A Phase 3 Study Evaluating the Safety and Efficacy of AR-15512, a Cold Thermoreceptor Modulator, for the Treatment of Dry Eye Disease (COMET-2)
Phase: PHASE3
Conditions: Dry Eye Disease
Sponsor: Aerie Pharmaceuticals

 
 
 
 
 
A Phase 3 Study Evaluating the Safety and Efficacy of AR-15512, 
a Cold Thermoreceptor Modulator, for the Treatment of Dry Eye 
Disease (COMET-2) 
 
 
STUDY ID: 
AR-15512-CS301 
 
 
PROTOCOL 
 
 
NCT05285644 

 
 
AR-15512 Ophthalmic Solution 
Clinical Study Protocol: AR-15512-CS301, Amendment 2 
Aerie Pharmaceuticals, Inc.
 
 
 
 
 
Confidential 
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Clinical Study Protocol  
Study Title: 
A Phase 3 Study Evaluating the Safety and Efficacy of AR-15512, 
a Cold Thermoreceptor Modulator, for the Treatment of Dry Eye 
Disease (COMET-2) 
Study Number: 
AR-15512-CS301 
Study Phase: 
3 
Product Name: 
AR-15512 
Indication: 
Dry Eye Disease 
Investigators: 
Multicenter 
 
 
Sponsor: 
Aerie Pharmaceuticals, Inc. 
Sponsor 
Contact: 
4301 Emperor Blvd. Suite 400 
Durham, NC 27703 
+1-909-237-5300 
NCT #: 
05285644 
 
 
Date 
Original Protocol (Rev 0): 
11 March 2022 
Amendment 1 (Rev 1): 
11 April 2022 
Amendment 2 (Rev 2) 
13 May 2022 
 
Confidentiality Statement 
This document contains Aerie Pharmaceuticals®, Inc.’s (Aerie) information that is 
confidential, a trade secret and/or proprietary in nature.  It is loaned to you for your 
confidential use on behalf of Aerie and is not to be photocopied, disclosed or transmitted to 
any other person or party who is not covered by a Confidential Disclosure Agreement with 
Aerie.  As the Principal Investigator you are responsible for the safekeeping and return of this 
document to Aerie upon request.  You will be sent updated information and/or amendments 
as they become available. 
 
 
 

 
 
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AR-15512 Ophthalmic Solution 
Clinical Study Protocol: AR-15512-CS301, Amendment 2 
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AR-15512 Ophthalmic Solution 
Clinical Study Protocol: AR-15512-CS301, Amendment 2 
Aerie Pharmaceuticals, Inc.
 
 
 
 
 
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SYNOPSIS 
Sponsor: 
Aerie Pharmaceuticals, Inc. 
Name of Finished Product: 
AR-15512 ophthalmic solution 0.003% 
Name of Active Ingredients: 
AR-15512 
Study Title: 
A Phase 3 Study Evaluating the Safety and Efficacy of AR-15512, a Cold Thermoreceptor Modulator, 
for the Treatment of Dry Eye Disease (COMET-2) 
Study Number: 
AR-15512-CS301 
Study Phase: 
3 
Primary Objective(s): 
To evaluate the safety and efficacy of topical ophthalmic 0.003% AR-15512 compared to its vehicle dosed 
twice daily (BID) in subjects with dry eye disease (DED). 
Study Design: 
This will be a Phase 3, multicenter, vehicle-controlled, double-masked, randomized study conducted at 
approximately 20 sites in the United States. All subjects enrolled will have DED. The study will consist 
of Screening (Day -14) and Baseline (Day 1) visits as well as follow-up visits at Day 7, Day 14, Day 28, 
and Day 90 (Study Exit). In addition, there will be a Day 60 dispensing visit. 
All subjects will be exposed to the Controlled Adverse Environment (CAE®) at the Screening visit to assess 
eligibility. At the end of the Screening visit, all qualified subjects will be assigned to administer AR-15512 
vehicle BID to both eyes for approximately 14 days during the vehicle run-in period. After the vehicle run-in 
period, subjects will be re-evaluated at the Baseline visit for signs and symptoms of DED. Only subjects who 
requalify, based on inclusion/exclusion criteria, will be enrolled in the study and randomized in a 1:1 ratio 
within each site to receive 0.003% AR-15512 or AR-15512 vehicle to be administered BID as 1 drop in each 
eye for 90 days. Efficacy will be assessed at the Baseline (Day 1) visit and Day 7, Day 14, Day 28, and Day 
90. At the end of the Day 90 visit, subjects will exit the study. Safety assessments will be conducted at each 
study visit. 
Study Population: 
This study is anticipated to enroll approximately 460 subjects with DED so as approximately 414 subjects 
complete Day 90. The anticipated dropout rate is 10%. To achieve this goal, approximately 1500 subjects 
may be screened. 
Key Inclusion Criteria  
Subjects must meet all of the following criteria to enter into the study: 
 
