Conditions: Rheumatoid Arthritis
Keywords: Arthritis Rheumatoid
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 25
Healthy volunteers: no

Brief summary:
This is a Phase 2 study to investigate the safety, tolerability, PK, and PD of ATI-450 plus methotrexate versus methotrexate alone in patients with moderate to severe RA.

Detailed description:
This is a Phase 2, randomized, investigator and patient-blind, sponsor-unblinded, parallel group, placebo-controlled study to investigate the safety, tolerability, PK, and PD of ATI-450 plus methotrexate versus methotrexate alone in patients with moderate to severe RA with inadequate response to methotrexate. All subjects will be required to complete a safety follow up visit 30 days post last study medication administration.

Arms:
arm 1: ATI-450 50mg oral tablet BID with a stable weekly dose of Methotrexate arm 2: Placebo oral tablet BID with a stable weekly dose of Methotrexate

Interventions: intervention 1: ATI-450 intervention 2: Placebo oral tablet intervention 3: Methotrexate
Intervention descriptions: intervention 1: Oral, small molecule MK2 inhibitor intervention 2: Placebo tablet manufactured to match ATI-450 in appearance intervention 3: 7.5 mg to 25 mg weekly

Protocol document:
Prot_SAP_002.pdf: 




Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-450-RA-201 
Version and Date: 3.0, 27July2020 
Page 3 of 85
 
 
Confidential 
 
 
PROTOCOL SIGNATURE PAGE – INVESTIGATOR 
I have read this protocol, which has been agreed by Aclaris Therapeutics, Inc., and given 
approval/favorable opinion by the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC), and I agree that it contains all necessary details for my staff and I to 
conduct this study as described. I will provide copies of the protocol and any 
amendments to all study personnel under my supervision and provide access to all 
information provided by Aclaris Therapeutics, Inc., or their specified designees. I will 
discuss the material with the study personnel to ensure that they are fully informed about 
the study. I understand that information contained in or pertaining to this protocol is 
confidential and should not be disclosed, other than to those directly involved in the 
execution or the ethical review of the study, without written authorization from Aclaris 
Therapeutics, Inc. It is, however, permissible to provide information to a patient in order 
to obtain consent. 
I agree to conduct this study according to this protocol and to comply with its 
requirements, patient to ethical and safety considerations and guidelines, and to conduct 
the study in accordance with the Declaration of Helsinki, International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP), and applicable 
regional regulatory requirements. I agree to comply with the procedures described for 
data recording and reporting and to permit monitoring and auditing by Aclaris 
Therapeutics, Inc., and inspection by the appropriate regulatory authorities. 
I agree to make my patients’ study records available to Aclaris Therapeutics, Inc., 
personnel, their representatives and relevant regulatory authorities in order to verify data 
that I have entered into the case report forms (CRFs). I will retain the study-related 
essential documents until Aclaris Therapeutics, Inc indicates that they are no longer 
needed. I am aware of my responsibilities as an investigator as provided by Aclaris 
Therapeutics, Inc. I understand that Aclaris Therapeutics, Inc., may decide to suspend or 
prematurely terminate the study at any time for whatever reason; such a decision will be 
communicated to me in writing. Conversely, should I decide to withdraw from execution 
of the study, I will communicate my intention immediately in writing to Aclaris 
Therapeutics, Inc. 
 
 
 
 
Print Name 
 
 
Title 
 
Institution 
 
 
 
Signature 
 
Date 


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-450-RA-201 
Version and Date: 3.0, 27July2020 
Page 4 of 85
 
 
Confidential 
 
 
SERIOUS ADVERSE EVENT CONTACT INFORMATION 
In the event of an SAE, the investigator will send a safety report form within 24 hours of 
becoming aware of the SAE to: 
 
 
 
 
 


















Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-450-RA-201 
Version and Date: 3.0, 27July2020 
Page 13 of 85
 
 
Confidential 
 
 
PROTOCOL SUMMARY 
 
Protocol Number: ATI-450-RA-201 
Protocol Title: A Phase 2a, Randomized, Investigator and Patient-blind, Sponsor-unblinded, Parallel 
Group, Placebo-controlled Study to Investigate the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of ATI-450 Plus Methotrexate (MTX) vs MTX Alone in Patients with Moderate to 
Severe Active Rheumatoid Arthritis with Inadequate Response to MTX 
Sponsor: Aclaris Therapeutics, Inc.  
Study Phase: Phase 2a 
Study Sites: 
 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
• 
To assess the safety and 
tolerability of ATI-450 plus 
MTX in patients with moderate 
to severe rheumatoid arthritis 
(RA) 
• 
Number and percent of adverse 
events (AEs) and serious adverse 
events (SAEs); mean change from 
baseline in laboratory values, vital 
signs, and electrocardiograms 
(ECGs) 
Secondary 
• 
To assess the 
pharmacodynamics (PD) of 
ATI-450 plus MTX in patients 
with moderate to severe RA 
 
• 
Median percent change from 
baseline in high sensitivity 
C-reactive protein (hsCRP) levels 
over time 
• 
Mean change from baseline in 
Disease Activity Score using 28 
joint count-C-reactive protein (CRP) 
(DAS28-CRP) over time 
• 
Proportion of patients with 
DAS28-CRP below 2.6 
• 
Mean change from baseline in 
Rheumatoid Arthritis Magnetic 
Resonance Imaging Score 
(RAMRIS) Hand-Wrist assessments 
of synovitis or osteitis at Week 12 
• 
Proportion of patients with 
American College of Rheumatology 
(ACR)20/50/70 over time 
 
• 
To assess the pharmacokinetics 
(PK) of ATI-450 in patients with 
moderate to severe RA who are 
receiving concomitant MTX 
• 
ATI-450 concentrations at trough 
and 2 hours post-dose 


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-450-RA-201 
Version and Date: 3.0, 27July2020 
Page 14 of 85
 
 
Confidential 
 
 
Exploratory 
• 
To assess the PD of ATI-450 
plus MTX in patients with 
moderate to severe RA 
• 
Mean change from baseline in 
endogenous cytokine levels (e.g., 
tumor necrosis factor-α [TNF-α], 
interleukin [IL]-1β, IL-6, IL-8, 
IFNγ, IL-17, IL-18, IL-10, IL-1α 
and IL-1RA)  
• 
Mean change from pre-dose in ex 
vivo stimulated cytokine levels (e.g., 
TNF-α, IL-1β, IL-6, IL-8, IFNγ, 
IL-17, IL-18, IL-10, IL-1RA, and 
IL-1α) 
• 
Ex vivo stimulated phosphoprotein 
modulation 
• 
Mean change from baseline in the 
cartilage loss score (CARLOS) 
Hand-Wrist magnetic resonance 
imaging (MRI) assessment of 
cartilage loss 
Study Design: 
This is a Phase 2, randomized, investigator and patient-blind, sponsor-unblinded, parallel group, 
placebo-controlled study to investigate the safety, tolerability, PK, and PD of ATI-450 plus MTX 
versus MTX alone in patients with moderate to severe RA.  
The study will consist of an up to 28-day screening period, a 12-week treatment period, and a 4-week 
follow-up period. The total duration of the study for patients remaining until their final follow-up 
assessment will be up to 20 weeks. 
The investigator will obtain signed informed consent from the patient before any study procedures are 
performed. 
During the screening period, each patient will be required to have all assessments performed as 
outlined in the Schedule of Assessments. The MRI is not to be performed until the site obtains the 
results of the patient’s hsCRP level to ensure that this assessment meets the entry criteria prior to 
performing the MRI. The patient will have the RAMRIS Hand-Wrist MRI assessment performed at 
their local institution and evaluated by a central radiology review team to determine if they meet the 
radiological inclusion criteria. Results for all of the screening assessments must be available at the time 
patient eligibility is reconfirmed prior to randomization and dosing. 
Patients whose eligibility is confirmed at baseline will be randomized in a 3:1 ratio to receive either 
ATI-450 tablets (50 mg twice daily [BID]) plus MTX, or matching placebo tablets plus MTX. Study 
medications will be administered orally for 12 weeks. Patients will be required to remain on a stable 
dose of MTX (7.5 mg to 25 mg/week) for the duration of the study.  
Patients will attend clinic visits on Days 7, 14, 28, 42, 56, and 84 (±1 day) for safety, efficacy, PK, and 
PD assessments. The morning dose of study medication will be administered in the clinic on each study 
visit day. 
At the completion of 4 weeks of treatment (Day 28), each patient’s safety data (e.g., AEs, laboratory 
values, vital signs, and ECGs) will be reviewed by the Aclaris medical monitor and Aclaris safety 
physician to ensure that the patient is tolerating the treatment regimen and is deemed suitable to 
continue treatment for the next 8 weeks. 


