY 
In addition to reporting adverse events throughout the study the investigator, a designated and 
appropriately trained staff member or the subject, will perform study following safety assessments 
according to the schedules noted below. 
 
9.1. 
Local Skin Reactions (LSR) 
The LSR assessment is the investigator’s assessment of the signs and the subject’s assessment of the 
symptoms associated with irritation at each Target DPN Lesion site, which includes the Target DPN 
Lesion and the area immediately surrounding the Target DPN Lesion.  
 
Local Skin Reactions: 
• Signs (assessed by the investigator): 
o Erythema 
o Edema 
o Scaling/dryness 
o Vesicles/bullae 
o Crusting 
o Erosion 
o Ulceration 
o Post-inflammatory hyper-pigmentation 
o Post-inflammatory hypo-pigmentation (does not include the superficial transient skin 
blanching/whitening related to the action of the study medications) 
o Atrophy 
o Scarring. 
 
• Symptoms (assessed by the subject): 
o Stinging/burning 
o Pruritus (itch). 
 
At Visits 2-8, the investigator and the subject will evaluate the LSR signs and the LSR symptoms at 
each Target DPN Lesion site respectively.  
 
The investigator will assess the LSR signs as follows: 
• Visits 2 and 4 (cohort 1) and Visits 2, 3 and 5 (cohort 2): 
o For each Target DPN Lesion site report the severity for all signs prior to any study 
medication treatment 


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o For every treated Target DPN Lesion site, 20 (±4) minutes after the Treatment 
Completion Time, report the severity for the following signs: 
 Erythema 
 Edema 
 Scaling/dryness 
 Vesicles/bullae 
 
• Visits 3 and 5-8 (cohort 1) and Visits 4 and 6-8 (cohort 2): 
o For each Target DPN Lesion site, report the severity for all signs. 
 
The subject will assess the LSR symptoms as follows: 
• Visits 2 and 4 (cohort 1) and Visits 2, Visit 3 and Visit 5 (cohort 2): 
o For each Target DPN Lesion site report the average of the severity over the previous 
24 hours for all symptoms prior to any study medication treatment 
o For every treated Target DPN Lesion site, 10 (±4) minutes after the Treatment 
Completion Time, report the average of the severity of the LSR for all symptoms 
since completion of the study medication treatment. 
• Visits 3 and 5-8 (cohort 1) and Visits 4 and 6-8 (cohort 2): 
o For each Target DPN Lesion site, report the average of the severity over the 
previous 24 hours for all symptoms. 
 
Both the subject and the study staff member will initial and date the source document to indicate 
the subject performed the LSR for symptoms as instructed. The staff member must not influence 
the subject’s assessment. 
 
The investigator should report the one integer that best describes the severity of each LSR sign for 
each Target Lesion site using the scale below. Each subject should report the one integer that best 
describes the severity of each LSR symptom for each Target Lesion site using the scale below: 
 
Table 6 
Grading of Local Skin Reactions 
Local Skin Reactions 
Grade 
Descriptor 
0 
None 
1 
Mild 
2 
Moderate 
3  
Severe 
 
9.2. 
Vital signs 
Vital signs will be measured by a qualified staff member at Visit 1, Visit 2 prior to randomization, 
Visit 4 (cohort 1 ONLY) prior to treatment and at Visit 8. The following items will be measured: 
• Body temperature 
• Pulse rate 
• Respiration rate 


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• Blood pressure (systolic and diastolic) after the subject sits quietly for at least 5 minutes 
• Height (at Visit 1 only) 
• Weight (at Visit 1 only). 
 
Any measure that is, in the opinion of the investigator, abnormal AND clinically relevant (CR) 
must be recorded as history if found prior to the first study medication treatment or as an AE if 
found after the first study medication treatment begins (Section 10.1).  
 
A systolic blood pressure >140mm Hg or a diastolic blood pressure >90mm Hg is considered 
abnormal and therefore must be defined as CR or not clinically relevant (NCR) on the CRFs.  
9.3. 
Clinical laboratory sampling 
Non-fasting blood samples for clinical laboratory analysis will be collected by a qualified staff 
member at Visit 1 and at Visit 8. Approximately 7.5 mL of blood will be collected for each 
chemistry sample and 3ml of blood will be collected for the complete blood count (CBC).  These 
blood samples will be sent to a central laboratory for analysis.  Refer to the study specific 
laboratory manual for instructions regarding handling of the blood samples and shipping 
instructions.   
 
The following tests, at a minimum, 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 
 
Total protein 
 
Uric acid 
 
 
 
The results of the clinical laboratory tests will be reported on the central laboratory’s standard 
reports. These laboratory results will be sent to the investigator via fax/email.  The investigator 
must review all laboratory reports in a timely manner and note NCS or CS to define the clinical 
significance of any result that is outside the normal range for the laboratory. The investigator must 
date and initial every laboratory report.  


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The investigator must review the Visit 1 laboratory results for all the measured analytes for each 
subject prior to Visit 2. The subject must not be enrolled to the study at Visit 2 if any of the Visit 
1 results are outside normal range for the laboratory AND, in the opinion of the investigator, CS. 
 
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.  
 
9.4. 
Urine pregnancy tests 
The investigator or designee will perform a urine pregnancy test for subjects who are WOCBP 
(Section 11) at Visit 1, at Visit 2 prior to randomization and at Visit 8.    
 
Subjects who are WOCBP must have a negative pregnancy test result at Visit 1 to continue in the 
study and at Visit 2 to be randomized. 
 
If the result of any post-randomization urine pregnancy test is positive, the subject will be 
withdrawn from the study and the subject’s pregnancy documented and followed (Section 11). 
 
9.5. 
Other Evaluations 
9.5.1. 
Demographics and medical history 
At Visit 1, the investigator or designee will collect demographic information including date of 
birth, sex at birth, race and, if appropriate, ethnicity for each subject.  
 
At Visit 1, the investigator must determine each subject’s Fitzpatrick skin type and document 
appropriately on the subject’s CRF. 
 
Table 7 
Fitzpatrick Skin Type Scoring System 
Skin Type 
Classification 
Description 
Type I 
always burns, never tans  
Type II 
usually burns, tan less than average (with difficulty) 
Type III 
sometimes mild burn, tan about average 
Type IV 
rarely burn, tan more than average (with ease) 
Type V 
very rarely burns, tans very easily  
Type VI 
never burns, never tans  
(Fitzpatrick, 1988) 
 
Medical history information will be recorded including all medical conditions and disease states 
that, at Visit 1: 
• Are ongoing 


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• Require concomitant therapy 
• Are, in the opinion of the investigator, relevant to the subject’s study participation. 
10. 
ADVERSE EVENTS 
10.1. 
Definitions 
10.1.1. 
Adverse events (AE) 
An adverse event (AE) is any untoward medical occurrence in a patient that develops or worsens 
in severity during the conduct of a clinical study of a pharmaceutical product and does not 
necessarily have a causal relationship to the study drug.  An adverse event can, therefore, be any 
unfavorable and unintended physical sign, symptom, or laboratory parameter that develops or 
worsens in severity during the course of the study, or significant worsening of the disease under 
study (or any concurrent disease), whether or not considered related to the study drug. 
• 
Accordingly, an adverse event could include any of the following: 
• 
intercurrent illnesses 
• 
physical injuries 
• 
events possibly related to concomitant medication 
• 
significant worsening (change in nature, severity, or frequency) of the disease under study 
or other pre-existing conditions.  (NOTE: A condition, recorded as pre-existing, that is 
intermittently symptomatic [e.g., headache] and which occurs during the study should be 
recorded as an adverse event.) 
• 
drug interactions 
• 
events occurring during diagnostic procedures or any washout phase of the study 
• 
laboratory or diagnostic test abnormalities occurring after the start of the study (i.e., after 
screening and once confirmed by repeat testing) that results in the withdrawal of the patient 
from the study, requires medical treatment or further diagnostic work-up, or is considered 
by the study investigator to be clinically significant.  NOTE: Abnormal laboratory test 
results at the screening visit that preclude a patient from entering the study or receiving 
study treatment are not considered adverse events, but will be recorded to monitor data 
from patients who do not meet screening criteria. 
Worsening of any of the Target Lesion assessments should be reported as an AE ONLY if 
the use of the study medication is interrupted or discontinued or if therapy is required to 
manage the event.  
 
The investigator must, for any Target Lesion related AE, question the subject in detail to 
determine if there are any confounding factors (e.g., irritation by clothing or activity, 
sunburn) for any such AE.  
 


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The investigator should, when certain, report a diagnosis rather than the signs, symptoms or 
clinically relevant abnormal laboratory values associated with the AE. Otherwise, signs, symptoms 
or abnormal laboratory values may be used to describe the AE. 
 
Any CR 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 was 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. 
 
10.1.3. 
Adverse event reporting period 
The investigator must start reporting non-serious AEs starting with the subject’s first study 
medication treatment continuing until Visit 6. Non-serious adverse events that occur between the 
time the subject was consent and the first application of study medication will be reported as 
medical history.   
 
Reporting for SAEs begins after the subject signs the informed consent and continues until Visit 6 
(regardless of relationship to study medication).  If a subject experiences a SAE after Visit 6 that 
is deemed to be related to study medication, the investigator must report this to the Sponsor using 
the study specific SAE report form.   


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10.1.4. 
Severity 
The investigator must 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 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. 
 