Male or female, 30 years of age or older at the Screening visit 
 
Have a previous history of DED, clinician diagnosed or patient reported, within the previous 
6 months prior to the Screening visit 
 
Have used and/or desired to use artificial tears for DED symptoms within 2 months prior to the 
Screening visit 
 
Both of the following signs of DED in the same eye: 
 
Total corneal fluorescein staining score of ≥ 2 and ≤ 15 based on the modified NEI grading 
scheme, with no one region scoring > 3 in at least 1 eye at the Screening visit only 

 
 
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 
Anesthetized Schirmer test score ≥ 2 and < 10 mm/5 min in at least 1 eye and the same eye 
must qualify at both Screening and Baseline visits 
 
A score of ≥ 50 based on Ocular Discomfort Score (ODS) assessed on a Visual Analog Scale (VAS) 
at both the Screening and Baseline visits 
 
A score of ≥ 50 based on SANDE (Symptoms Assessment iN Dry Eye) at both the Screening and 
Baseline visits  
 
Increase in the signs and symptoms of DED based on the CAE exposure at the Screening visit only 
demonstrated by: 
a. 
≥ 1-point increase in inferior region corneal staining score (assessed using sodium 
fluorescein staining) in at least 1 eye based on the Ora Calibra® grading scale after the 
90 minute CAE® exposure 
b. Ora Calibra ODS score ≥ 3 at 2 or more consecutive time points in at least 1 eye during 
CAE® exposure within ≤ 20 minutes of entering the CAE® (if a subject has an ocular 
discomfort rating of 3 at time 0 for an eye, the subject must report an ocular discomfort 
rating of 4 for 2 consecutive measurements for that eye within ≤ 20 minutes of entering the 
CAE) 
 
Corrected visual acuity equal to or better than logMar +0.7 (Snellen equivalent equal to or better 
than 20/100), as assessed by Early Treatment of Diabetic Retinopathy Study (ETDRS) scale in both 
eyes at both the Screening and Baseline visits 
 
Key Exclusion Criteria 
Subjects meeting any of the following criteria during the Screening and/or Baseline visits (i.e., qualification 
visits) will be excluded from entry into the study: 
 
History or presence of any ocular disorder or condition (other than DED) in either eye that would, 
in the opinion of the investigator, interfere with the interpretation of the study results or subject 
safety, such as: significant corneal or conjunctival scarring; pterygium or nodular pinguecula; 
conjunctivitis, or inflammation not associated with DED; anterior (epithelial) basement membrane 
corneal dystrophy or other clinically significant corneal dystrophy or degeneration; evidence of 
keratoconus; etc. (Note: Blepharitis and/or Meibomian gland disease not requiring treatment are 
allowed.) 
 
Current evidence of other significant ophthalmic disease requiring topical medication 
(e.g., glaucoma, ocular hypertension), which may interfere with vision (e.g., cataract, macular 
degeneration) or other disease which the investigator believes may interfere with study findings or 
interpretation 
 
History of ocular surgery within 1 year prior to the Screening visit, including punctal cautery, 
corneal refractive, or anterior segment surgeries that affect corneal sensitivity (e.g., cataract surgery 
or any surgery involving limbal or corneal incision) 
 
Have had a corneal transplant in either or both eyes 
 
Use of contact lenses in either eye within 7 days prior to the Screening visit or planned use during 
the study 
 