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-450-RA-201 
Version and Date: 3.0, 27July2020 
Page 15 of 85
 
 
Confidential 
 
 
On Day 84 (Week 12), patients will complete the end of study assessments. A safety follow-up visit 
will be conducted 30 days (+7) after the last dose of study medication.  
The study is randomized and blinded to the investigator, patient, site personnel, and sponsor 
representatives responsible for clinical monitoring at the investigational to prevent bias in treatment 
allocation and in the assessment of treatment effect. The Aclaris statistician, medical and safety 
monitor will be unblinded to each patient’s treatment assignment. 
Study Duration:  
The start of the study will be the date on which the first patient provides informed consent, and the end 
of the study will be the date of the last patient’s last assessment.  
Planned Number of Patients: It is planned to enroll 25 patients in order to obtain 15 evaluable 
patients. An evaluable patient is a patient who meets all entry criteria and completes 12 weeks of 
treatment. 
Target Population:  
Inclusion Criteria 
Patients must meet the following criteria to be eligible for participation in the study: 
1. Able to comprehend and be willing to sign the Institutional Review Board (IRB)-approved 
subject informed consent form (ICF) prior to administration of any study-related procedures. 
2. Diagnosis of adult-onset RA as defined by the 2010 American College of 
Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria.  
  
 
 
6. Patients must have definitive intra-articular synovitis or osteitis defined as a score of 1 or 
greater on a Hand-Wrist MRI as assessed by central imaging reader (using RAMRIS). 
7. On a stable   MTX dose (defined as 7.5 mg to 25 mg weekly) and a stable dose of folic or 
folinic acid (defined as ≥ 5mg/week) for at least 4 weeks prior to the screening visit. 
8. Male or non-pregnant, non-nursing female patients between 18 and 70 years of age, inclusive.  
• 
Female patients who are of childbearing potential must use 2 methods of highly 
effective contraception* - one of which must be a physical barrier- for the duration of 
the study and for 30 days after the last dose  
• 
Male patients of childbearing potential with a female partner of childbearing potential 
must agree to use a condom plus another highly effective form of birth control for the 
duration of the study and for 90 days after the last dose  
9. Female patients must have a negative serum pregnancy test at screening and a negative urine 
pregnancy test prior to dosing on Day 1. 
10. Screening laboratory evaluations (hematology, chemistry, coagulation, and urinalysis) must 
fall within the normal range of the central laboratory's reference ranges unless the results have 
been determined by the investigator to not be clinically significant. 
11. Willing and capable of taking appropriate coronavirus disease 2019 (COVID-19) risk 
mitigation precautions (e.g., wearing a mask in public, adhering to social distancing, etc.) as 
recommended or required by local, state, or federal guidelines during participation in the study. 


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-450-RA-201 
Version and Date: 3.0, 27July2020 
Page 16 of 85
 
 
Confidential 
 
 
*Highly effective birth control is defined as those which result in a low failure rate (i.e., less than 1% 
per year) when used consistently and correctly such as implants, injectables, combined oral 
contraceptives, some intrauterine devices, heterosexual abstinence, or vasectomized. The requirements 
for highly effective birth control do not apply to female patients of nonchildbearing potential (i.e., 
physiologically incapable of becoming pregnant) defined as: 
• 
Has had a complete hysterectomy greater than or equal to 3 months prior to dosing or 
• 
Has had a bilateral oophorectomy (ovariectomy) or 
• 
Has had a bilateral tubal ligation or fallopian tube inserts or 
• 
Is postmenopausal (i.e., cessation of regular menses for at least 12 consecutive months with no 
alternative pathological or physiological cause and have a serum follicle-stimulating hormone 
(FSH) level >40 mIU/mL) or 
• 
Medically documented ovarian failure 
 
Exclusion Criteria 
A patient who meets any of the following exclusion criteria will not be eligible for inclusion in the 
study: 
1. Patient has a current acute or chronic immunoinflammatory disease other than RA which may 
impact the course or assessment of RA. 
2. Patient has an uncontrolled non-immunoinflammatory disease that may place the patient at 
increased risk during the study or impact the interpretation of results. 
3. History or evidence of active or latent tuberculosis. 
4. Known hypersensitivity to MTX or ATI-450. 
5. Patient has a history of either alcoholism/current alcoholic, alcoholic liver disease, or other 
chronic liver disease. 
6. Active infection requiring treatment with antibiotics. 
7. Positive for HIV, hepatitis B or C. Patients with serologic evidence of hepatitis B vaccination 
(hepatitis B surface antibody without the presence of hepatitis B surface antigen) will be 
allowed to participate. 
8. Tests performed at a central laboratory at screening that meet any of the criteria below (out of 
range labs may be rechecked one time, after consultation with sponsor or designee, before 
patient is considered a screen failure): 
• 
White blood cell count <3.0×103 cells/mm3  
• 
Absolute neutrophil count <1.5×103 cells/mm3 
• 
Lymphocyte count <0.5×103 cells/mm3  
• 
Platelet count <100×103 cells/mm3  
• 
Hemoglobin <10 g/dL  
• 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
≥1.5×upper limit of normal (ULN) 




Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-450-RA-201 
Version and Date: 3.0, 27July2020 
Page 18 of 85
 
 
Confidential 
 
 
• 
Evidence of atrial fibrillation, atrial flutter, complete right or left bundle branch block, 
Wolff-Parkinson-White Syndrome, or other significant rhythm disturbance 
• 
Evidence of acute ischemia 
• 
Screening or pre-dose baseline mean QTcF >450 msec for males or >470 msec for 
females (use of the ECG algorithm is acceptable for this purpose)  
• 
Personal or family history of congenital long QT syndrome or sudden death 
• 
Any other finding that is considered clinically significant 
19. Any joint procedure in the past 90 days prior to screening. 
20. Known exposure to an individual with a confirmed diagnosis of COVID-19 at any time during 
the screening period. 
21. Vaccination with a live or attenuated vaccine within 6 weeks prior to Baseline (Visit 2) or 
planned vaccination with these vaccines at any time during treatment or within 6 weeks 
following discontinuation of study medication. 
 
Test Product: 
Name: ATI-450 (50 mg) 
Dose: 50 mg BID 
Mode of administration: Oral tablets 
Concomitant Product 
Name: Methotrexate (MTX) 
Dose: Patients are to remain on their stable dose of MTX (defined as 7.5 mg to 25 mg per week) 
throughout the 12-week treatment period 
Mode of administration: Oral tablets 
Control Product: 
Name: Placebo 
Dose: 0 mg; administered BID 
Mode of administration: Oral tablets 
Statistical Methods:  
Details of all statistical summaries will be provided in the study-specific statistical analysis plan (SAP). 
Analyses will be performed using SAS® (SAS Institute, Cary, NC, US) by the sponsor or its 
representatives. 
The SAP will be approved prior to any lock of the study database and unblinding of the study data. The 
SAP will provide a detailed description of the statistical methods and expand on the details provided in 
the protocol. 
All data will be presented by treatment group. Descriptive statistics (number of observations, mean, 
standard deviation, median, minimum, and maximum) will be provided for continuous variables, and 
counts and percentages will be presented for categorical variables. 


Sponsor Name: Aclaris Therapeutics, Inc. 
Protocol Number: ATI-450-RA-201 
Version and Date: 3.0, 27July2020 
Page 19 of 85
 
 
Confidential 
 
 
Baseline is defined as the last non-missing measurement before or on the date of first administration of 
study medication. 
Determination of Sample Size 
The sample size for this study was determined based upon feasibility constraints as opposed to a formal 
power computation. Approximately 25 patients are planned to be enrolled with the expectation that at 
least 15 patients will complete the 12-weeks of treatment. 
Interim Analyses 
This study is being conducted as a sponsor-unblinded study. The safety and efficacy will be assessed 
on an ongoing basis during the conduct of the trial via multiple unblinded interim analyses. The 
frequency of the interim analyses will be approximately weekly depending upon the rate of enrollment. 
Since there is no formal statistical hypothesis, there will be no alpha spending adjustment made for 
multiple analyses. There is no scenario for which the study would be stopped early for efficacy.  
Analysis Populations 
• 
The Safety population will include all patients who have been administered at least one dose of 
study medication. 
• 
The Intent-to-treat (ITT) population will include all randomized patients. 
• 
The Per-Protocol population will include all patients who have completed their Day 84 visit 
and have valid hsCRP values for at least 6 of the 7 scheduled collection times. 
• 
The PK population will include all patients who receive at least 1 dose of ATI-450 and provide 
at least one plasma concentration value.   
Efficacy Analyses 
All efficacy summaries will be conducted on both the ITT and Per-Protocol populations. 
• 
The hsCRP levels, change from baseline in hsCRP and percent change from baseline in hsCRP 
will be summarized over time using continuous statistical summary measures. Determination 
of sustained treatment effect for hsCRP will be based upon the median percent change from 
baseline in hsCRP over time in the Per-Protocol population.  
• 
The DAS28-CRP, RAMRIS and CARLOS Hand Assessments, 66/68 swollen/tender joint 
count, Patient’s Global Assessment of Disease Activity, Patient’s Assessment of Arthritis Pain, 
and Physicians Global Assessment of Disease Activity, as well as their corresponding changes 
from baseline will be summarized over time (for all scheduled timepoints) using continuous 
statistical summary measures. The focus of the MRI analyses will be the synovitis and osteitis 
scores.  
• 
The number and proportion of patients with DAS28-CRP <2.6 and the number and proportion 
of patients meeting American College of Rheumatology (ACR) 20/50/70 will be tabulated at 
each scheduled visit, separately. 
Safety Analyses 
The Safety population will be used for the analysis of safety data (AEs, exposure to study medication, 
clinical laboratory values, vital signs, and ECG). 
 