10.1.5. 
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 possibility that there is a causal relationship between the 
study medication and the AE. 
 
Not Related – There is not a reasonable possibility that there is a causal relationship 
between the study medication and the AE. 
 
The term “reasonable causal relationship” means there are facts 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 or designee 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?”   
 
The investigator or designee will monitor the subject for at least 20 minutes after the Treatment 
Completion Time at Visit 2 and at Visit 4 to elicit AEs in a similar manner. 
 
If appropriate, based on the subject’s response to non-directed questioning regarding AEs, the 
investigator or designee will follow-up with directed questions and appropriate evaluations.  
 
Any AE noted during the reporting period must be reported in the source documents and on the 
appropriate AE CRF.  


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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 
2. 
Immediately inform the Drug Safety Monitor of the SAE by telephone: 
 
Kenneth Kostenbader, MD 
Aclaris Therapeutics, Inc. 
640 Lee Road, Suite 200 
Wayne, PA 19087 
Telephone:  484-329-2176 
Serious Adverse Event Facsimile:  484-324-2359 
Email:  kkostenbader@aclaristx.com 
 
3. 
Within 24-hours complete, as fully as possible, an AE CRF and an SAE form; fax or e-mail 
the forms and any other relevant information (e.g., concomitant medication CRF, medical 
history CRF, laboratory test results) to the Drug Safety Monitor. 
4. 
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 Drug Safety Monitor 
agree that the SAE is satisfactorily resolved. 
5. 
Inform the Drug Safety Monitor of SAE updates by telephone followed by an SAE form 
update sent by fax or by e-mail. 
6. 
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. 
Withdrawal Due to an Adverse Event 
Any patient who experiences an adverse event may be withdrawn from study drug at any time at the 
discretion of the investigator.  If a patient is withdrawn wholly or in part because of an adverse event, both 
the adverse events page and termination page of the CRF will be completed at that time.  The patient will 
be monitored until the event has resolved or stabilized, until a determination of a cause unrelated to the 
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professional.  The investigator must inform the medical monitor as soon as possible of all patients who are 
being considered for withdrawal due to adverse events.  Additional reports must be provided when 
requested. 
11. 
PREGNANCY 
WOCBP include any female who has experienced menarche and who has not undergone successful 
surgical sterilization (e.g., hysterectomy, hysteroscopy, bilateral tubal ligation, bilateral 
oophorectomy or bilateral minilaparotomy) or is not postmenopausal. Postmenopausal is defined 
as ≥12 months with no menses without an alternative medical cause. Women who are WOCBP 
and are using an active method of birth control, are practicing abstinence or where the partner is 
sterile (e.g., vasectomy), should be considered to be WOCBP. 
 
All WOCBP must use an active method of birth control during the course of the study, in a manner 
such that risk of failure is minimized. Abstinence or having a sterile partner is not an active method 
of birth control. 
 
Prior to trial enrollment, WOCBP must be advised of the importance of avoiding pregnancy during 
trial participation and the potential risk factors for a pregnancy.  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 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 (Section 10). 
 
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 
follow-up procedures should be considered if indicated. In addition, the investigator must report 
to the 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. 
  


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12. 
STATISTICAL CONSIDERATIONS 
12.1. 
Sample Size and Power Considerations 
The results of this first DPN study are intended to provide the data required for sample size 
estimation for future studies. 
12.2. 
Statistical Analysis of Efficacy Data 
Efficacy summaries and analyses (where appropriate) will be based on the per protocol (PP) 
population of all treated subjects completing all treatment visits and Visit 8 with no major 
protocol violations.  In addition, efficacy summaries may be presented for the intent to treat 
(ITT) population of all treated subjects with at least one post-baseline visit, using last 
observation carried forward (LOCF) to impute missing data.  Efficacy endpoints will include 
summary statistics (frequency distributions, proportions, means, medians and standard 
deviations, as appropriate) by visit for the following parameters: Physician’s DPN Lesion 
Assessment scale results per treated lesion, subject responders defined by Physician’s DPN 
Lesion Assessment scale outcome, and changes from baseline treated lesion diameter.   
 
Comparative inferential analyses will be conducted for data collected from subjects in Cohort 2.  
The primary efficacy comparisons between the two Cohort 2 treatment groups will be made on 
the per-subject mean change across all treated lesions in Physician’s DPN Lesion Assessment 
scale from baseline to the final visit using an ANCOVA model. A similar secondary analysis will 
be performed on the pre-subject mean percent of treated lesions that are clear (PLA=0), and a 
similar analysis based on clear or near-clear lesions (PLA < 2).  Another secondary analysis will 
be performed on subject responders with all treated lesion PLA scores = 0, as well as a similar 
analysis on subject responders with all treated lesion PLA scores < 2.  An analysis of change 
from baseline lesion diameter will be conducted using the same methodology as the primary 
efficacy analysis.  All analyses will be conducted at each post-baseline visit where possible.   
Summaries will also be presented by subject Fitzpatrick Skin Type. 
 
12.3. 
Exploratory Analysis  
Exploratory efficacy endpoints will include summary statistics (frequency distributions, 
proportions, means, medians and standard deviations, as appropriate) by visit for the following 
parameters: Subject Self-Assessment scale results per treated lesion, and subject responders 
defined by Subject Self-Assessment scale outcome.  Analyses similar to the secondary analyses 
described above will be conducted on the Subject Self-Assessment scale results.  Summaries will 
also be presented by subject Fitzpatrick Skin Type. Summaries will be based on the PP population 
12.4. 
Statistical Analysis of Safety Data 
Safety analyses will include descriptive statistics calculated on the safety parameters using the ITT 
population. The proportion of subjects with treatment-emergent adverse events will be tabulated 
and presented by study treatment group and Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class. Vital signs, LSR scores and clinically relevant abnormal 
laboratory results will also be tabulated and presented.  
 


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Data from all 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-treatment values in vital signs. Adverse 
event summaries will be presented showing the proportion of subjects experiencing adverse events, 
both overall and by MedDRA System Organ Class. 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1. 
Protocol Amendments 
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the IEC/IRB, except when necessary to 
eliminate immediate safety concerns to the patients or when the change involves only logistics or 
administration.  The principal investigator and the sponsor will sign the protocol amendment. 
 
13.2. 
Protocol Deviations, Violations and Exceptions 
A protocol deviation is non-adherence to protocol-specific study procedures or schedules that 
does not involve inclusion/exclusion criteria, primary objective variable criteria, and/or 
GCP guidelines.  Deviations are considered minor and do not impact the study.  Deviations include 
study procedures that occurred outside the treatment windows (except for treatment application 
days), use of prohibited medications,  
 
A protocol violation is defined as any divergence from the protocol-specific inclusion/exclusion 
criteria, use of any prohibited medications to treat an identified DPN target lesion or a divergence 
from GCP guidelines.  Protocol violations will be identified and recorded, by study center 
personnel, on the CRF. 
 
As a matter of policy, sponsor/CRO will not grant exceptions to protocol-specific entry criteria to 
allow patients to enter a study.  If under extraordinary circumstances such action is considered 
ethically, medically, and scientifically justified for a particular patient, prior approval from 
sponsor/CRO and the responsible IRB/IEC, in accordance with the Sponsor/CROs Standard 
Operating Procedure (SOP), is required before the patient will be allowed to enter the study.  If 
investigative center personnel learn that a patient who did not meet protocol eligibility criteria was 
entered in a study (a protocol violation), they must immediately inform sponsor/CRO.  Such 
patients will be discontinued from the study, except in a rare instance following review and written 
approval by sponsor/CRO and the responsible IRB/IEC, according to the applicable SOP 
13.3. 
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 CRFs.  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.  
 


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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. 
 
13.4. 
Monitoring 
The conduct of the study will be closely monitored by the Aclaris Therapeutics, Inc.  study 
monitor /CRO to verify adherence to ICH Good Clinical Practice (GCP) guidelines, applicable 
SOPs, the protocol, other written instructions and regulatory guidelines.   
The study monitor is the primary association between the sponsor/CRO and each investigator.  
The main responsibilities of the study monitors are to visit each investigator before, during, and 
after the study to ensure adherence to the protocol that all data are correctly and completely 
recorded and reported, and that informed consent is obtained and recorded for all patients before 
their participation in the study. 
The study monitors will contact each investigator and visit the study center at regular intervals 
throughout the study.  The study monitor will be permitted to check and verify the various 
records (CRFs, corresponding subject medical records, study medication dispensing records and 
study medication storage area, and any other documents considered source documentation) to 
verify adherence to the protocol and to ensure the completeness, consistency, and accuracy of the 
data being recorded.  If electronic case report forms (eCRFs) are used for the study, the study 
monitor will indicate verification by electronically applying source document verification (SDV) 
flags to the eCRF and will ensure that all required electronic signatures are being implemented 
accordingly. 
As part of the supervision of study progress, other sponsor/CRO personnel may, on request, 
accompany the study monitor on visits to the study center.  Each investigator and assisting staff 
must agree to cooperate with the study monitor to resolve any problems, errors, or possible 
misunderstandings concerning the findings detected in the course of these monitoring visits. 
13.5. 
Data Management 
Data will be collected using CRFs that are specifically designed for this study.  The data collected 
on the CRFs will be captured in a clinical data management system (CDMS) that meets the 
technical requirements described in US 21 Code of Federal Regulations (CFR) Part 11.  The 
CDMS will be fully validated to ensure that it meets the scientific, regulatory, and logistical 
requirements of the study before it is used to capture data from this study.  Before using the CDMS, 
all users will receive training on the system and study specific training.  After they are trained, 
users will be provided with individual system access rights. 