Punctal or intracanalicular plug present in either eyelid within 14 days prior to the Screening visit or 
anticipated plug insertion or occlusion at any time during the study 
 
Regular use of lid hygiene within 14 days prior to the Screening visit or any planned use during the 
study 
 
Use of lid heating therapy (i.e., LipiFlow®, iLUX®, TearCare®) or Meibomian gland 
probing/therapeutic expression within 1 year prior to the Screening visit or anticipated during the 
study 
 
Use of artificial tears within 2 hours prior to the Screening visit or anticipated use during the study 
 
Use of any topical ocular anti-inflammatory medication within 30 days prior to the Screening visit 
or anticipated use during the study (e.g., ocular cyclosporine [Restasis®, Cequa™], lifitegrast 
[Xiidra®], or any other prescription ophthalmic product for DED, topical ocular corticosteroid- or 
non-steroidal-anti-inflammatory agents, or autologous serum 

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
Use of any topical ocular glaucoma medication within 30 days prior to the Screening visit or
anticipated use during the study

Regular use of any other topical ocular medication within 14 days prior to the Screening visit or
anticipated use during the study (e.g., eye whitening products [Visine®, Lumify®], topical ocular
antibiotics, topical ocular antihistamines, mast cell stabilizers, age-related blurry near vision
(presbyopia) drops [Vuity™], or other over-the-counter [OTC], herbal, prescription, or nutritional
supplements). Note: Occasional short-term use of these topical ocular medications will be permitted
provided that no drops were used within 24 hours of the Screening visit or anticipated use within
24 hours of any study visit

Use of Tyrvaya™ (varenicline solution, nasal spray 0.03mg) within 30 days prior to the Screening
visit or anticipated use during the study

Use of medications for the treatment of severe DED and/or Meibomian gland disease such as oral
pilocarpine, oral cevimeline, oral macrolides, oral tetracyclines, oral tetracycline derivatives, and
oral retinoids within 30 days prior to the Screening visit or anticipated use during the study

Initiation, discontinuation, or change in dose of a systemic medication known to cause ocular drying
(e.g., antihistamines or tricyclic antidepressants) less than 14 days prior to the Screening visit or a
change in dosage is anticipated during the study. Note: Occasional short-term use of medications
such as systemic antihistamines will be permitted provided that use was not within 24 hours of the
Screening visit or anticipated use within 24 hours of any study visit

Initiation, discontinuation, or change in dose of a systemic corticosteroid less than 60 days prior to
the Screening visit or a change in dosage is anticipated during the study. Note: Non-ocular topically
applied corticosteroids (including topical creams, nasal sprays and inhalers) will be permitted during
the study and the dose is not required to be stable

Initiation, discontinuation, or change in dose of a systemic immunomodulator (e.g.,
hydroxychloroquine, methotrexate, cyclosporine) less than 60 days prior to the Screening visit or a
change in dosage is anticipated during the study
Study Interventions and Dosing Regimens: 
Vehicle Run-in Period 

Topical ocular administration of one drop of AR-15512 vehicle in both eyes BID
Randomized Intervention Period (1:1) 

Topical ocular administration of one drop of 0.003% AR-15512 ophthalmic solution in both eyes
BID

Topical ocular administration of one drop of AR-15512 vehicle in both eyes BID
Duration of Study: 
Approximately 15 weeks (2 weeks of vehicle run-in period followed by 13-week randomized intervention 
period) 
Efficacy Assessments: 
Primary Assessments:  

Unanesthetized Schirmer test
Secondary Assessments: 

SANDE (Symptom Assessment iN Dry Eye) Questionnaire Score

Ocular Discomfort Score (ODS) - Visual Analog Scale (VAS)

Eye Dryness Score based - VAS

 
 
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Safety Assessments: 
 
Vital signs (heart rate and blood pressure) 
 