AEs will be coded with the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-
emergent adverse events (TEAEs) are defined as AEs with an onset date on or after the date of first 
administration of study medication and through the completion of the last follow up visit or the date of 
last administration of study medication + 30 days (whichever occurs later). TEAEs will be presented by 
system organ class and preferred term in frequency tables. Patients with multiple AEs will be counted 




Sponsor Name: Aclaris Therapeutics, Inc. 
 
Protocol Number: ATI-450-RA-201 
 
Version and Date: 3.0, 27July2020   
 
 
Page 21 of 85 
 
 
           Confidential 
 
SCHEDULE OF ASSESSMENTS 
Table 1 
Schedule of Assessments 
Assessment 
Screening 
Visit 1 
Day -28 to 
Day -1 
Visit 2 
Baseline 
Day 1 
Visit 3 
Day 7 
Visit 4 
Day 14 
Visit 5 
Day 28 
Visit 6 
Day 42 
Visit 7 
Day 56 
Visit 8 
Day 84 
(Week 12) 
Visit 9 
Follow-up 
30 days 
(+ 7 days) 
 
 
 
+/-1 day 
 
Informed Consent  
X 
 
 
 
 
 
 
 
 
Eligibility Review 
X 
X 
 
 
 
 
 
 
 
RA and Other Medical 
History and Demographics 
X 
 
 
 
 
 
 
 
 
QuantiFERON Gold Test 
for TB 
X 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
X 
Full Physical Exam1 
X 
 
 
 
 
 
 
X 
X 
Limited Physical Exam 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 Testing by 
RT-PCR 
 
X 
 
 
 
 
 
 
 
HIV and Hep Screen 
X 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
 
 
X 
 
 
X 
X 
Hematology, Coagulation, 
Chemistry, Lipids, and 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
hsCRP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 












Sponsor Name: Aclaris Therapeutics Inc. 
Protocol Number: ATI-450-RA-201 
Version and Date: 3.0, 27July2020 
Page 27 of 85
 
 
Confidential 
 
LIST OF ABBREVIATIONS 
 
ACR 
American College of Rheumatology 
ACR/EULAR 
American College of Rheumatology/European League Against 
Rheumatism 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ATF2 
activating transcription factor 2 
AUC 
area under the concentration-time curve 
AUC0-α 
area under the concentration-time curve from time zero to infinity 
β-hCG 
beta human chorionic gonadotrophin 
BID 
twice daily 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CARLOS 
cartilage loss score 
CFR 
Code of Federal Regulations 
Cmax 
maximum plasma concentration 
COVID-19 
coronavirus disease 2019 
CRF 
case report form  
CRP 
C-reactive protein 
CSR 
clinical study report 
DAS 
Disease Activity Score 
DAS28-CRP 
Disease Activity Score using 28 joint count-C-reactive protein 
DMARD 
disease-modifying antirheumatic drugs 
ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration rate 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 


Sponsor Name: Aclaris Therapeutics Inc. 
Protocol Number: ATI-450-RA-201 
Version and Date: 3.0, 27July2020 
Page 28 of 85
 
 
Confidential 
 
HAQ-DI 
Health Assessment Questionnaire – Disability Index 
HIPAA 
Health Insurance Portability and Accountability Act 
hsCRP 
high sensitivity C-reactive protein 
IB 
Investigator's Brochure 
IC 
Inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IEC 
Independent Ethics Committee 
IL 
interleukin 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
JAK 
Janus kinase 
LPS 
lipopolysaccharide 
MAPK 
mitogen-activated protein kinase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MK2 
MAPK-activated protein kinase 2 
MRI 
magnetic resonance imaging 
MTX 
methotrexate 
NOMID 
neonatal-onset multisystem inflammatory disease 
NSAIDS 
non-steroidal anti-inflammatory drugs 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PRAK 
p38α-related/activated protein kinase 
QTL 
quality tolerance limits 
RA 
rheumatoid arthritis 
RAMRIS 
Rheumatoid Arthritis Magnetic Resonance Imaging Score 
RT-PCR 
reverse transcription polymerase chain reaction 
SAE 
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SAP 
statistical analysis plan 


Sponsor Name: Aclaris Therapeutics Inc. 
Protocol Number: ATI-450-RA-201 
Version and Date: 3.0, 27July2020 
Page 29 of 85
 
 
Confidential 
 
t1/2 
half-life 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum plasma concentration 
TMF 
trial master file 
TNFα 
tumor necrosis factor-α 
ULN 
upper limit of normal 
VAS 
visual analog scale 
WBC 
white blood cell 














Sponsor Name: Aclaris Therapeutics Inc. 
Protocol Number: ATI-450-RA-201 
Version and Date: 3.0, 27July2020 
Page 36 of 85
 
 
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2 STUDY OBJECTIVES AND ENDPOINTS 
The objectives and endpoints for this study are provided in Table 2 below.  
Table 2 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To assess the safety and 
tolerability of ATI-450 plus 
MTX in patients with moderate 
to severe RA 
• 
Number and percent of AEs and 
SAEs; mean change from baseline in 
laboratory values, vital signs, and 
ECGs 
Secondary 
• 
To assess the PD of ATI-450 
plus MTX in patients with 
moderate to severe RA 
 
• 
Median percent change from 
baseline in high sensitivity 
C-reactive protein (hsCRP) levels 
over time 
• 
Mean change from baseline in 
Disease Activity Score using 
28 joint count-C-reactive protein 
(DAS28-CRP) over time 
• 
Proportion of patients with 
DAS28-CRP below 2.6 
• 
Mean change from baseline in 
Rheumatoid Arthritis Magnetic 
Resonance Imaging Score 
(RAMRIS) Hand-Wrist assessments 
of synovitis or osteitis at Week 12 
• 
Proportion of patients with 
American College of Rheumatology 
(ACR)20/50/70 over time 
 
• 
To assess the PK of ATI-450 in 
patients with moderate to severe 
RA who are receiving 
concomitant MTX 
• 
ATI-450 concentrations at trough 
and 2 hours post-dose  
Exploratory 
• 
To assess the PD of ATI-450 
plus MTX in patients with 
moderate to severe RA 
• 
Mean change from baseline in 
endogenous cytokine levels (e.g. 
TNF-α, IL-1β, IL-6, IL-8. IFNγ, IL-
17, IL-18, IL-10, IL-1α, and IL-
1RA)  
• 
Mean change from pre-dose in ex 
vivo stimulated cytokine levels (e.g. 
TNF-α, IL-1β, IL-6, IL-8, IFNγ, IL-
17, IL-18, IL-10, IL-1RA and IL-1α) 
• 
Ex vivo stimulated phosphoprotein 
modulation 


Sponsor Name: Aclaris Therapeutics Inc. 
Protocol Number: ATI-450-RA-201 
Version and Date: 3.0, 27July2020 
Page 37 of 85
 
 
Confidential 
 
• 
Mean change from baseline in the 
cartilage loss score (CARLOS) 
Hand-Wrist magnetic resonance 
imaging (MRI) assessment of 
cartilage loss 
 


Sponsor Name: Aclaris Therapeutics Inc. 
Protocol Number: ATI-450-RA-201 
Version and Date: 3.0, 27July2020 
Page 38 of 85
 
 
Confidential 
 
3 STUDY PLAN 
3.1 
Overall Study Design and Plan 
The study visit schedule and planned assessments at each visit are detailed in Table 1. 
This is a Phase 2a, randomized, investigator- and patient-blind, sponsor-unblinded, 
parallel group, placebo-controlled study to investigate the safety, tolerability, PK, and PD 
of ATI-450 plus MTX versus MTX alone in patients with moderate to severe RA.  
Approximately 25 patients are planned to be enrolled with the expectation that at least 
15 patients will complete the 12-weeks of treatment. The study will consist of an up to 
28-day screening period, a 12-week treatment period, and a 4-week follow-up period. 
The total duration of the study for patients remaining in the study until their final 
follow-up assessment will be up to 20 weeks. 
The investigator will obtain signed informed consent from the patient before any study 
procedures are performed. For further details regarding the informed consent process, see 
Section 9.3. 
During the screening period each patient will be required to have all assessments 
performed as outlined in the Schedule of Assessments (Table 1). The MRI is not to be 
performed until the site obtains the results of the patient’s hsCRP level to ensure that this 
assessment meets entry criteria prior to performing the MRI. The patient will have the 
RAMRIS Hand-Wrist assessment performed at their local institution and evaluated by a 
central radiology review team to determine if they meet the radiological inclusion 
criteria. Results for all of the screening assessments must be available at the time patient 
eligibility is reconfirmed prior to randomization and dosing. 
Patients whose eligibility is confirmed at baseline will be randomized in a 3:1 ratio to 
receive either ATI-450 tablets (50 mg BID) plus MTX, or matching placebo tablets plus 
MTX. Study medications will be administered orally for 12 weeks. Patients will be 
required to remain on a stable dose of MTX (7.5 mg to 25 mg/week) and a stable dose of 
folic or folinic acid (≥ 5mg/week) for the duration of the study.  
Patients will attend clinic visits on Days 7, 14, 28, 42, 56, and 84 (±1 day) for safety, 
efficacy, PK, and PD assessments. The morning dose of study medication will be 
administered in the clinic on each study visit day. 
After 4 weeks of treatment (Day 28), each patient’s safety data (e.g., AEs, laboratory 
values, vital signs, ECGs) will be reviewed by the Aclaris medical monitor and the 
Aclaris safety physician to ensure that the patient is tolerating the treatment regimen and 
is deemed suitable to continue treatment for the next 8 weeks. This review is described in 
more detail in the study-specific safety management plan.  