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All required study data will be collected from primary source documents (or direct electronic 
capture from validated instrument operating systems, where applicable) by appropriately 
designated and trained personnel at the clinical facility, and CRFs must be completed for each 
patient screened consistent with the data source.  Patients’ actual identity will be coded 
appropriately and should not be discernible from the data provided on the CRF.  CRF content will 
be verified against data sources by the study monitor,and reviewed for consistency by Data 
Management using both automated logical checks and manual review.  All data collected will be 
approved by the Investigator at the clinical site.  This approval acknowledges the Investigator’s 
review and declaration that the data are complete and accurate. 
The handling of data, including data quality assurance, will comply with regulatory guidelines, 
including ICH and GCP, and the sponsor/CRO SOPs and working instructions.  Data management 
and control processes specific to this study will be described in a data management plan.  All steps 
and actions taken regarding data management and quality assurance will be documented in a data 
handling report.    At the end of the study, the database will be locked and the data will be released 
for reporting and statistical analysis 
13.6. 
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, Helsinki Declaration, and 
in respect of the Aclaris Therapeutics, Inc. and/or sub-contractor SOPs for study conduct and 
monitoring. 
Audits may be carried out by the 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., CRFs, 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.  
13.7. 
Record Retention 
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. 
/CRO/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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If the Investigator cannot guarantee this archiving requirement at the investigative site for any or 
all of the documents, special arrangements must be made between the Investigator and the Sponsor 
to store these in sealed containers in an off-site storage location so that they can be returned to the 
Investigator in case of a regulatory audit.  Where source documents are required for the continued 
care of the patient, appropriate copies will be made for off-site storage. 
No trial document should be destroyed without prior written agreement between the Sponsor and 
the Investigator. Should the Investigator wish to assign the trial records to another party or move 
them to another location, the Investigator must notify the Sponsor in writing of the new responsible 
person and/or the new location 
14. 
ETHICS AND GENERAL STUDY CONDUCT CONSIDERATIONS 
14.1. 
Institutional Review Board (IRB)/Ethics Committee (EC) 
This protocol and any accompanying material, including information that will be provided to 
prospective patients (such as advertisements, patient information sheets, or study descriptions 
used to induce study participation or obtain informed consent) must be submitted to the Central 
IRB for approval.  Approval of each such submission must be obtained from the committee 
before it may be used in the study and must be documented in a written notification to the 
Investigator specifying the protocol number, protocol version, documents reviewed, and date on 
which the committee met and granted the approval.  In particular, each informed consent 
document must bear clear evidence (written, stamp, date of approval, etc.) of IRB approval 
before it may be presented to prospective (or ongoing, as appropriate) study patients for 
signature. 
Written evidence of the approval must be made available to the Sponsor.  Any modifications 
made to the protocol and of correspondingly modified informed consent documents made after 
receipt of Central IRB approval must also be submitted to the committee for approval before 
implementation unless the modification is made on an emergency basis to protect the welfare of 
study patients.  In the latter case, the Central IRB must be notified promptly and their written 
approval must be obtained as soon after the fact as possible. 
Appropriate reports on the progress of the study will be made to the Central IRB and the Sponsor 
by the Investigator in accordance with applicable regulatory regulations and in conformity with 
policies established by both the Central IRB and the Sponsor.  The shortest time interval between 
required reports required by either party or by regulations will prevail. 
The Investigator at each investigative site, or his/her nominee, will be responsible for reporting 
any SAEs to the Central IRB as soon as possible, and in accordance with the guidelines of the 
Central IRB. 
The Sponsor will be responsible for reporting all serious, life threatening or fatal adverse study 
drug events with a causal relationship to the study drug to appropriate regulatory agencies within 
their required timelines. 


Protocol: A101-DPN-201 
Amendment 1 
Version 2.0:  28 MARCH 2018 
Aclaris Therapeutics, Inc. 
 
 
                                                                Page 56 of 60 
.  The Investigator is responsible for obtaining written, informed consent(s) from each 
prospective patient interested in participating in this study before performing any study-related 
procedures.  Written informed consent must be obtained after adequate, thorough, and clear 
explanation of the aims, methods, objectives, and potential hazards of the study, as well as any 
use of the patient’s genetic information from the study.  The Investigator must use the most 
current Central IRB-approved consent form for documenting written informed consent.  Each 
informed consent will be appropriately signed and dated by the patient and the person obtaining 
consent.  The investigational site must retain the original signed consent and provide a copy to 
the patient.   
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.  
The Sponsor will use information developed in this clinical study in connection with the 
development of A-101 Solution and, therefore, may disclose it as required to other clinical 
Investigators participating in other studies and to regulatory agencies.  In order to allow the use 
of the information derived from this clinical study, the Investigator understands that he/she has 
an obligation to provide all data produced during this study to the Sponsor. 
The Sponsor considers that clinical data (complete or incomplete) constitute financially sensitive 
information.  Consequently, the Sponsor requires that discussion of results in any form, electronic, 
verbal, or written before study completion and full reporting should only be undertaken with the 
Sponsor’s prior written consent. 
Individual patients’ medical information obtained as a result of this study is considered 
confidential.  The Investigator and the study center will adhere to all applicable laws relating to 
the protection of patient information.  To assure that patients’ confidentiality is maintained, 
patients’ data will be identified by a study-assigned number and date of birth only.  
All Sponsor personnel will handle patients’ data in a confidential manner in accordance with 
applicable regulations governing clinical research.  Patients’ records will be inspected only in 
connection with this research project.  Information generated as a result of a patient’s participation 
in this study may be disclosed to third parties for research and regulatory purposes in any country 
as determined by the Sponsor.  However, patients will not be individually identified but will be 
referred to only by the study assigned number and the patient’s date of birth. 
. 
14.3. 
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. 
 


Protocol: A101-DPN-201 
Amendment 1 
Version 2.0:  28 MARCH 2018 
Aclaris Therapeutics, Inc. 
 
 
                                                                Page 57 of 60 
14.4. 
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. 
 
 
 
 
 
 


Protocol: A101-DPN-201 
Amendment 1 
Version 2.0:  28 MARCH 2018 
Aclaris Therapeutics, Inc. 
 
 
                                                                Page 58 of 60 
15. 
Appendices 
15.1. 
Subject Instructions 
A-101-DPN-201 SUBJECT INSTRUCTION SHEET 
Please follow these instructions carefully. Contact the study staff at the telephone number noted 
below if you have any questions about the study: 
 
Contact: 
 
 
 
 
 
   Telephone:                                      
 
DURING THE STUDY: 
• Continue your routine cleansing regimen except avoid vigorous scrubbing of the Target 
DPN Lesions (e.g., loofah, back brushes, scrubbing straps, abrasive washcloths, sponges 
and cleansing pads, etc.) 
• Continue your routine cosmetics and skin care products 
• Avoid exposing your Target DPN Lesions to excessive natural or artificial ultraviolet 
radiation (e.g., sunlight, tanning beds) and use sunscreen on the Target Lesion, if excessive 
exposure cannot be avoided 
• The use of the following therapies to treat any of the Target DPN Lesions are prohibited 
o Retinoids (oral or topical) 
o Corticosteroids (oral or topical) 
o Antimetabolites 
o LASER, light or other energy-based therapy 
o Liquid nitrogen, electrodesiccation, curettage, imiquimod, ingenol mebutate 
o Microdermabrasion or superficial chemical peels 
o Antibiotics (oral or topical) 
• Use of self-tanner lotions/sprays are prohibited during the study. 
• Bring this subject instruction sheet with you to each visit. 
 
 
ON STUDY VISIT DAYS: 
• When appropriate for the Target Lesion location wear loose fitting clothing to the visit 
(Note: clothing that comes in contact with the study medication may be bleached) 
• Starting prior to Visit 2, do not apply any topical products to the Target Lesions, except for 
routine cleansing products, within 12 hours prior to the visit 
• After any study visit where a study medication treatment was performed do not: 
o Wash/submerge the Target Lesions for at least 6 hours 
o Apply any topical products to the Target Lesions for at least 6 hours. 
• Apply Aquaphor to each of the DPN Target Lesions beginning the morning after Visit 2 (Day 1) 
and Visit 4 (Day 22, if applicable, cohort 1) or after Visit 3 (Day 15) and Visit 5 (Day 29) for 
cohort 2 subjects, if applicable. 
 
 


Protocol: A101-DPN-201 
Amendment 1 
Version 2.0:  28 MARCH 2018 
Aclaris Therapeutics, Inc. 
 
 
                                                                Page 59 of 60 
STUDY VISIT SCHEDULE: 
VISIT 2: 
Date:                            Time: 
VISIT 3: 
Date:                            Time: 
VISIT 4: 
Date:                            Time: 
VISIT 5: 
Date:                            Time: 
VISIT 6: 
Date:                            Time: 
VISIT 7: 
Date:                            Time: 
VISIT 8: 
Date:                            Time: 
Thank you for following these instructions 
 
 
 


Protocol: A101-DPN-201 
Amendment 1 
Version 2.0:  28 MARCH 2018 
Aclaris Therapeutics, Inc. 
 