Hematology, chemistry, and urinalysis 
 
Adverse events 
 
Corrected visual acuity  
 
Intraocular pressure 
 
Dilated fundus exam 
Statistical Methods: 
Sample Size Determination 
Two hundred two (202) intention-to-treat (ITT) population subjects (study eyes) per treatment group yields 
99% power to conclude superiority of 0.003% AR-15512 over vehicle in the proportion of subjects ≥ 10 mm 
in unanesthetized Schirmer score on Day 14, assuming a true difference of proportions (AR-15512 vs 
vehicle) of 80% vs 30% and a two-sided alpha = 0.05. 
Additionally, 202 ITT population subjects (study eyes) per treatment group yields 99% power to conclude 
superiority of 0.003% AR-15512 over vehicle in the mean change from Baseline in SANDE score on Day 28 
assuming a true difference (AR-15512 minus vehicle) of -7.9, a common standard deviation of 17.72, and a 
two-sided alpha = 0.05.  
Accounting for subject discontinuations, approximately 460 total subjects (230 per treatment arm) will be 
randomized assuming a dropout rate of 10%. 
 
Primary endpoint 
 
Proportion of subjects ≥ 10 mm increase in unanesthetized Schirmer score on Day 14  
 
Secondary endpoints 
 
Change from Baseline in SANDE score on Day 28 
 
Change from Baseline in unanesthetized Schirmer score on Day 14 
 
Change from Baseline in SANDE Score on Day 90 
 
Change from Baseline in ODS - VAS on Day 90 
 
Change from Baseline in Eye Dryness - VAS Day 90 

 
 
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 
Proportion of subjects ≥ 10 mm increase in unanesthetized Schirmer score on Day 90 
 
Change from Baseline in unanesthetized Schirmer score on Day 90 
 
Statistical Analyses 
Analysis of primary efficacy will be based on difference of proportions tests for dichotomous endpoints and 
analysis of covariance (ANCOVA) for change from Baseline endpoints. Available data only will be used if 
the discontinuation rate is < 5% in each arm; otherwise, an estimand based on multiple imputation will be 
used for the primary analysis.  
Analysis of secondary efficacy will be conducted as described for the primary efficacy endpoints, using 
difference of proportions tests or ANCOVA with available data only if the discontinuation rate is < 5% in 
each arm and multiple imputation otherwise. The secondary efficacy endpoints will only be formally tested if 
the endpoint is significant at the α=0.05 level. Testing of the secondary efficacy endpoints will be conducted 
using a fixed-sequence hierarchical strategy. 
Date of Original Approved Protocol (Rev 0): 11 March 2022 
Date of Most Recent Protocol Amend (Rev 2): 13 May 2022 
 

 
 
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TABLE OF CONTENTS 
SYNOPSIS ..........................................................................................................................5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..............................14 
1. 
INTRODUCTION ....................................................................................................16 
1.1 
Background ..........................................................................................................16 
1.2 
Clinical Development of AR-15512 ....................................................................17 
1.3 
Risk/Benefit Assessment ......................................................................................18 
2. 
STUDY OBJECTIVES ............................................................................................19 
2.1 
Primary Objective(s) ...........................................................................................19 
3. 
INVESTIGATIONAL PLAN ..................................................................................19 
3.1 
Overall Study Design and Plan ...........................................................................19 
3.2 
Rationale for Study Design and Control Group ...............................................20 
3.3 
Study Duration and Dates ...................................................................................21 
4. 
STUDY POPULATION SELECTION ...................................................................21 
4.1 
Study Population ..................................................................................................21 
4.2 
Inclusion Criteria .................................................................................................21 
4.3 
Exclusion Criteria ................................................................................................22 
4.4 
Screen Failures .....................................................................................................24 
4.5 
During-Study Restrictions...................................................................................24 
4.5.1 
Prior and Concomitant Therapy ..................................................................24 
4.5.2 
Fluid and Food Intake ...................................................................................27 
4.5.3 
Subject Activity Restrictions .........................................................................27 
4.5.4 
Women of Childbearing Potential and Acceptable Contraceptive 
Methods ...........................................................................................................27 
5. 
STUDY INTERVENTIONS ....................................................................................28 
5.1 
Description of Study Interventions.....................................................................28 
5.1.1 
Investigational Product .................................................................................28 
5.1.2 
Vehicle (Control) ............................................................................................29 
5.2 
Selection and Timing of Dose for Each Patient .................................................29 
5.3 
Method of Assigning Patients to Study Intervention Groups ..........................29 
5.4 
Masking .................................................................................................................30 
5.5 
Unmasking ............................................................................................................30 
5.6 
Study Intervention Compliance ..........................................................................30 
5.7 
Packaging and Labeling ......................................................................................31 
5.8 
Storage ..................................................................................................................31 
5.9 
Accountability ......................................................................................................32 
5.9.1 
Receipt and Disposition of Study Medication .............................................32 
5.9.2 
Return of Study Intervention ........................................................................32 
6. 
STUDY PROCEDURES ..........................................................................................32 
6.1 
Informed Consent ................................................................................................32 
6.2 
Demographics, Medical and Surgical History...................................................33 
6.3 
Prior and Concomitant Medication Assessments .............................................33 
6.4 
Clinical Laboratory Tests....................................................................................33 
6.4.1 
Laboratory Parameters .................................................................................33 