Sponsor Name: Aclaris Therapeutics Inc. 
Protocol Number: ATI-450-RA-201 
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End of study assessments will be conducted on Day 84 (Week 12). A safety follow-up 
visit will be conducted 30 days (+7 days) after the last dose of study medication. 
The study is randomized and blinded to the investigator, patient, site personnel and 
Aclaris clinical monitors involved in site and patient monitoring with regard to ATI-450 
and placebo to prevent bias in treatment allocation and in the assessment of treatment 
effect. See Section 6.2 for details on access to the treatment codes in the event of 
emergency unblinding. The Aclaris statistician, medical and safety monitor will be 
unblinded to each patient’s treatment assignment. 
3.2 
Discussion of Study Design 
The study is designed to assess the safety and tolerability of ATI-450 in a relevant patient 
population (i.e., patients with RA). 
The study will also describe the PK and PD of ATI-450 in a relevant disease. The 
efficacy hypothesis to be explored is described in Section 1.2 and provides justification 
for recruiting a population with active RA and elevated hsCRP.  
Investigator and patient blinding will maintain integrity for assessments of safety and 
AEs. The 3:1 randomization schedule will maximize the number of patients receiving 
active drug to allow for a more robust assessment for the change from baseline in hsCRP. 
The 12-week treatment period is sufficient to explore the tachyphylaxis signal (observed 
within that timeframe by p38 MAPK inhibitors). Treatment of all patients with MTX 
ensures that all patients will receive active treatment for their RA throughout the study. 
3.3 
End of Study 
A patient is considered to have completed the study if he/she has completed all study 
visits. The end of the study is defined as the date of the last visit or date of last procedure 
of the last patient in the study. 




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distancing, etc.) as recommended or required by local, state, or federal guidelines 
during participation in the study. 
*Highly effective birth control is defined as those which result in a low failure rate (i.e., 
less than 1% per year) when used consistently and correctly such as implants, injectables, 
combined oral contraceptives, some intrauterine devices, heterosexual abstinence, or 
vasectomized. The requirements for highly effective birth control do not apply to female 
patients of nonchildbearing potential (i.e., physiologically incapable of becoming 
pregnant) defined as: 
• Has had a complete hysterectomy greater than or equal to 3 months prior to 
dosing or 
• Has had a bilateral oophorectomy (ovariectomy) or 
• Has had a bilateral tubal ligation or fallopian tube inserts or 
• Is postmenopausal (i.e., cessation of regular menses for at least 12 consecutive 
months with no alternative pathological or physiological cause and have a serum 
follicle-stimulating hormone (FSH) level >40 mIU/mL) or 
• Medically documented ovarian failure 
4.2 
Exclusion Criteria 
A patient who meets any of the following exclusion criteria will not be eligible for 
inclusion in the study: 
1. Patient has a current acute or chronic immunoinflammatory disease other than RA 
which may impact the course or assessment of RA. 
2. Patient has an uncontrolled non-immunoinflammatory disease that may place the 
patient at increased risk during the study or impact the interpretation of results. 
3. History or evidence of active or latent tuberculosis (TB). 
4. Known hypersensitivity to MTX or ATI-450. 
5. Patient has either a history of alcoholism/current alcoholic, alcoholic liver disease, 
or other chronic liver disease. 
6. Active infection requiring treatment with antibiotics. 
7. Positive for HIV, hepatitis B or C. Patients with serologic evidence of hepatitis B 
vaccination (hepatitis B surface antibody without the presence of hepatitis B 
surface antigen) will be allowed to participate. 
8. Tests performed at a central laboratory at screening that meet any of the criteria 
below (out of range labs may be rechecked one time, after consultation with 
sponsor or designee, before patient is considered a screen failure): 
• White blood cell (WBC) count <3.0×103 cells/mm3  


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• ANC <1.5×103 cells/mm3 
• Lymphocyte count <0.5×103 cells/mm3  
• Platelet count <100×103 cells/mm3  
• Hemoglobin <10 g/dL  
• Aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) ≥1.5×upper limit of normal (ULN) 
• Total bilirubin level >2×ULN unless the patient has been diagnosed 
with Gilberts’ disease and this is clearly documented 
• Estimated glomerular filtration rate (eGFR), <40 mL/min/1.73m2 
based on Modification of Diet and Renal Disease formula 
9. Any clinically significant laboratory abnormality that would affect interpretation 
of study data or safety of the patient’s participation in the study, per judgment of 
investigator. 
10. Patient has clinically significant abnormal findings other than RA from physical 
examination conducted at screening visit (Visit 1) and at baseline visit (Visit 2) 
that may affect the interpretation of study data or the safety of the patient’s 
participation in the study, per the judgment of the investigator. 
11. Patient has a clinically important history of a medical disorder that would 
compromise patient safety or data quality (per investigator's judgment). 
12. Blood pressure levels (in supine position after at least 5 minutes rest): <90 mmHg 
or >140 mmHg for systolic blood pressure or <40 mmHg or >90 mmHg for 
diastolic blood pressure. 
13. Has taken any of the following within the defined time period prior to screening 
visit: 
• Conventional synthetic disease-modifying antirheumatic drugs 
(DMARDs) (leflunomide, cyclosporine, azathioprine): 30 days 
• Rituximab or other B cell inhibitors: 6 months  
• Biologic DMARDs (infliximab, golimumab, adalimumab, certolizumab 
pegol, abatacept, and tocilizumab): 8 weeks  
• Etanercept and anakinra:  4 weeks 
• Janus kinase (JAK) inhibitors: 30 days  
• Investigational small molecules: 30 days 


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• Intra-articular corticosteroid injection: 30 days  
14. Are currently receiving corticosteroids at doses greater than 10 mg per day of 
prednisone (or equivalent) or have been receiving an unstable dosing regimen of 
corticosteroids within 2 weeks of the screening visit.  
15. Have started treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or 
have been receiving an unstable dosing regimen of NSAIDs within 2 weeks of the 
screening visit. 
16. Patients with history of stroke. 
17. Significant cardiac disease that would affect interpretation of study data or the 
safety of the patient’s participation in the study, per judgment of the investigator, 
including recent myocardial infarction or unstable angina, or heart failure with 
New York Heart Association Class III or IV symptoms. 
18. Patients with the following screening or pre-dose ECG findings, specifically: 
• Evidence of atrial fibrillation, atrial flutter, complete right or left bundle 
branch block, Wolff-Parkinson-White Syndrome, or other significant 
rhythm disturbance 
• Evidence of acute ischemia 
• Screening or pre-dose baseline mean QTcF >450 msec for males or 
>470 msec for females (use of the ECG algorithm is acceptable for this 
purpose) 
• Personal or family history of congenital long QT syndrome or sudden 
death 
• Any other finding that is considered clinically significant 
19. Any joint procedure in past 90 days prior to screening 
20. Known exposure to an individual with a confirmed, active diagnosis of  
COVID-19 at any time during the screening period. 
21. Vaccination with a live or attenuated vaccine within 6 weeks prior to Baseline 
(Visit 2) or planned vaccination with these vaccines at any time during treatment 
or within 6 weeks following discontinuation of study medication. 
4.3 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but 
who do not meet 1 or more criterion required for participation and are not subsequently 
randomized to treatment in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure patients, to meet the 
Consolidated Standards of Reporting Trials publishing requirements, and to respond to 


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queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any SAE(s). 
Individuals who are screen failures due to out of range laboratory values can be retested 
once during the 28-day screening period. If the repeated lab values remain exclusionary, 
the subject will be considered a screen failure. Redrawing samples if previous samples 
were unable to be analyzed would not count as a retest since the previous result was 
never obtained.  
Patients that screen fail for the study may be re-screened at a later date (i.e., after the 28-
day screening window has expired) following re-consent. A new patient ID must be 
assigned in this instance. 
4.4 
Premature Discontinuation 
4.4.1 
Premature Discontinuation of Investigational Product 
Patients should discontinue the study medication if any of the following occurs:  
 
• Confirmed, active infection with the severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) virus 
• Serious infection  
• Invasive fungal infection 
• Malignancy (except for non-melanoma skin cancer)  
• Hepatitis B virus reactivation 
• Demyelinating disease 
• Heart failure 
• Lupus-like syndrome 
• Hypersensitivity reaction 
• Gastrointestinal perforation 
• WBC count: <1×103/µL 
• ANC: <0.5×103/µL 
• Lymphocyte count: <0.3×103/µL 
• Platelet count: <50×103/µL 
• Hemoglobin: <6.5 g/dL 


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• AST or ALT: 
o >5×ULN persisting for 2-weeks after study medication interruption or 
second occurrence of >5×ULN 
o >3×ULN and (total bilirubin >2×ULN or international normalized ratio 
[INR] >1.5) 
o >3×ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%) 
• Serum creatinine: >2×ULN persisting for 2-weeks after study medication 
interruption or second occurrence of >2×ULN  
• The patient withdraws his/her consent to participate in the study. 
• The patient develops an illness that would interfere with his/her continued 
participation in the study. 
• The patient is noncompliant with study procedures or medication, in the opinion 
of the investigator. 
• The patient is confirmed to be pregnant. 
• The sponsor or regulatory agency requests withdrawal of the patient. 
The investigator will make every effort to ensure that patients who prematurely 
discontinue study medication complete the Day 84, end of study assessments. 
Patients who discontinue study medication prematurely may be replaced at discretion of 
the sponsor. 
4.4.2 
Premature Discontinuation from the Study 
Participation in the study is strictly voluntary. A patient has the right to withdraw from 
the study at any time for any reason, without any reprisal. 
The investigator has the right to terminate participation of a patient for any of the 
following reasons:  
• Difficulties in obtaining blood samples 
• Violation of the protocol 
• Severe AEs or SAEs  
• Any other reason relating to the patient's safety or integrity of the study data 