 
                                                                Page 60 of 60 
16. 
References 
 
Calonje, E. (2012). Dermatosis papulosa nigra. In E. Calonje, McKee's Pathology of the Skin (p. 
1028). Elsevier. 
Fitzpatrick, T. (1988). The Validity and Practicality of Sun Reactive Skin Types I through VI. 
Arch Dermatology, 869-871. 
Hairston, M. (1961). Dermatosis Papulosa Nigra. Archives of Dermatology, 655-658. 
Kundu, S. L. (2017, February 28). Dermatology Education: Dermatosi Papulosa Nigra (DPN). 
Retrieved from Skin of Color Society: http://skinofcolorsociety.org/dermatology-
education/1399-2 
Lupo, M. P. (2007). Dermatosis Papulosis Nigra: Treatment Options. Journal of Drugs in 
Dermatology, 29-30. 
 

SAP_001.pdf: 
 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol Number: A-101-DPN-201 
A Phase 2 Open Label, Single Arm Pilot Study of A-101 Topical Solution in Subjects 
with Dermatosis Papulosa Nigra 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
 
 




Aclaris Therapeutics, Inc. 
 
 
SAP for Protocol Number: A-101-DPN-201 
 
 
 
 
 
Page 3 of 26 
Date: 19-February-2019 
 
 
Table of Contents 
1 
STUDY OBJECTIVES AND SAMPLE SIZE RATIONALE ...................................6 
1.1 
STUDY OBJECTIVES ................................................................................................6 
1.1.1 
Primary Objective .....................................................................................................6 
1.1.2 
Secondary Objectives................................................................................................6 
1.1.3 
Exploratory Objective ...............................................................................................6 
1.1.4 
Safety Assessments ...................................................................................................6 
1.2 
SAMPLE SIZE .............................................................................................................6 
2 
STUDY DESIGN SUMMARY .....................................................................................7 
2.1 
VISITS ..........................................................................................................................7 
2.2 
SUBJECTS .................................................................................................................14 
2.2.1 
Number of Subjects ................................................................................................14 
2.2.2 
Diagnosis and Main Criteria for Inclusion..............................................................14 
2.2.3 
Study Population Characteristics ............................................................................14 
2.2.4 
Replacement Subjects .............................................................................................14 
2.3 
TREATMENT AND RANDOMIZATION ...............................................................14 
2.3.1 
Study Medications, Treatment, and Mode of Administration ................................14 
2.3.2 
Randomization ........................................................................................................14 
2.3.3 
Administration of Treatment...................................................................................15 
2.3.4 
Duration of Treatment ............................................................................................15 
2.4 
ASSESSMENTS ........................................................................................................15 
2.4.1 
Evaluators ...............................................................................................................15 
2.4.2 
Evaluations – Efficacy ............................................................................................16 
2.4.2.1 
Physician’s DPN Lesion Assessment ..................................................................16 
2.4.2.2 
Lesion Dimensions ..............................................................................................16 
2.4.2.3 
Subject Self-assessment Scale .............................................................................17 
2.4.3 
Evaluations – Safety ...............................................................................................17 
2.4.3.1 
Local Skin Reaction (LSR) .................................................................................17 
2.4.3.2 
Adverse Events ....................................................................................................18 


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Date: 19-February-2019 
 
2.4.3.3 
Laboratory Sampling ...........................................................................................18 
2.4.3.4 
Vital Signs ...........................................................................................................19 
2.4.4 
Other Evaluations ...................................................................................................20 
3 
STATISTICAL METHODOLOGY ..........................................................................21 
3.1 
GENERAL STATISICAL CONSIDERATIONS ......................................................21 
3.2 
ANALYSIS POPULATION AND DISPOSITION OF SUBJECTS .........................21 
3.2.1 
Data Sets Analyzed .................................................................................................21 
3.2.2 
Disposition of Subjects ...........................................................................................22 
3.3 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .....................22 
3.4 
MEDICAL HISTORY................................................................................................22 
3.5 
PRIOR/CONCOMITANT MEDICATIONS .............................................................22 
3.6 
EFFICACY ANALYSIS ............................................................................................22 
3.6.1 
Physician’s Leasion Assessment (PLA) Analyses ..................................................22 
3.6.2 
Subject Self Assessment (SSA) Analyses...............................................................23 
3.7 
SAFETY ANALYSIS ................................................................................................24 
3.7.1 
Study Drug Exposure And Compliance ..................................................................24 
3.7.2 
Local Skin Reaction (LSR) .....................................................................................24 
3.7.3 
Adverse Events .......................................................................................................24 
3.7.4 
Laboratory Tests .....................................................................................................25 
3.7.5 
Vital Signs ...............................................................................................................25 
3.8 
INTERIM ANALYSES ..............................................................................................25 
4 
CHANGES TO PLANNED ANALYSES ..................................................................26 
 


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SAP for Protocol Number: A-101-DPN-201 
 
 
 
 
 
Page 5 of 26 
Date: 19-February-2019 
 
List of Abbreviations 
Abbreviations/Acroynms 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
ATC 
antomical therapeutic chemical 
BUN 
blood urea nitrogen 
CS 
clinically significant 
CRF 
case report form 
DPN 
dermatosis papulosa nigra
FST 
Fitzpatrick skin type 
ITT 
intent-to-treat 
LDH 
lactate dehydrogenase 
LSR 
local skin reaction 
Max 
maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
minimum 
mm 
millimeters 
NCS 
non-clinically significant 
PLA 
physician’s lesion assessment 
PP 
per-protocol 
PT 
preferred term 
SAE 
serious adverse event 
SSA 
subject self-assessment 
Std Dev 
standard deviation 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 


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SAP for Protocol Number: A-101-DPN-201 
 
 
 
 
 
Page 6 of 26 
Date: 19-February-2019 
 
1 
STUDY OBJECTIVES AND SAMPLE SIZE RATIONALE 
1.1 
STUDY OBJECTIVES 
This study is to assess safety and efficacy of A-101 Solution 40% when applied to up to 4 
dermatosis papulosa nigra (DPN) Target Lesions in subjects with Fitzpatrick Skin Type (FST) 
5 or 6.   
There are 2 cohorts in the study.  The first cohort of the study will enroll a total of 12 subjects 
(6 subjects with a FST of 5 and 6 subjects with a FST of 6).  The second cohort of the study a 
total of 24 subjects will be a randomized to a two-arm cohort: 
• 
A-101 40% without medically abrading the identified DPN prior to treatment 
• 
A-101 40% with the identified DPN lesions medically abraded prior to treatment 
Primary and Secondary Objectives are summarized below. 
1.1.1 
Primary Objective 
The main objective of this study is to evaluate the safety and efficacy of hydrogen peroxide, 
A-101 Solution 40% for the treatment of DPN lesions on subjects with a FST of 5 or 6. 
1.1.2 
Secondary Objectives 
The secondary objective of this study is to assess durability of response. 
1.1.3 
Exploratory Objective 
An exploratory objective of this study is to evaluate the subject’s assessment of the treatment 
with A-101 to DPN lesions using a Subject Self-Assessment Scale. 
1.1.4 
Safety Assessments 
Safety will be evaluated based on clinical laboratory studies (hematology and clinical 
chemistry), vital signs, urine pregnancy tests, assessment of local skin reactions (LSRs), 
assessment of adverse events (AEs), and concomitant medication review. 
1.2 
SAMPLE SIZE 
A total of 36 subjects are planned to be enrolled/randomized in the study. 
 
 


Aclaris Therapeutics, Inc. 
 
 
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Page 7 of 26 
Date: 19-February-2019 
 
2 
STUDY DESIGN SUMMARY 
All enrolled/randomized subjects will receive at least one application of A-101 40% solution 
on up to four target DPN lesions on the subject’s face or neck.  Subjects in cohort 1 may 
receive a second application of A-101 40% Solution if the lesions meet the criteria for 
retreatment at Visit 4 (Day 22).  Subjects in cohort 2 may receive up to 3 treatment 
applications if the lesions meet the criteria for retreatment at Visit 3 (Day 15) and Visit 5 (Day 
29).  All subjects will be followed on study protocol until Visit 8 (Day 106). 
Protocol provides a more detailed description of the study. 
2.1 
VISITS 
The protocol defined study visits for cohort 1 are: 
• Visit 1 (Day -13 to 0) screening 
• Visit 2 (Day 1) enrollment and study medication treatment 
• Visit 3 (Day 8) follow up visit 
• Visit 4 (Day 22) follow up visit and second application of study medication if DPN 
target lesions meet criteria for retreatment 
• Visit 5 (Day 29) follow up visit 
• Visit 6 (Day 50) follow up visit 
• Visit 7 (Day 78) follow up visit; 
• Visit 8 (Day 106) follow up visit; end of study 
 
The protocol defined study visits for cohort 2 are: 
• Visit 1 (Day -13 to 0) screening 
• Visit 2 (Day 1) randomization and study medication treatment 
• Visit 3 (Day 15) follow up visit and second application of study medication if DPN 
target lesions meet criteria for retreatment 
• Visit 4 (Day 22) follow up visit 
• Visit 5 (Day 29) follow up visit and third application of study medication if DPN 
target lesions meet criteria for retreatment 
• Visit 6 (Day 50) follow up visit 
• Visit 7 (Day 78) follow up visit; 
• Visit 8 (Day 106) follow up visit; end of study 
 
Study procedures for subjects in cohort 1 and 2 are detailed in the following two tables. 
 