 
 
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6.4.2 
Sample Collection, Storage and Shipping ....................................................33 
6.4.3 
Pregnancy Testing ..........................................................................................33 
6.5 
Dispensing Study Intervention............................................................................33 
6.6 
Efficacy Assessments ...........................................................................................34 
6.6.1 
Symptom Questionnaire (Visual Analog Scale (VAS))...............................34 
6.6.2 
Symptom Assessment in Dry Eye Questionnaire ........................................35 
6.6.7 
Unanesthetized Schirmer Test ......................................................................39 
6.8 
Safety Assessments ...............................................................................................45 
6.8.1 
Vital Signs .......................................................................................................45 
6.8.2 
Corrected Visual Acuity ................................................................................46 
6.8.3 
Biomicroscopy ................................................................................................46 
6.8.4 
Intraocular Pressure ......................................................................................46 
6.8.5 
Dilated Fundoscopy .......................................................................................46 
6.9 
Adverse Events Assessments ...............................................................................47 
6.9.1 
Performing Adverse Event Assessments ......................................................47 
6.9.2 
Adverse Event Definitions .............................................................................47 
6.9.3 
Reporting Adverse Events .............................................................................48 
6.9.4 
Severity............................................................................................................49 
6.9.5 
Relationship ....................................................................................................50 
6.9.6 
Expectedness ...................................................................................................50 
6.9.7 
Clinical Laboratory Adverse Events ............................................................51 
6.9.8 
Serious Adverse Events, Serious Adverse Reactions or Suspected 
Unexpected Serious Adverse Reactions .......................................................51 
6.10 
Participant Discontinuation/Withdrawal from the Study ................................52 
6.10.1 
Actions after Discontinuation .......................................................................52 
6.10.2 
Discontinuation of the Entire Study .............................................................53 
6.10.3 
Completed Study ............................................................................................53 
7. 
STUDY ACTIVITIES ..............................................................................................53 
7.1 
Screening and Run-In Period .............................................................................53 
7.1.1 
Screening Visit (Day -14 [+3* days]) ............................................................53 

 
 
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7.2 
Randomized Intervention Period .......................................................................54 
7.2.1 
Baseline (Day 1) Procedures .........................................................................54 
7.2.2 
Day 7 (± 2 days) Procedures ..........................................................................56 
7.2.3 
Day 14 (± 2 days) Procedures ........................................................................56 
7.2.4 
Day 28 (± 2 days) Procedures ........................................................................57 
7.2.5 
Day 60 (± 5 days) Procedures ........................................................................58 
7.2.6 
Day 90 (-2 / +5 days) Procedures ..................................................................58 
7.3 
Early Termination Procedures ...........................................................................60 
7.4 
Unscheduled Visits ...............................................................................................60 
8. 
QUALITY CONTROL AND ASSURANCE .........................................................60 
9. 
PLANNED STATISTICAL METHODS ................................................................61 
9.1 
General Considerations .......................................................................................61 
9.1.1 
Unit of Analysis ..............................................................................................61 
9.1.2 
Study Eye Selection ........................................................................................61 
9.1.3 
Missing Data ...................................................................................................62 
 