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If a patient is withdrawn from the study, the study monitor/sponsor will be informed 
immediately. If there is a medical reason for withdrawal, the patient will remain under the 
supervision of the investigator until satisfactory health has returned. 
If the patient withdraws consent for disclosure of further information, the sponsor may 
retain and continue to use any collected data before such a withdrawal of consent. If a 
patient withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
Although a patient is not obliged to give his/her reason(s) for withdrawing prematurely 
from a study, the investigator should make a reasonable effort to ascertain the reason(s), 
while fully respecting the patient's rights. 
At the time of premature study discontinuation, the investigator should make every effort 
to ensure the patient completes the assessments indicated at the end of study (Week 12) 
visit; see Table 1. 
Patients who prematurely discontinue from the study cannot subsequently rejoin the 
study. For details on the discontinuation of study sites or the study as a whole, see 
Section 14. 
4.4.3 
Lost to Follow-up 
A patient will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the patient and reschedule the missed visit as 
soon as possible, counsel the patient on the importance of maintaining the 
assigned visit schedule, and ascertain whether or not the patient wishes to and/or 
should continue in the study. 
• Before a patient is deemed lost to follow-up, the investigator (or designee) must 
make every effort to regain contact with the patient (where possible, 2 telephone 
calls and, if necessary, a certified letter to the patient’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
patient’s research record. 
• Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 


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5 DESCRIPTION OF STUDY ASSESSMENTS 
Refer to Table 1 for the Schedule of Assessments. 
5.1 
Demographics and Other Screening Assessments 
Screening assessments that are also part of the safety assessments are described in 
Section 5.3. 
5.1.1 
Medical History 
Relevant medical history and current medical condition, including RA disease phenotype 
and duration as well as date of first diagnosis and previous treatments including any 
previous biologic or non-biologic therapy for RA will be recorded in the electronic case 
report form (eCRF).  
At the baseline visit, inclusion/exclusion criteria will be reviewed and updated to ensure 
the patient remains qualified for the study. Significant findings that are observed after the 
patient has signed the ICF and prior to the first dose of study medication will be recorded 
as medical history on the eCRF. Any event observed after the patient has signed the ICF 
that meets the definition of a SAE will be recorded on the SAE eCRF.   
5.1.2 
Demographics 
Demographic data, including year of birth/age, sex (at birth), and race, will be recorded in 
the eCRF. 
5.1.3 
Tuberculosis Test 
An interferon-gamma release assay/QuantiFERON TB Gold test for active/latent TB will 
be performed at screening with analysis conducted by the sponsor’s designated central 
laboratory. Patients with a negative test result will be eligible for the study.  
In case of indeterminate results, the test may be repeated once. The patient can be 
included in the study if the repeat test is negative; however, if the repeat test is positive or 
indeterminate, the patient will be excluded from the study. 
5.1.4 
Screening Clinical Laboratory Assessments 
Blood samples will be collected for clinical chemistry, coagulation, hematology, hsCRP, 
lipids, FSH, hepatitis B surface antigen, hepatitis B core antibody, hepatitis C antibody, 
and HIV-1/HIV-2. A serum pregnancy test will be performed on women of childbearing 
potential. All laboratory analyses will be performed by the sponsor’s designated central 
laboratory. 










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processing, storage and shipment of samples for hsCRP will be provided in a separate 
laboratory manual.  
5.3 
Safety Assessments 
5.3.1 
Adverse Events 
AEs will be followed, recorded, and reported in line with the procedures described in 
Section 7. 
5.3.2 
Clinical Laboratory Evaluations 
Laboratory assessments will be performed by a central laboratory. Blood and urine 
samples will be collected at the times indicated in Table 1. On dosing day(s), sampling 
for the analysis of clinical laboratory parameters will be performed before the 
administration of study medication. 
Unless indicated otherwise, all laboratory samples will be processed and shipped to the 
central laboratory, as described in the central laboratory manual. The central laboratory 
will analyze the samples or send them to reference laboratory(ies) for analysis, as 
indicated in the manual. Refer to the central laboratory manual for the maximum total 
volume of blood to be collected per patient throughout the study. 
The following parameters will be assessed:  
Hematology: hemoglobin, hematocrit, red blood cells, platelets, total WBC count, 
differential WBC count, and ANC 
Coagulation: INR, partial thromboplastin time, and prothrombin time 
Biochemistry: albumin, alkaline phosphatase (ALP), ALT, amylase, AST, blood urea 
nitrogen (BUN), calcium, creatine phosphokinase, creatinine, hsCRP, gamma 
glutamyltransferase, glucose, inorganic phosphatase, lactate dehydrogenase, lipase, 
magnesium, potassium, sodium, chloride, bicarbonate, total bilirubin, total protein, and 
uric acid 
Lipids: total cholesterol, high-density lipoprotein, low-density lipoprotein, and 
triglycerides 
Urinalysis: pH, specific gravity, creatinine, glucose, bilirubin, blood, and protein 
Refer to the laboratory manual for details regarding the collection, processing, and 
shipping of the blood and urine samples. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. If 
known, the underlying etiology of the clinically relevant laboratory changes should be 


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reported as the AE, rather than the abnormal laboratory result itself. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those that are not associated with the underlying disease under 
study, unless judged by the investigator to be more severe than expected for the patient’s 
condition. 
All laboratory tests with values considered clinically significantly abnormal during the 
patient’s participation in the study or within 30 after the last dose of study medication 
should be repeated until the values return to normal, or baseline, or are no longer 
considered clinically significant by the investigator or medical monitor. 
If such values do not return to normal/baseline within a period of time judged reasonable 
by the investigator, then the sponsor should be notified. 
5.3.2.1 
Potential Drug-induced Liver Injury 
Hy’s Law cases have the following 3 components: 
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 
≥3 fold elevations above the ULN of ALT or AST than the placebo 
2. Among study patients showing such aminotransferase elevations, often with 
aminotransferases much greater than 3×ULN, one or more also shows elevation of 
serum total bilirubin to >2×ULN or INR >1.5, without initial findings of 
cholestasis (elevated ALP) 
3. No other reason can be found to explain the combination of increased 
aminotransferase and total bilirubin, such as viral hepatitis A, B, or C; evidence 
for biliary obstruction; acute alcoholic hepatitis (recent drinking and AST 
>2×ALT are supportive); recent history of severe hypotension or congestive heart 
failure; other underlying viral disease; pre-existing or acute liver disease; or 
another drug (including non-prescription products such as herbal supplements) 
capable of causing the observed injury 
During the study, the investigator will remain vigilant for increases in liver biochemistry. 
The investigator is responsible for determining whether a patient meets potential 
drug-induced liver injury criteria at any point during the study. 
In the event that a patient shows laboratory results of:  
• AST or ALT: 
o >5×ULN persisting for 2-weeks after study medication interruption 
or second occurrence of >5×ULN 
o >3×ULN and (total bilirubin >2×ULN or INR >1.5) 


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o >3×ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%) 
Please refer to Appendix 1 Possible Hy’s Law Liver Chemistry Action and Follow-up 
Assessments for further information. 
5.3.3 
Pregnancy 
All patients are required to meet the requirements relating to pregnancy and use of 
contraception described in the inclusion and exclusion criteria (see Section 4.1 and 
Section 4.2, respectively).  
Serum beta human chorionic gonadotrophin (β-hCG ) testing will be performed for 
female patients of childbearing potential at screening (within 28 days of Day -1), and a 
urine pregnancy test will be performed on Day 1 (prior to dosing) and throughout the 
study.  
The pregnancy test must be negative for the patient to be eligible. The serum pregnancy 
tests will be analyzed by the central laboratory, and the urine pregnancy tests will be 
analyzed locally. 
Monitoring for pregnancies in female patients will continue from the patient’s inclusion 
in the study until the follow-up visit. Male patients will be required to inform the 
investigator if their partner becomes pregnant during the study. The investigator should 
inform the sponsor within 24 hours of learning of the pregnancy or partner pregnancy by 
completing and submitting a pregnancy report form to the sponsor (or designee). 
If a patient becomes pregnant, study medication will be permanently discontinued and 
she will be withdrawn from the study after completing the assessments planned for the 
end of study visit 8 (see Table 1). Any pregnant patient and the fetus will be closely 
followed up throughout the duration of the pregnancy to determine the outcome 
(including spontaneous miscarriage, elective termination, normal birth, or congenital 
abnormality). The investigator will ask the patient to provide informed consent to record 
information on the health of the baby. Generally, follow-up will be required for no longer 
than 6 to 8 weeks beyond the estimated delivery date. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE. Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, 
stillbirth, congenital abnormalities, ectopic pregnancy) will be considered SAEs. 
For any male study patient whose partner becomes pregnant, the investigator will attempt 
to collect pregnancy information on the male patient’s partner while the male patient is in 
this study.  