 


Aclaris Therapeutics, Inc. 
 
 
SAP for Protocol Number: A-101-DPN-201 
 
Page 8 of 26 
Date: 19-February-2019 
 
 
Table 1: 
Study Procedures for Cohort 1 Subjects 
 
 
Visit 
V1 
Screening 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Treatment Day 
-13 to 0 
1 
8 
22 
29 
50 
78 
106 
Treatment Window 
N/A 
N/A 
+ 7 days 
+ 4 days 
+7 days 
± 7days 
± 7 days 
± 7 days 
Study Procedures 
 
Informed Consent 
X 
Inclusion Criteria/Exclusion 
Criteria 
X 
X1 
 
 
 
 
 
 
Subject Identifier 
X2 
Medical history/demographics 
X 
Fitzpatrick Skin Type Assessment 
X3 
Vital Signs 
X 
X4 
X 
X 
Prior Medications/Therapies 
X5 
Clinical Chemistry and CBC6 
X 
X 
Urine Pregnancy Test7 
X 
X 
X 
Target Lesion Identification8 
X 
Physician’s DPN Lesion 
Assessment9 
X 
X 
 
X 
 
X 
X 
X 
Subject Self-Assessment Scale10 
X 
X 
X 
X 
X 
X 
Lesion Dimensions11 
X 
X 
X 
X 
X 
X 
Standardized Photography12 
X 
X 
X 
X 
X 
X 
Subject Enrollment 
 
X13 
Local Skin Reactions 
 
X14 
X 
X14 
X 
X 
X 
X 
Study Medication Application 
 
X15 
X15 
Wound Care16 
 
X 
X 
Subject Instructions 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapies17 
 
X 
X 
X 
X 
X 
X 
X 
Adverse Events18 
 
X 
X 
X 
X 
X 
1 Subject inclusion/exclusion criteria will be re-assessed prior to study enrollment during Visit 2. 
2 Investigational sites will assign a unique five-digit subject identifier to each subject at Visit 1. This subject identifier will be used in all study 
documentation for the duration of the study. 
3 Each subject’s skin must be assessed during Visit 1 using the Fitzpatrick Skin Type Assessment. Refer to Protocol Section 9.5.1 for the scale. 


Aclaris Therapeutics, Inc. 
 
 
SAP for Protocol Number: A-101-DPN-201 
 
Page 9 of 26 
Date: 19-February-2019 
 
4 Vital signs [including temperature, pulse, respiratory rate, blood pressure, and weight (Visit 1 only)] will be measured by a qualified staff member 
at Visit 1, Visit 2 prior to study enrollment, and at Visit 8. 
5 Prior medications/therapies will be collected for a time-period of 13 days prior to Visit 2.  Refer to Protocol Section 7.7 for a list of permitted 
and restricted concomitant medications. 
6 A complete blood count (including hematocrit, hemoglobin, platelet count, red blood cell count, white blood cell count and differential (absolute and 
%) including basophils, eosinophils, lymphocytes, monocytes and neutrophils and a clinical chemistry panel including albumin, alkaline phosphatase, 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), bicarbonate, calcium, chloride, creatinine, glucose, 
lactate dehydrogenase (LDH), phosphorus, potassium, sodium, total bilirubin, total protein, and uric acid. 
7 Woman of child bearing potential will be required to have a urine pregnancy test at Visit 1, at Visit 2 prior to enrollment and at Visit 8. 
8 The treating investigator will identify up to 4 Target DPN Lesions. Each lesion that is identified to be treated must be in an inconspicuous area. 
9 The investigator will assess each DPN target lesion based on a 4- point Physician’s DPN Lesion Assessment Scale. In order to be eligible for 
enrollment at Visit 2, the subject must have at least one DPN lesion that is between 2mm and 5 mm in diameter. At Visit 2 and if applicable at 
Visit 4, the investigator must assess each DPN lesion that is to be treated prior to application of the study medication. 
10 Subjects will use a Subject Self-Assessment Scale to assess each Target DPN Lesion at Screening Visit 1, at Visit 2 prior to application of the study 
medication, at Visit 4 (prior to study medication, if applicable), at Visit 6, Visit 7 and Visit 8. 
11 The investigator will measure the diameter and thickness of each identified Target DPN Lesions at Visit 1 and prior to enrollment. at Visit 2.  At 
Visit 4 prior to retreatment (if applicable, at Visit 6, Visit 7 and at Visit 8 the investigator will only measure the diameter of each Target DPN Lesion. 
12 At Visits 1, Visit 2 (prior to study medication application), Visit 4 prior to study medication application if applicable, Visit 6, Visit 7, and at Visit 
8, a qualified investigational center staff member will take a photograph of each DPN lesion that has been treated using the Aclaris supplied camera.  
All photographs will be sent to a central imaging laboratory. 
13 Subjects will be enrolled to the study at Visit 2 prior to application of study medication.  Investigational study staff will re-confirm subject 
eligibility prior to study enrollment. 
14 Both the investigator and the subject will assess each Target DPN Lesion for symptoms associated with irritation.  At Visit 2 and Visit 4, the 
investigator will assess the Target DPN Lesions prior to application of the study medication and 20 (± 4) minutes after treatment with the study 
medication. At Visit 2 and Visit 4, the subject will assess the Target DPN Lesions prior to application of the study medication and 10 (±4) minutes 
after the treatment of the study medication. 
15 A-101 study medication will be applied by the treating physician.  All Target DPN Lesions will be treated with study medication following 
enrollment at Visit 2.  If a Target DPN Lesion meets the criteria for re-treatment as defined in Section 7.5, the lesion will be re-treated at Visit 4.  
Following application of study medication, subjects must NOT wash/submerge the Target DPN Lesions for at least 6 hours and they must NOT 
apply any topical products to the Target DPN Lesions for at least 6 hours. 
16 All subjects will be required to apply Aquaphor to all Target DPN Lesions the morning after study medication application.  Sites will be provided 
supplies of Aquaphor by the Sponsor. 
17 All concomitant therapies including (topical and oral) prescription medications, over the counter medications and natural supplements and non-
drug therapies including chiropractic, physical therapy, and energy-based therapy must be documented in the subject CRF.  Subjects must not 
apply any topical products (e.g. moisturizers, sunscreen, etc.) to their Target Lesions within 12 hours prior to any study visit. 


Aclaris Therapeutics, Inc. 
 
 
SAP for Protocol Number: A-101-DPN-201 
 
Page 10 of 26 
Date: 19-February-2019 
 
18 The reporting period for Serious Adverse Events (SAEs) begins when the subject signs the informed consent. Refer to Section 10 for instructions 
on the reporting of SAEs. Non-serious clinical adverse events will be collected following the application of the study medication at Visit 2. Non-
serious adverse events that occur between the time of consent and study medication application will be documented as medical history.  All safety 
reporting (AEs and SAEs) will conclude at Visit 5 (approximately 21 days after last study medication application) except for clinical adverse events 
related to local skin reactions. These events will be collected through V8. 
 
 


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SAP for Protocol Number: A-101-DPN-201 
 
Page 11 of 26 
Date: 19-February-2019 
 
Table 2: Study Procedures for Cohort 2 Subjects 
 
Visit 
V1 
Screening 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Treatment Day 
-13 to 0 
1 
15 
22 
29 
50 
78 
106 
Treatment Window 
N/A 
N/A 
+ 4 days 
+ 2 days 
+4 days 
± 7days 
± 7 days 
± 7 days 
Study Procedures 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion Criteria/Exclusion 
Criteria 
X 
X1 
 
 
 
 
 
 
Subject Identifier 
X2 
 
 
 
 
 
 
 
Medical history/demographics 
X 
 
 
 
 
 
 
 
Fitzpatrick Skin Type Assessment 
X3 
 
 
 
 
 
 
 
Vital Signs 
X 
X4 
 
 
 
 
 
X 
Prior Medications/Therapies 
X5 
 
 
 
 
 
 
 
Clinical Chemistry and CBC6 
X 
 
 
 
 
 
 
X 
Urine Pregnancy Test7 
X 
X 
 
 
 
 
 
X 
Target Lesion Identification8 
X 
 
 
 
 
 
 
 
Physician’s DPN Lesion 
Assessment9 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Self-Assessment Scale10 
X 
X 
X 
X 
X 
X 
X 
X 
Lesion Dimensions11 
X 
X 
X 
X 
X 
X 
X 
X 
Standardized Photography12 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Randomization 
 
X13 
 
 
 
 
 
 
Local Skin Reactions 
 
X14 
X14 
X 
X14 
X 
X 
X 
Study Medication Application 
 
X15 
X15 
 
X15 
 
 
 
Wound Care16 
 
X 
X 
 
X 
 
 
 
Subject Instructions 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapies17 
 
X 
X 
X 
X 
X 
X 
X 
Adverse Events18 
 
X 
X 
X 
X 
X 
 
 
1 Subject inclusion/exclusion criteria will be re-assessed prior to study enrollment during Visit 2. 
2 Investigational sites will assign a unique five-digit subject identifier to each subject at Visit 1. This subject identifier will be used in all study 
documentation for the duration of the study. 
3 Each subject’s skin must be assessed during Visit 1 using the Fitzpatrick Skin Type Assessment. Refer to Protocol Section 9.5.1 for the scale. 