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The investigator will record pregnancy information on the appropriate form and submit it 
to the sponsor within 24 hours of learning of the partner’s pregnancy. The investigator 
will obtain informed consent from the female partner to collect information about the 
pregnancy and its outcome. Information on the status of the pregnant partner and the 
fetus will be forwarded to the sponsor. Generally, the follow-up will be no longer than 
6 to 8 weeks following the estimated delivery date. Any termination of the pregnancy 
will be reported regardless of fetal status (presence or absence of anomalies) or indication 
for the procedure. Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, 
stillbirth, congenital abnormalities, ectopic pregnancy) will be considered SAEs. 
5.3.4 
12-lead Electrocardiogram 
12-lead ECG will be obtained as outlined in Table 1 using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. 
The ECG tracing should clearly identify the patient, include the date and time of the 
assessment and the signature and date of the person who made the interpretation; the 
tracing will be archived at the study site. Abnormal, clinically significant ECG results 
will be recorded as AEs. 
5.3.5 
Vital Signs 
Vital signs will be measured prior to dosing and immediately following dosing in a 
semi-supine position after 5 minutes’ rest and will include temperature, systolic and 
diastolic BP, pulse, and respiratory rate. Abnormal, clinically significant vital sign results 
will be recorded as AEs. If known, the underlying etiology for the abnormal clinically 
significant vital sign will be recorded as an AE rather than the vital sign itself.  
5.3.6 
Physical Examination 
The complete physical examination will include assessments of the standard physical 
examination items, including general appearance, skin, eyes, ears, nose, throat, head and 
neck, heart, chest and lungs, abdomen, extremities, lymph nodes, musculoskeletal, 
neurological, and other body systems, if applicable, for describing the status of the 
patient’s health. 
The brief physical examination will include, at a minimum, signs of RA. 
Body weight and height (height at screening only) will also be measured and recorded. 
The patient should be dressed in lightweight clothing, without shoes. 
Investigators should pay attention to clinical signs related to previous serious illnesses. 
Any new abnormalities or worsening of existing abnormalities should be reported as 
AEs, as appropriate (see Section 7). 












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Some of these vaccines include varicella (“chickenpox”) vaccine, oral polio vaccine, and 
the inhaled flu vaccine.   
Following vaccination with live or attenuated component vaccines, the virus may be shed 
in bodily fluids, including stool, and there is a potential risk that the virus may be 
transmitted.  General guidelines suggest that exposure should be avoided following 
vaccination with these vaccines for the stated time period: 
• Varicella or attenuated typhoid fever vaccination for 4 weeks following 
vaccination; 
• Oral polio vaccination for 6 weeks following vaccination; 
• Attenuated rotavirus vaccine for 10 days following vaccination; 
• Inhaled flu vaccine for 1 week following vaccination. 
6.9 
Overdose 
There is limited clinical experience with ATI-450. In the event of an overdose, patients 
should receive appropriate supportive medical care and be followed until 
resolution/stabilization of any clinical issues. 
Any instance of overdose (suspected or confirmed and irrespective of whether or not it 
involved ATI-450) must be communicated to the sponsor (or a specified designee) within 
24 hours of its occurrence. 
Any overdose associated with clinical symptoms will be recorded as an AE or SAE, as 
appropriate. Details of any signs or symptoms and their management should be recorded, 
including details of any treatments administered for the overdose. All overdoses with 
clinical symptoms meeting the SAE criteria must be reported as described in Section 7.4. 
6.10 
 Compliance 
The investigator (or designee) will explain the correct use of the study medication to each 
patient and will check that each patient is following the instructions properly. 
Compliance will be assessed at each visit by counting returned tablets and will be 
documented in the source documents and eCRF. Any deviation from the correct use of 
the study medications will be recorded in the eCRF. 
A record of the number of tablets (ATI-450 or placebo) dispensed to and taken by each 
patient will be maintained and reconciled with study medication and compliance records. 
The study medication start and stop dates, including dates for study medication delays 
and/or dose reductions, will also be recorded in the eCRF. 
Weekly dose of MTX and folic/folinic acid will be recorded at the clinic visits in the 
eCRF.  


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6.11 
Accountability 
The study medication must not be used for any purpose other than that defined in this 
protocol. All supplies of study drug will be accounted for in accordance with Good 
Clinical Practice (GCP). 
The pharmacist or (designee) should maintain accurate records of all study medication 
supplies received during the study. These records should include the dates and amounts 
of study medication that were received at the site, dispensed, and destroyed or returned to 
the sponsor (or designee). The records should include dates, quantities, batch/serial 
numbers, expiration dates (if applicable), and the unique code numbers assigned to the 
study medication and study patients. If errors or damage in the study medication 
shipments occur, the investigator should contact the sponsor (or its designee) 
immediately. Copies of the study medication accountability records will be provided by 
each investigator for inclusion in the trial master file (TMF). The study monitor will 
periodically check the supplies of study medication held by the investigator or pharmacist 
to verify accountability of the study medication used. 
The investigator (or designee) will administer the study medication only to the identified 
patients in this study, according to the procedures described in this study protocol.  
After the end of the study, all unused study medication and all medication containers 
should be destroyed at the study center or returned to the sponsor (or designee) for 
destruction. In either instance, complete documentation will be returned to the sponsor. 


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7 ADVERSE EVENTS 
7.1 
Definitions 
7.1.1 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical study patient 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to 
the medicinal (investigational) product. 
7.1.2 
Serious Adverse Events 
An SAE is any untoward medical occurrence that meets any of the following criteria: 
• Results in death. 
• Is life-threatening. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event that may not result in death, be life-threatening, or 
require hospitalization. The event will be considered an SAE when, based upon 
appropriate medical and scientific judgment, the event may jeopardize the patient and 
may require medical or surgical intervention to prevent one of the outcomes listed 
above. Examples of such events include: intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result 
in inpatient hospitalization, or the development of drug dependency or drug abuse. 
Definition of Terms 
Life-threatening: an AE is life-threatening if the patient was at immediate risk of death 
from the event as it occurred; i.e., it does not include a reaction that, if it had occurred in 
a more severe form, might have caused death. For example, drug-induced hepatitis that 
resolved without evidence of hepatic failure would not be considered life-threatening 
even though drug-induced hepatitis can be fatal. It does not include an AE or suspected 
adverse reaction that, had it occurred in a more severe form, might have caused death. 
Hospitalization: AEs requiring hospitalization or prolongation of hospitalization should 
be considered SAEs. Hospitalization for elective surgery, or for procedures planned prior 


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to the patient providing informed consent, or routine clinical procedures that are not the 
result of an AE (e.g., elective surgery for a pre-existing condition that has not worsened) 
need not be considered AEs or SAEs. If anything untoward is reported during the 
procedure, that occurrence must be reported as an AE or SAE as per the definitions. 
In general, hospitalization signifies that the patient has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician's office or outpatient 
setting. When in doubt as to whether hospitalization occurred or was necessary, the AE 
should be considered serious. 
Disability/incapacity: an AE is incapacitating or disabling if the experience results in a 
substantial and/or permanent disruption of the patient’s ability to carry out normal life 
functions. 
7.1.3 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
Laboratory abnormalities without clinical significance should not be recorded as AEs or 
SAEs. However, laboratory abnormalities (e.g., clinical chemistry, hematology, 
coagulation, lipids, and urinalysis abnormalities) that require medical or surgical 
intervention or lead to study medication interruption, modification, or discontinuation 
must be recorded as an AE or SAE, as applicable. In addition, laboratory or other 
abnormal assessments (e.g., in ECGs, X-rays, or vital signs) that are associated with signs 
and/or symptoms must be recorded as an AE or SAE if they meet the definition of an AE 
or SAE as described in Sections 7.1.1 and 7.1.2. If the underlying cause for the laboratory 
abnormality is known, record the etiology or diagnosis (e.g., anemia), rather than the 
laboratory result (i.e., decreased hemoglobin). 
For specific information on handling of clinical laboratory abnormalities, see 
Section 5.3.2. 
7.2 
Assessment of Adverse Events 
7.2.1 
Severity 
The investigator will determine the intensity of the AE according to the definitions 
below: 
• Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities 
• Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities 
• Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with a SAE. Severe is a category utilized for 


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rating the intensity of the event; both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the pre-defined 
outcomes as described in the definition of an SAE, not when it is rated as severe.  
7.2.2 
Causality 
The investigator is obligated to assess the relationship between study medication and 
each occurrence of an AE/SAE. The investigator will use her/his best clinical judgment to 
determine the relationship. Alternative causes, such as underlying disease(s), concomitant 
therapy, and other risk factors, as well as the temporal relationship of the event to study 
intervention administration will be considered and investigated. The investigator will also 
consult the IB in his/her assessment. 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 no reasonable possibility that there is a causal relationship between the study 
medication and the AE 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
7.3 
Documenting and Reporting Adverse Events 
Reporting of SAEs will begin when the patient has provided informed consent and will 
continue up to the end of study visit or 30 days after the last study drug administration 
whichever is later. Reporting of AEs will begin when the patient receives the first dose of 
study medication and will continue up to the end of study visit or 30 days after the last 
study drug administration, whichever is later. Any clinical AE that occurs between the 
time of consent and dosing Day 1 will be recorded as medical history. 
Occurrence of AEs may be volunteered spontaneously by the patient; discovered as a 
result of general, nonleading verbal questioning by the study staff; or determined by 
physical examination or other safety assessments. All AEs will be monitored and 
recorded in the CRF throughout the entire study. 
For all AEs, the investigator must pursue and obtain adequate information (a description 
of the event, severity, time of occurrence [including whether the AE onset was before, 
during, or after the study medication administration if the AE started on a dosing day], 
duration, and any action, e.g., treatment/follow-up tests). The outcome of the event 
should be provided along with the investigator’s assessment of the relationship to the 


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study medication. The investigator must also assess whether the event meets the criteria 
for classification as an SAE. 
It is the investigator’s responsibility to review all documentation (e.g., hospital notes, 
laboratory reports, and diagnostic reports) related to an AE. Wherever possible, the 
investigator’s diagnosis, not the individual signs and symptoms, will be documented as 
the AE. 
Investigators are not obligated to actively seek AEs or SAEs after the patient’s 
conclusion of study participation. However, if the investigator learns of any SAE, 
including death, at any time after a patient has been discharged from the study, and 
he/she considers the event to be reasonably related to the study medication or study 
participation, the investigator must promptly notify the sponsor. 
7.4 
Reporting of Serious Adverse Events 
Upon becoming aware of a SAE whether or not related to the study medications, the 
investigator must: 
1. Take the appropriate medical action to ensure the patient’s safety. 
2. Immediately, and no longer than within 24-hours, report the SAE to the safety 
monitor, ensuring that the patient information is de-identified to: 
 
 
 
 
3. Print a copy of the email confirmation from 
 and place in the study file. 
4. Within 24-hours complete, as fully as possible an SAE form; email the forms and 
any other relevant information (e.g., concomitant medication eCRF, medical 
history eCRF, laboratory test results) to 
(Aclaris Therapeutics, Inc. 
safety monitor). 
5. Monitor and document the progress of the SAE until it resolves or, if not resolved 
after the patient’s last study visit, until in the opinion of the investigator the AE 
reaches a clinically stable outcome with or without sequelae AND the investigator 
and Aclaris Therapeutics, Inc. safety and medical monitor agree that the SAE is 
satisfactorily resolved. 
6. Report any SAE updates within 24-hours of knowledge to the safety monitor via 
email (or fax) and update the SAE form. 
7. Comply with the appropriate regulatory requirements and Aclaris Therapeutics, 
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The investigator is obliged to respond to any request for follow-up information (e.g., 
additional information, event outcome, final evaluation, or other records where needed) 
or to any question the sponsor (or designee) may have concerning the SAE within the 
same timelines as those noted above for initial reports. This is necessary to ensure prompt 
assessment of the event by the sponsor (or designee) and, as applicable, to allow the 
sponsor to meet strict regulatory timelines associated with expedited reporting obligations 
for events of this nature. 
7.5 
Adverse Event and Serious Adverse Event Follow-up 
During the study (and after the end of study visit), all AEs and SAEs should be followed 
proactively by the investigator until the event resolves or the condition stabilizes to a 
level acceptable to the investigator, until the event is otherwise explained, or until the 
patient is lost to follow-up. At the time the patient’s study participation ends, all ongoing 
AEs and SAEs should be evaluated for resolution. New or updated information will be 
recorded in the originally completed eCRF and the investigator will submit any updated 
SAE information to the sponsor within 24 hours of receipt of the information. 
7.6 
Safety Reporting Oversight 
In accordance with ICH GCP, the sponsor (or designee) will inform investigators of 
“findings that could affect adversely the safety of patients, impact the conduct of the trial, 
or alter the IRB/Independent Ethics Committee (IEC) approval/favorable opinion to 
continue the trial.” 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study medication under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators. To 
support compliance with these requirements, the investigator must provide requested 
information in a timely manner. 
An investigator who receives an investigator safety report describing SAEs or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate, according to local 
requirements. 








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9 ETHICS AND RESPONSIBILITIES 
9.1 
Good Clinical Practice 
This study will be conducted in accordance with the Note for Guidance on GCP ICH 
Harmonised Tripartite Guideline E6 (R1)/Integrated Addendum E6 (R2); US FDA Code 
of Federal Regulations (CFR) (Title 21 Parts 50, 56, 312), requirements for the conduct 
of clinical studies as provided in the EU Directive 2001/20/EC, the general guidelines 
indicated in the Declaration of Helsinki; and all applicable regulatory requirements. 
9.2 
Institutional Review Board/Independent Ethics Committee 
Before initiating a study, the investigator/institution must have written and dated 
approval/favorable opinion from the IRB/IEC for the study protocol/amendment(s), 
written ICF, any ICF updates, patient recruitment procedures (e.g., advertisements), and 
any written information to be provided to patients and a statement from the IRB/IEC that 
these comply with GCP requirements (if applicable). A current copy of the IB should be 
included as part of the written application to the IRB/IEC. 
The IRB/IEC approval(s) must identify the protocol version as well as the documents 
reviewed. Any amendments to the protocol will require IRB/IEC approval before the 
implementation of the changes made to the study, except for changes necessary to 
eliminate an immediate hazard to the study patients. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings, including adverse 
drug reactions that are both serious and unexpected, as required by IRB/IEC 
procedures 
• Providing oversight of the conduct of the study at the site and adherence to the 
requirements of all applicable regulations 
• Promptly reporting deviations from, or changes to, the protocol to eliminate 
immediate hazards to the study patients 
9.3 
Informed Consent 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s) and should adhere to GCP and to the ethical 
principles that have their origin in the Declaration of Helsinki. Prior to the beginning of 


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the study, the investigator should have the IRB/IEC written approval/favorable opinion of 
the written ICF and any other written information to be provided to patients. 
• The investigator or his/her representative will explain the purpose and nature of the 
study as well as possible adverse effects to the patient or his/her legally acceptable 
representative and answer all questions regarding the study. 
• Patients must be informed that their participation is voluntary, and consent can be 
withdrawn at any point. 
• Patients or their legally acceptable representative will be required to sign a statement 
of informed consent that meets the requirements of US FDA CFR Title 21 Part 50, 
local regulations, ICH guidelines, Health Insurance Portability and Accountability 
Act (HIPAA) requirements in the US, and the IRB/IEC or study site. 
• Prior to a patient’s participation in the study, the written ICF should be signed and 
personally dated by the patient or by the patient's legally acceptable representative, 
and by the person who conducted the informed consent discussion. 
• The medical record must include a statement that written informed consent was 
obtained before the patient was enrolled in the study and the date the written consent 
was obtained. 
• The original copy of the signed ICF will be retained at the study site. 
• A copy of the ICF and any other written information must be provided to the patient 
or the patient’s legally acceptable representative. 
• If the ICF is revised, the revised ICF must have received the IRB/IEC 
approval/favorable opinion in advance of its use. Patients must be informed of the 
changes to the ICF and must re-consent to the most current version during their 
participation in the study. The patient or the patient’s legally acceptable 
representative should be informed in a timely manner if new information becomes 
available that may be relevant to the patient’s willingness to continue participation in 
the study. The communication of this information should be documented. 
9.4 
Data Monitoring Committee 
There is no data monitoring committee for this study.  
9.5 
Financing and Insurance 
9.5.1 
Contractual and Financial Details 
The investigator (and/or, as appropriate, the site’s administrative representative) and the 
sponsor will sign a clinical study agreement prior to the start of the study, outlining 


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overall sponsor and investigator responsibilities in relation to the study. The contract 
should describe whether costs for pharmacy, laboratory, and other protocol-required 
services are being paid directly or indirectly. 
9.5.2 
Insurance, Indemnity, and Compensation 
Aclaris Therapeutics, Inc., will maintain an appropriate clinical study insurance policy. 
9.5.3 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 


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


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Changes to information in the medical record (progress notes) and other source 
documents are to be initialed and dated on the day the change is made by the investigator 
(or designee). If the reason for the change is not apparent, a brief explanation for the 
change is to be written adjacent to the change. Changes to the eCRF will be electronically 
tracked. 
10.1 
Source Documentation 
Source documents contain the results of original observations and activities of a clinical 
investigation. They are the original records in which raw data are first recorded. Source 
documents include, but are not limited to, medical records (progress notes), ECG and 
computer printouts, screening logs, completed scales, quality of life questionnaires, and 
recorded data from automated instruments. 
The investigator/site personnel should maintain adequate and accurate source documents 
and study records that include all pertinent observations on each of the site’s study 
patients. Source data should be attributable, legible, contemporaneous, original, accurate, 
and complete. Changes to source data should be traceable, should not obscure the original 
entry, and should be explained if necessary (e.g., via an audit trail). 
All source documents from this study are to be maintained by the investigator and made 
available for inspection by authorized persons. The investigator will provide direct access 
to source documents/data for study-related monitoring, audits, IRB/IEC review, and 
regulatory inspections. The sponsor should verify that each patient has consented, in 
writing, to direct access to his/her original medical records for study-related monitoring, 
audit, IRB/IEC review, and regulatory inspection. 
10.2 
Case Report Form Completion and Data Management 
An eCRF will be used to store and transmit patient information. The file structure and 
format for the eCRF will be provided by the sponsor or its representative and should be 
handled in accordance with the instructions provided. 
The eCRF must be reviewed and electronically signed and dated by the investigator. 
Access to the eCRF will be strictly password protected and limited to personnel directly 
participating in the study. Data should be entered into the eCRF completely by authorized 
site personnel (e.g., investigators and the study coordinator). The eCRF must be 
completed as soon as possible after any patient evaluation or communication. If data are 
to be changed due to erroneous input or other reason, an electronic audit trail will track 
the changes. The eCRFs and computers that store them must be accessible to study 
monitors and other regulatory auditors. Changes to the eCRF will be electronically 
tracked. 