Aclaris Therapeutics, Inc. 
 
 
SAP for Protocol Number: A-101-DPN-201 
 
Page 12 of 26 
Date: 19-February-2019 
 
4 Vital signs [including temperature, pulse, respiratory rate, blood pressure, and weight (Visit 1 only)] will be measured by a qualified staff member at Visit 1, 
Visit 2 prior to study enrollment, and at Visit 8. 
5 Prior medications/therapies will be collected for a time-period of 13 days prior to Visit 2.  Refer to Protocol Section 7.7 for a list of permitted and 
restricted concomitant medications. 
6 A complete blood count (including hematocrit, hemoglobin, platelet count, red blood cell count, white blood cell count and differential (absolute and %) 
including basophils, eosinophils, lymphocytes, monocytes and neutrophils and a clinical chemistry panel including albumin, alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), bicarbonate, calcium, chloride, creatinine, glucose, lactate 
dehydrogenase (LDH), phosphorus, potassium, sodium, total bilirubin, total protein, and uric acid. 
7 Woman of child bearing potential will be required to have a urine pregnancy test at Visit 1, at Visit 2 prior to enrollment and at 
Visit 8. 
8 The treating investigator will identify up to 4 Target DPN 
Lesions. 
9 The investigator will assess each DPN target lesion based on a 4-point Physician’s DPN Lesion Assessment Scale. In order to be eligible for enrollment at 
Visit 2, the subject must have at least one DPN lesion that is between 2mm and 5 mm in diameter. The investigator must assess each DPN lesion that is 
to be treated prior to application of the study medication at Visit 2, if applicable at Visit 3 and Visit 5. 
10 Subjects will use a Subject Self-Assessment Scale to assess each Target DPN Lesion at Screening Visit 1, Visit 2 (prior to application of the study 
medication), Visit 3 (prior to study medication, if applicable), Visit 4, Visit 5 (prior to study medication, if applicable), Visit 6, Visit 7 and Visit 8. 
11 The investigator will measure the diameter and thickness of each identified Target DPN Lesions at Visit 1 and prior to enrollment. at Visit 2. At Visit 3 
(prior to treatment, if applicable), Visit 4, Visit 5 (prior to retreatment if applicable), Visit 6, Visit 7 and Visit 8 the investigator will only measure the 
diameter of each Target DPN Lesion. 
12 At Visits 1, Visit 2 (prior to study medication application) Visit 3 (prior to study medication application, if applicable), Visit 4, Visit 5 (prior to study 
medication application if applicable), Visit 6, Visit 7, and Visit 8, a qualified investigational center staff member will take a photograph of each DPN 
lesion that has been treated using the Aclaris supplied camera. All photographs will be sent to a central imaging laboratory. 
13 Subjects will be enrolled to the study at Visit 2 prior to application of study medication.  Investigational study staff will re-confirm subject eligibility 
prior to study enrollment. 
14 Both the investigator and the subject will assess each Target DPN Lesion for symptoms associated with irritation. At Visit 2, Visit 3 and Visit 5, the 
investigator will assess the Target DPN Lesions prior to application of the study medication and 20 (± 4) minutes after treatment with the study medication, 
if applicable. At Visit 2, Visit 3, and Visit 5, the subject will assess the Target DPN Lesions prior to application of the study medication and 10 (±4) minutes 
after the treatment of the study medication, if applicable. 
15 A-101 study medication will be applied by the treating physician.  All Target DPN Lesions will be treated with study medication following enrollment at 
Visit 2.  Subjects randomized to ARM B will be required to have their Target DPN Lesions medically abraded prior to treatment with A-101 study 
medication.  If a Target DPN Lesion meets the criteria for re-treatment as defined in Section 7.5, the lesion will be re-treated at Visit 3, and Visit 5. Following 
application of study medication, subjects must NOT wash/submerge the Target DPN Lesions for at least 6 hours and they must NOT apply any topical 
products to the Target DPN Lesions for at least 6 hours. 
16 All subjects will be required to apply Aquaphor to all Target DPN Lesions the morning after study medication application.  Sites will be provided 
supplies of Aquaphor by the Sponsor. 


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17 All concomitant therapies including (topical and oral) prescription medications, over the counter medications and natural supplements and non-drug 
therapies including chiropractic, physical therapy, and energy-based therapy must be documented in the subject CRF.  Subjects must not apply any topical 
products (e.g. moisturizers, sunscreen, etc.) to their Target Lesions within 12 hours prior to any study visit. 
18 The reporting period for Serious Adverse Events (SAEs) begins when the subject signs the informed consent. Refer to Section 10 for instructions on the 
reporting of SAEs. Non-serious clinical adverse events will be collected following the application of the study medication at Visit 2. Non-serious adverse 
events that occur between the time of consent and study medication application will be documented as medical history.  All safety reporting (AEs and SAEs) 
will conclude at Visit 5 (approximately 21 days after last study medication application) except for clinical adverse events related to local skin reactions. 
These events will be collected through V8. 
 
 


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2.2 
SUBJECTS 
2.2.1 
Number of Subjects 
A total of 36 subjects will be treated on the study at 2 investigational sites in US. 
2.2.2 
Diagnosis and Main Criteria for Inclusion 
Adult subjects with up to 4 DPN Target Lesions with FST 5 or 6. 
2.2.3 
Study Population Characteristics 
Subjects with a clinical diagnosis of DPN who meet all the inclusion criteria and none of the 
exclusion criteria will be eligible to enroll/randomize in the study.  Detailed inclusion and 
exclusion criteria, see protocol sections 5.1 and 5.2.  
2.2.4 
Replacement Subjects 
If a subject is enrolled to the study but does not receive a dose of study drug, then the 
subject will be replaced. 
2.3 
TREATMENT AND RANDOMIZATION 
2.3.1 
Study Medications, Treatment, and Mode of Administration 
A-101 Solution 40% is hydrogen peroxide that will be supplied in a glass ampule with an 
applicator to be applied to a DPN lesion. 
2.3.2 
Randomization 
Cohort 1 of this study is an open label study.  Subject randomization is not applicable for this 
part of the study. 
Subjects that are determined to be eligible for treatment in Cohort 2 will be randomized in a 
1:2 ratio to one of the following treatment arms. 
• ARM A:  A-101 40% Solution; No medical abrasion to the Target DPN Lesions 
Treatment Days 1, 15 and 29 
• ARM B:  A-101 40% Solution applied after medically abrading the Target DPN 
Lesions; Treatment Days 1, 15 and 29 
 


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2.3.3 
Administration of Treatment 
The study medications are for external, topical use on the DPN Target Lesions on the 
appropriate study subject only. 
The treating investigator performing the study medication treatments must comply with the 
study medication handling warnings.  In cohort 1, the treating physician will apply the A-101 
Solution 40% to each DPN Target Lesion at Visit 2 and at Visit 4, if applicable. 
At Visit 4, any Target Lesion that has a Physician DPN Lesion Assessment grade of >0 and 
ONLY DPN Target Lesions that have a Physician DPN Lesion Assessment grade of >0, 
must receive study medication treatment UNLESS either of the following criteria apply to 
the DPN Target Lesion: 
• The DPN Target Lesion has a Visit 4 pre-treatment LSR grade of 3 (severe) for 
any sign or symptom AND the grade has increased compared to the Visit 3 
• The DPN Target Lesion is, in the investigator’s opinion, not appropriate for 
a retreatment (the investigator must note the reason on the subject’s 
Comments CRF page). 
In cohort 2, for those subjects randomized to ARM B, the treating physician will medically 
abrade the Target DPN Lesion prior to apply the A-101 study medication.  All subjects in 
cohort 2 will be allowed to have up to 3 treatment applications of the A-101 study 
medication.  If subjects meet the criteria as outlined above, subjects in cohort 2 may receive 
2 additional study medication applications at Visit 3 (Day 15) and Visit 5 (Day 29). 
2.3.4 
Duration of Treatment 
The duration of the study participation is anticipated to be a maximum of 127 days per 
subject.  The final visit (Visit 8), has a maximum allowable visit window of 7 days. 
2.4 
ASSESSMENTS 
2.4.1 
Evaluators 
The investigator, a designated and appropriately trained staff member (e.g., sub investigator) 
or the subject will perform the study assessments according to the defined schedules. 


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2.4.2 
Evaluations – Efficacy 
2.4.2.1 
Physician’s DPN Lesion Assessment 
The Physician’s DPN Lesion Assessment is the investigator’s assessment of the severity of 
the Target DPN Lesion at a particular time point. The investigator should NOT refer to any 
other assessments to assist with these assessments. 
At Visits 1, 2, 3 (cohort 2 ONLY), 4 (cohort 1 ONLY), 5 (cohort 2 ONLY), 6, 7 and 8, the 
investigator will assess the Target DPN Lesion using the scale below and report the one integer 
that best describes the severity of the Target DPN Lesion. At Visit 2, and if appropriate at Visit 
4 for cohort 1 subjects or Visit 3 and Visit 5 for cohort 2 subjects, the investigator must 
complete the Physician’s DPN Lesion Assessment prior to the study medication treatment. 
 