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Data will be entered/loaded into a validated electronic database using a clinical data 
management system. Computerized data cleaning checks will be used in addition to 
manual review to check for discrepancies and to ensure consistency of the data. 
10.3 
Study Files and Record Retention 
All data derived from the study will remain the property of the sponsor. The sponsor 
assumes accountability for actions delegated to other individuals. 
Records must be retained in accordance with the current ICH Guidelines on GCP. All 
essential study documents, including records of patients, source documents, eCRFs, and 
the study medication inventory, must be kept on file. 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region, or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of ATI-450. However, essential 
documents may be retained for a longer period if required by the applicable regulatory 
requirements or by agreement with the sponsor. The sponsor is responsible for informing 
the investigator when these documents need no longer be retained. 
The investigator is not to dispose of any records relevant to this study without written 
permission from the sponsor and is to provide the sponsor the opportunity to collect such 
records. The investigator shall take responsibility for maintaining adequate and accurate 
hard copy source documents of all observations and data generated during this study. 
Such documentation is subject to inspection by the sponsor, its representatives, and 
regulatory authorities. 
If an investigator moves, withdraws from a study, or retires, the responsibility for 
maintaining the records may be transferred to another person who will accept 
responsibility. Notice of transfer must be made to and agreed by the sponsor. 


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11 AUDITING AND MONITORING 
Sponsor-assigned monitors will conduct regular site visits to the investigational facilities 
for the purpose of monitoring various aspects of the study, such as assessing patient 
enrollment, compliance with protocol procedures, completeness and accuracy of data 
entered into the CRFs, verification of CRF data against original source documents, and 
occurrence of AEs. The investigator must agree to sponsor-authorized personnel having 
direct access to the clinical (or associated) files and clinical study supplies (dispensing 
and storage areas) to ensure compliance with applicable regulations, and the investigator 
will assist with the sponsor’s monitoring activities. 
Quality control will occur at each stage of data handling to ensure that all data are reliable 
and have been processed correctly. The sponsor should ensure oversight of any 
study-related duties and functions carried out on its behalf, including study-related duties 
and functions that are subcontracted to another party by the sponsor’s contracted contract 
research organization (CRO). 
The CRFs should be completed in a timely manner and on an ongoing basis to allow 
regular review by the study monitor. 
Details describing the strategy, responsibilities, and requirements of the study monitoring 
are provided in the study monitoring plan.  
The purpose of an audit is to assess whether ethics, regulatory, and quality requirements 
are being fulfilled. The sponsor or its representative may conduct audits at the 
investigative sites including, but not limited to, drug supply, presence of required 
documents, the informed consent process, and comparison of CRFs with source 
documents. Government regulatory authorities may also inspect the investigator during or 
after the study. The investigator (or designee) should contact the sponsor/CRO 
immediately if this occurs. All medical records (progress notes) must be available for 
audit. The investigator must agree to participate with audits conducted at a convenient 
time in a reasonable manner. 
11.1 
Risk and Quality Tolerance Limits 
The sponsor will review risk control measures outlined within the study specific 
monitoring plan periodically to ascertain whether the implemented clinical quality 
management activities remain effective and relevant. The clinical quality management 
approach and any important deviations from the predefined quality tolerance limits and 
remedial actions adopted will be described in the CSR. 
11.2 
Protocol Adherence and Deviations 
The investigator and site personnel should conduct the study in compliance with the 
protocol and should use continuous vigilance to identify and report protocol deviations. 


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


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


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


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14 STUDY START AND TERMINATION 
The study start date is the date on which the first patient provides informed consent.  
The end of the study is defined as the date of the last patient’s last assessment. 
Both the sponsor and the investigator reserve the right to terminate the study or the 
participation in the study at an investigator’s site at any time. In terminating the study, the 
sponsor and the investigator will assure that adequate consideration is given to the 
protection of the patients’ interests. 
If the study is prematurely terminated or suspended for any reason, the 
sponsor/investigator/site personnel should promptly inform the study patients and should 
assure appropriate therapy and follow-up for the patients. Where required by the 
applicable regulatory requirements, the IRB/IEC should be informed promptly and be 
provided with a detailed written explanation of the termination or suspension. 
If the investigator terminates or suspends a study without prior agreement of the sponsor, 
the investigator should inform the site personnel. The investigator/site personnel should 
promptly inform the sponsor and the IRB/IEC. The investigator/site personnel should 
also provide the sponsor and the IRB/IEC a detailed written explanation of the 
termination or suspension. 


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


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16 APPENDICES 
16.1 
Appendix 1 Possible Hy’s Law Liver Chemistry Action and Follow-up 
Assessments 
Suggested Actions and Follow-up Assessments 
Actions 
Follow-Up Assessments 
• 
Immediately discontinue study medication. 
• 
Report the event to the sponsor or designee 
within 24 hours. 
• 
Complete a SAE data collection tool if the 
event also met the criteria for an SAE.2 
• 
Perform liver chemistry follow-up assessments.  
• 
Monitor the participant until liver chemistry 
test abnormalities resolve, stabilize, or return to 
baseline (see MONITORING). 
• 
Do not restart/rechallenge participant with 
study treatment unless allowed per-protocol 
and sponsor approval is granted.  
• 
If restart/rechallenge is either not allowed per-
protocol or not granted, permanently 
discontinue study treatment. The participant 
may continue in the study for any protocol-
specified follow-up assessments  
MONITORING: 
If ALT ≥3xULN AND bilirubin ≥2xULN or INR 
>1.5: 
• 
Repeat liver chemistry tests (ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow-up assessments within 24 
hours. 
• 
Monitor participant twice weekly until liver 
chemistry test abnormalities resolve, stabilize, 
or return to baseline. 
• 
A specialist or hepatology consultation is 
recommended. 
If ALT ≥3xULN AND bilirubin <2xULN and 
INR ≤1.5: 
• 
Repeat liver chemistry tests (include ALT, 
AST, alkaline phosphatase, bilirubin) and 
• 
Viral hepatitis serology3 
• 
Obtain INR and recheck with each 
liver chemistry assessment until the 
transaminases values show 
downward trend 
• 
Obtain blood sample for ATI-450 
drug concentration4   
• 
Serum creatine phosphokinase 
(CPK) and lactate dehydrogenase 
(LDH) 
• 
Fractionate bilirubin, if total 
bilirubin ≥2xULN 
• 
Obtain complete blood count with 
differential to assess eosinophilia 
• 
Record the appearance or worsening 
of clinical symptoms of liver injury, 
or hypersensitivity, on the AE eCRF  
• 
Record use of concomitant 
medications (including 
acetaminophen, herbal remedies, and 
other over-the-counter medications) 
on the concomitant medications 
CRF 
If ALT ≥3xULN AND bilirubin ≥ 
2xULN or INR >1.5: 
• 
Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG) or gamma globulins. 
• 
Serum acetaminophen adduct high 
performance liquid chromatography 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in participants with definite or 


Sponsor Name: Aclaris Therapeutics Inc. 
Protocol Number: ATI-450-RA-201 
Version and Date: 3.0, 27July2020 
Page 84 of 85
 
 
Confidential 
 
perform liver chemistry follow-up assessments 
within 24 to 72 hours. 
• 
Monitor participants weekly until liver 
chemistry abnormalities resolve, stabilize, or 
return to baseline. 
likely acetaminophen use in the 
preceding week.9) 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin 
fractionation is not immediately available, discontinue study treatment if ALT ≥3xULN and bilirubin 
≥2xULN. Additionally, if serum bilirubin fractionation testing is unavailable, record the 
absence/presence of detectable urinary bilirubin on dipstick which is indicative of direct bilirubin 
elevations suggesting liver injury.  
2. All events of ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) or ALT ≥3xULN and INR 
>1.5 may indicate severe liver injury (possible ‘Hy’s Law’) and must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis). The INR measurement is not required and 
the stated threshold value will not apply to participants receiving anticoagulants.  
3. Hepatitis A IgM antibody; hepatitis B surface antigen (HBsAg) and hepatitis B Core Antibody 
(HBcAb); hepatitis C RNA; cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM 
antibody (or if unavailable, heterophile antibody or monospot testing); and hepatitis E IgM antibody.  
4. Drug concentration sample may not be required for participants known to be receiving placebo or non-
comparator treatments. Record the date/time of the blood sample draw and the date/time of the last 
dose of study treatment prior to the blood sample draw on the CRF. If the date or time of the last dose 
is unclear, provide the participant’s best approximation. If the date/time of the last dose cannot be 
approximated do not obtain a blood sample. Instructions for sample handling and shipping are in the 
reference manual. 


Sponsor Name: Aclaris Therapeutics Inc. 
Protocol Number: ATI-450-RA-201 
Version and Date: 3.0, 27July2020 
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17 REFERENCES 
 
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