Table 3: Physician’s DPN Lesion Assessment Definitions 
 
Grade Descriptor 
0 
Clear:  no visible DPN lesion; 
1 
Near Clear:  a slightly visible DPN lesion; lesion may be macular 
2 
Small:  a visible DPN lesion with a diameter of less than 3 mm 
3 
Large:  a visible DPN lesion that is elevated with a diameter of ≥3 mm 
 
At Visit 1 and Visit 2, for the subject to be eligible for enrollment to the study the identified 
DPN lesions must have a Physician’s Lesion Assessment of grade ≥ 2. 
2.4.2.2 
Lesion Dimensions 
At Visit 1 and at Visit 2 prior to enrollment the investigator will be required to measure the 
diameter and thickness of each Target DPN Lesion.  For subjects enrolled to cohort 1 the 
investigator will measure the diameter of each Target DPN Lesion using the ruler at Visit 4 
(prior to retreatment, if applicable), Visit 6, Visit 7 and Visit 8. For subjects randomized to 
cohort 2, the investigator will measure the diameter of each Target DPN Lesion at Visit 3 (prior 
to retreatment if applicable), Visit 4, Visit 5 (prior to retreatment if applicable) Visit 6, Visit 7 
and Visit 8. 
At Visit 1 for the subject to be enrolled and at Visit 2 for the subject to be enrolled each Target 
DPN Lesion must have: 
• A diameter that is between 2 mm and less than 5 mm. 
• A height or thickness that is ≤ 2 mm. 


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2.4.2.3 
Subject Self-assessment Scale 
For subjects enrolled to cohort 1, each subject will use the Subject Self-Assessment Scale to 
assess each Target DPN Lesions at the following visits:   Visit 1, Visit 2 (prior to treatment), 
Visit 4 (prior to treatment), Visit 6, Visit 7 and Visit 8. For subjects randomized to cohort 2, 
each subject will use the Subject Self-Assessment Scale to assess each Target DPN Lesion at the 
following visits: Visit 1, Visit 2 (prior to treatment), Visit 3 (prior to retreatment, if applicable), 
Visit 4, Visit 5 (prior to retreatment, if applicable) Visit 6, Visit 7 and Visit 8. 
 
Table 4: Subject Self-Assessment Scale 
 
Grade Descriptor 
0 
No Visible DPN Lesion 
1 
Mild; Slightly raised DPN lesion 
2 
Moderate; Obviously raised DPN lesion 
3 
Severe; Prominent DPN lesion 
2.4.3 
Evaluations – Safety 
2.4.3.1 
Local Skin Reaction (LSR) 
The LSR assessment is the investigator’s assessment of the signs and the subject’s assessment of 
the symptoms associated with irritation at each Target DPN Lesion site, which includes the 
Target DPN Lesion and the area immediately surrounding the Target DPN Lesion. 
At Visits 2-8, the investigator and the subject will evaluate the LSR signs and the LSR symptoms 
at each Target DPN Lesion site respectively. 
The investigator will assess the LSR signs as follows: 
• Visits 2 and 4 (cohort 1) and Visits 2, 3 and 5 (cohort 2): 
o For each Target DPN Lesion site report the severity for all signs prior to any 
study medication treatment 
o For every treated Target DPN Lesion site, 20 (±4) minutes after the 
Treatment Completion Time, report the severity for the following signs: 
 Erythema 
 Edema 
 Scaling/dryness 
 Vesicles/bullae 
• Visits 3 and 5-8 (cohort 1) and Visits 4 and 6-8 (cohort 2): 
o For each Target DPN Lesion site, report the severity for all signs. 
The subject will assess the LSR symptoms as follows: 
• Visits 2 and 4 (cohort 1) and Visits 2, Visit 3 and Visit 5 (cohort 2): 


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o For each Target DPN Lesion site report the average of the severity over the 
previous 24 hours for all symptoms prior to any study medication treatment. 
o For every treated Target DPN Lesion site, 10 (±4) minutes after the Treatment 
Completion Time, report the average of the severity of the LSR for all 
symptoms since completion of the study medication treatment. 
• Visits 3 and 5-8 (cohort 1) and Visits 4 and 6-8 (cohort 2): 
o For each Target DPN Lesion site, report the average of the severity over 
the previous 24 hours for all symptoms. 
 
Both the subject and the study staff member will initial and date the source document to 
indicate the subject performed the LSR for symptoms as instructed. The staff member must 
not influence the subject’s assessment. 
The investigator should report the one integer that best describes the severity of each LSR sign 
for each Target Lesion site using the scale below. Each subject should report the one integer 
that best describes the severity of each LSR symptom for each Target Lesion site using the 
scale below: 
Table 5: Grading of Local Skin Reactions 
 
Grade 
Descriptor 
0 
None 
1 
Mild 
2 
Moderate 
3 
Severe 
2.4.3.2 
Adverse Events 
Non-serious AEs will be recorded starting with the subject’s first study medication treatment 
at Visit 2 and continuing through Visit 6.  All SAEs regardless of relationship to study 
medication will be collected and reported from the time the Informed Consent is signed 
through Visit 6. 
2.4.3.3 
Laboratory Sampling 
Non-fasting blood samples for clinical laboratory analysis will be collected by a qualified staff 
member at Visit 1 and at Visit 8.  Approximately 7.5 mL of blood will be collected for each 
chemistry sample and 3ml of blood will be collected for the complete blood count (CBC).   
These blood samples will be sent to a central laboratory for analysis.  Refer to the study 
specific laboratory manual for instructions regarding handling of the blood samples and 
shipping instructions.   
Laboratory tests (minimum) are as follows: 


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Chemistry 
Hematology 
Albumin 
Hematocrit 
Alkaline phosphatase 
Hemoglobin 
Alanine aminotransferase 
Platelet count 
Aspartate aminotransferase 
Red blood cell morphology 
Blood urea nitrogen 
Red blood cell count 
Bicarbonate 
White blood cell count 
Calcium 
White blood cell differential 
Chloride 
% & absolute 
Creatinine 
Basophils 
Glucose 
Eosinophils 
Lactate dehydrogenase 
Lymphocytes 
Phosphorus 
Monocytes 
Potassium 
Neutrophils 
Sodium 
 
Total bilirubin 
 
Total protein 
 
Uric acid 
 
2.4.3.4 
Vital Signs 
Vital signs will be measured by a qualified staff member at Visit 1, Visit 2 prior to 
randomization, Visit 4 (cohort 1 ONLY) prior to treatment and at Visit 8. 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 (at Visit 1 only) 
 Weight (at Visit 1 only) 
Any measure that is, in the opinion of the investigator, abnormal AND clinically significant 
(CS) must be recorded as history if found prior to the first study medication treatment or as 
an AE if found after the first study medication treatment begins. 
A systolic blood pressure >140mm Hg or a diastolic blood pressure >90mm Hg is considered 
abnormal and therefore must be defined as CS or non-clinically significant (NCS) on the 
Case Report Forms (CRFs). 


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2.4.4 
Other Evaluations 
At Visit 1, the investigator or designee will collect demographic information including date 
of birth, sex at birth, race, ethnicity, and FST for each subject. 
Table 6: Fitzpatrick Skin Type (FST) Scoring System 
Skin Type Classification 
Description
Type I 
Always burns, never tans (pale white; blond or red hair; blue eyes; 
freckles)
Type II 
Usually burns, tans minimally (white; fair; blond or red hair; blue, 
green, or hazel eyes) 
Type III 
Sometimes mild burn, tans uniformly (cream white; fair with any hair 
or eye color) 
Type IV 
Burns minimally, always tans well (moderate brown) 
Type V 
Very rarely burns, tans very easily (dark brown) 
Type VI 
Never burns, never tans (deeply pigmented dark brown to darkest 
brown) 
 
 
 


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3 
STATISTICAL METHODOLOGY 
This plan describes methods planned for the analysis and display of efficacy and safety 
endpoints.  Summaries will be based on mainly descriptive summaries for each assessment.  
3.1 
GENERAL STATISICAL CONSIDERATIONS 
Descriptive statistics (mean, standard deviation [Std Dev], median, minimum [Min], and 
maximum [Max]) will be used for continuous variables; number and percentage of subjects 
will be used for discrete variables.  In general, the last measurement prior to the first dose of 
study treatment will be used as the baseline value.  Nominal visits will be used for by-visit 
summaries and analyses. 
All treatment group comparisons will be made at the 0.05 level using a two-sided hypothesis 
test, unless otherwise specified. 
Summaries will be presented by each arm, ie, Cohort 1 FST 5, Cohort 1 FST 6, Cohort 2 Arm 
A, Cohort 2 Arm B, and Total (combining both cohorts subjects). 
All tabulations of summary statistics, graphical presentations, and statistical analyses will be 
performed using SAS® Version 9.2 or higher. 
3.2 
ANALYSIS POPULATION AND DISPOSITION OF SUBJECTS 
3.2.1 
Data Sets Analyzed 
Per-protocol (PP) analysis set 
All treated subjects completing all treatment visits and Visit 8 with no major protocol 
violations. 
Intent-to-Treat (ITT) analysis set 
Intent-to-Treat (ITT) analysis set includes all treated subjects with at least one post-baseline 
visit. 
Safety analysis set 
The Safety Analysis Set includes all treated subjects. 
 


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3.2.2 
Disposition of Subjects 
The numbers of subjects screened (ie, signed informed consent), enrolled/randomized, 
treated, and discontinued from treatment (by reason), will be summarized for each cohort 
separately. 
3.3 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and baseline characteristics will be summarized for the PP and Safety analysis 
sets.  Gender, race, ethnicity, and FST will be summarized with number and percentage 
presented for each category.  Age, height, weight will be described with summary statistics 
(n, mean, Std Dev, median, minimum, and maximum). 
3.4 
MEDICAL HISTORY 
Medical history will be summarized by body system class using the Safety analysis sets. 
3.5 
PRIOR/CONCOMITANT MEDICATIONS 
The number and percentage of prior medications, and concomitant medications will be 
summarized by Antomical Therapeutic Chemical (ATC) and preferred term (PT) separately 
using Safety analysis set. 
Medications taken any time prior to the first study treatment are counted as prior medications.  
Those taken any time on or after the first application of study medication through 30 days 
after the last application of study are counted as concomitant. 
Subject will be counted only once within each classification.  The same subject may 
contribute to two or more preferred terms within the same ATC classification. 
3.6 
EFFICACY ANALYSIS 
All efficacy analyses and summaries will be performed on the PP analysis population by 
randomized treatment group.  The primary efficacy analysis will be repeated on the ITT 
population. 
3.6.1 
Physician’s Leasion Assessment (PLA) Analyses 
PLA related parameters will be summarized at lesion level and at subject level. 
At each visit or applicable visit, the following analyses will be performed: 
 Descriptive statistics will be provided for the per-subject mean change from baseline 
in PLA for each post-baseline scheduled visit separately for the PP population. 


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 Descriptive statistics will be provided for the per-subject mean change from baseline 
in PLA for each post-baseline scheduled visit separately for the ITT population. 
 The number and percent of subjects having all lesions with PLA score of 0 will be 
provided for each post-baseline scheduled visit separately (PP population). 
 The number and percent of subjects having all lesions with PLA score <= 1 will be 
provided for each post-baseline scheduled visit separately (PP population). 
The following treatment group comparisons will be performed for PLA endpoints from 
Cohort 2:     
 Tretment group comparisons will be made for the change from baseline in per-subject 
mean PLA score at each post-baseline scheduled visit for the PP population.  These 
comparisons will be made using a repeated measures mixed model where treatment 
group and time (visit) are included as class variables and baseline per-stubject mean 
PLA score and number of treated lesions will be included as continuous covariates.  
The per-subject PLA measures over time will be treated as repeated measures by 
including subject as a random effect.  An unstructured variance covariance matrix will 
be assumed.  If the model experiences convergence issues with the unstructured 
variance covariance assumption, then a compound symmetric assumption will be 
used.  The difference in least square means for the treatment groups along with 
corresponding 95% confidence intervals and p-values will be provided for each of the 
scheduled visits.  A plot of the treatment group least square means (and 95% 
confidence intervals) across time (visit) will be provided. 
 Tretment group comparisons will be made for the change from baseline in per-subject 
mean PLA score at each post-baseline scheduled visit for the ITT population using 
LOCF for missing data.  The model for analysis and output will match that of the PP 
population analysis and output described above. 
 A logistic regression will be used to make treatment comparions in the proportion of 
subjects having all lesions with PLA score of 0 (PP population).  This analysis will be 
perfomed at each scheduled visit separately.  This model will include a class variable 
for treatment group as well as baseline per-subject mean PLA score and number of 
treated lesions as a continuous covariate.  Model based odds ratios, corresponding 
95% confidence intervals and p-values will be provided at each scheduled visit. 
 Similarly, a logistic regression will be used to make treatment comparions in the 
proportion of subjects having all lesions with PLA score of <= 1.  This model and 
output will be the same as described for the PLA score = 0 analysis. 
3.6.2 
Subject Self Assessment (SSA) Analyses 
Descriptive statistics will be provided for the per-subject mean change from baseline in the 
subject self-assessment scale for each post-baseline scheduled visit separately. 
     


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3.7 
SAFETY ANALYSIS 
The safety and tolerability of the investigational products will be determined by LSR, 
reported AEs, laboratory tests and vital signs.   The Safety analysis set with actual treatment 
received (as opposed to randomized treatment) will be used for all safety summaries, unless 
otherwise specified.   
3.7.1 
Study Drug Exposure And Compliance 
Duration of treatment (Last study treatment application date – First study treatment 
application date + 1) will be summarized descriptively using the Safety analysis set.  Number 
and percentage of subjects at each visit will be summarized by the number of target/non-
target lesions being treated.  In addition, number and percentage of subjects with re-treatment 
will be summarized for the applicable visits (Visit 4 for cohort 1 subjects, and Visits 3 and 5 
for cohort 2 subjects). 
3.7.2 
Local Skin Reaction (LSR) 
For each visit, all predefined signs and symptoms at pre-medication and post-medication will 
be summarized by maximum severity cross all lesions for a subject.  Number and percentage 
of subjects with grades 1, 2, 3, 4 will be tabulated for each sign (investigator)/symptom 
(subject) and at each visit.  In addition, the maximum severity for each sign and symptom 
will also summarized cross all visits.  Similar summaries will be presented for lesions.  That 
is, number and percentage of lesions with grades 1, 2, 3, 4 will be tabulated for each sign and 
symptom at each visit and over all visits. 
For treatment visits (ie, Visits 2 and 4 [cohort 1] and Visits 2, 3 and 5 [cohort 2]), for each 
sign (investigator assessment: Erythema, Edema, Scaling/dryness, Vesicles/bullae) or 
symptom (subject assessment: Stinging/burning, Pruritus [itch]) will be summarized using 
shift table.  Severity grade shift from pre-medication to post-medication will be analyzed.  
Number and percentage of lesions with shifts will be presented.  Number of treated lesions 
will be used as the denominator for percentage calculation. 
3.7.3 
Adverse Events 
All subjects will be assessed regularly for the potential occurrence of adverse events (AEs) 
from the date of informed consent to Visit 6.  The incidence of treatment-emergent AEs 
(TEAEs) will be defined for new or worsening events from the first study treatment until 30 


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days after the last study treatment.  Summaries will be conducted using MedDRA (version 
21.1), by System Organ Class (SOC) and Preferred Term (PT).   
An overview of adverse events for the ITT analysis set will be provided, summarizing the 
incidence of the following: 
• 
Count of TEAEs; 
• 
Subjects with TEAEs; 
• 
Count of Treatment-emergent serious AEs (TESAE); 
• 
Subjects with TESAE; 
• 
TEAE by maximum severity; 
• 
TESAE by maximum severity; 
• 
Subjects with TEAEs that lead to discontinuation of study; 
• 
Subjects with TESAEs that lead to discontinuation of study; 
• 
Subjects with Related TEAEs; 
• 
Subjects with Related TESAEs. 
3.7.4 
Laboratory Tests 
For each laboratory test, a summary will be provided for each visit.  The absolute value and 
its change from baseline will be descriptively presented.  
3.7.5 
Vital Signs 
Vital signs measurements include pulse rate, temperature, systolic blood pressure, and 
diastolic blood pressure.  Measures at baseline and changes from baseline to post baseline 
visit will be summarized.  The number and percentage of subjects with abnormal blood 
pressure will be summarized. 
3.8 
INTERIM ANALYSES 
There is no interim analyses planned for the study. 
 
 


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4 
CHANGES TO PLANNED ANALYSES 
After communications with the FDA, the sponsor is no longer persuing a separate indication 
for in patients with DPN.  Therefore, an abbreviated report will be produced for A-101-DPN-
201.  This abbreviated report will contain all the safety of a full report, but only the primary 
and key secondary efficacy analyses will be reported.  As a result, the following descriptive 
statistics mentioned in the protocol will not be produced: 
 Number and percentage of lesions by PLA score categories (clear, near-clear, small, 
and large): overall, separately for face or neck target lesions, separately for subjects 
with FST 5 and 6; 
 Summary statistics on PLA score (mean of all lesions): overall and separately for 
subjects with FST 5 and 6; 
 Summary statistics on percentage of lesions that are clear (PLA=0): overall, 
separately for face or neck target lesions, separately for subjects with FST 5 and 6; 
 Summary statistics on percentage of lesions that are clear or near clear (PLA=0 or 1): 
overall, separately for face or neck target lesions, separately for subjects with FST 5 
and 6; 
 Number and percentage of lesions by location (face, or neck): overall and separately 
for subjects with FST 5 and 6. 
Furthermore, the following hypothesis tests will not be performed: 
 Change in percentage of lesions that are clear (PLA=0) from baseline evaluation to 
the last evaluation of the lesions ANCOVA model; 
 Change in percent of lesions that are clear (PLA=0) or near-clear (PLA=1) from 
baseline evaluation to the last evaluation of the lesions ANCOVA model; 
 Change in longest lesion diameter from baseline to the last lesion measurement 
ANCOVA model; 
 
The protocol also states that efficacy summaries may be presented for the intent-to-treat 
(ITT) population using LOCF to impute missing data.  The primary endpoint will be 
summarized and analyzed for the ITT population using LOCF to impute missing data, but 
none of the other efficacy endpoints will be summarized or analyzed for the ITT population. 
 
Lastly, the ANCOVA model described in the protocol for the primary endpoint has been 
replaced with a repeated measures mixed model in order to capture changes over time in the 
primary efficacy endpoint and account for within subject correlation in the repeated measures 
over time.  The number of treated lesions is also being added as a covariate in the primary 
efficacy model and the logistic regression model for responders which was not considered in 
the protocol.