 
9.3 
Analysis Populations ............................................................................................64 
9.3.1 
Intent-to-Treat Population ............................................................................64 
9.3.2 
Per Protocol Population ................................................................................64 
9.3.3 
Safety Population ...........................................................................................64 
9.4 
Demographics and Baseline Characteristics .....................................................64 
9.5 
Efficacy Analyses .................................................................................................65 
9.5.1 
Primary Efficacy Endpoints..........................................................................65 
9.5.2 
Primary Efficacy Analyses ............................................................................65 
9.5.3 
Secondary Efficacy Endpoints ......................................................................66 
9.5.4 
Secondary Efficacy Analyses ........................................................................67 
9.6 
Safety Endpoints and Analyses ...........................................................................69 
10.  ADMINISTRATIVE CONSIDERATIONS ...........................................................69 
10.1 
Investigators .........................................................................................................69 
10.2 
Medical Monitor ...................................................................................................69 
10.3 
Institutional Review Board Approval ................................................................70 
10.4 
Ethical Conduct of the Study ..............................................................................70 
10.5 
Subject Information and Consent ......................................................................71 
10.6 
Subject Confidentiality ........................................................................................71 
10.7 
Study Monitoring .................................................................................................71 
10.8 
Interactive Response Technology .......................................................................72 
10.9 
Case Report Forms and Study Records .............................................................72 
10.10  Protocol Deviations ..............................................................................................73 
10.11  Access to Source Documentation ........................................................................73 
10.12  Data Generation and Analysis ............................................................................74 
10.13  Retention of Data .................................................................................................74 

 
 
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10.14  Financial Disclosure .............................................................................................74 
10.15  Publication and Disclosure Policy ......................................................................75 
11.  REFERENCES .........................................................................................................76 
12.  APPENDICES ...........................................................................................................78 
 
TABLE OF TABLES 
 
 
Table 3 
Study Intervention Dispensing Schedule ...............................................34 
 
TABLE OF FIGURES 
Figure 1 
 Study Design Diagram ............................................................................20 
Figure 2 
Ocular Discomfort: Visual Analog Scale ...............................................35 
Figure 3 
SANDE Questionnaire .............................................................................36 
 
LIST OF APPENDICES 
Appendix 1 
 Schedule of Visits and Procedures.........................................................78 
 

 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ANCOVA 
Analysis of Covariance 
AE 
Adverse Event 
AR 
Adverse Reaction 
BID 
Twice Daily 
CAE 
Controlled Adverse Environment 
CFB 
Change From Baseline 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CONSORT 
Consolidated Standards of Reporting Trials 
CRO 
Contract Research Organization 
DED 
Dry Eye Disease 
DHHS 
Department of Health and Human Services 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
EDS 
Eye Dryness Score 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GRAS 
Generally Recognized as Safe 
ICF 
Informed Consent Form 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 

 
 
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IUS 
Intrauterine Hormone-Releasing System 
IV 
Intravenous 
LOCF 
Last Observation Carried Forward 
LOGMAR 
Logarithm of the Minimum Angle of Resolution 
LS 
Least Square 
NCS 
Not Clinically Significant 
ODS 
Ocular Discomfort Score 
OTC 
Over-the-Counter 
OD 
Right Eye 
OS 
Left Eye 
OU 
Both Eyes 
PP 
Per Protocol 
 
 
SAE 
Serious Adverse Event 
SANDE 
The Symptom Assessment Questionnaire iN Dry Eye 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SOP 
Standard Operating Procedure 
SD 
Standard Deviation 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
TID 
Three Times Daily 
TRPM8 
Transient Receptor Potential Melastatin 8 
ULN 
Upper Limit of Normal 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
WOCBP 
Women of Child-Bearing Potential 

 
 
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1. INTRODUCTION 
AR-15512 is a potent and selective agonist of Transient Receptor Potential Melastatin 8 
(TRPM8) that is being developed for the treatment of the signs and symptoms of dry eye 
disease (DED). 
1.1 
Background 
DED is a multifactorial disease of the ocular surface characterized by a loss of homeostasis 
of the tear film, and accompanied by ocular symptoms, in which tear film instability and 
hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities 
play etiological roles (Craig 2017). Epidemiological data suggest the prevalence of DED falls 
in the range of 5% to 50% of the global population ≥ 50 years old, depending on the 
definition of DED that was used (Baudouin 2014, Bron 2014, Rolando 2010, Smith 2007, 
Stapleton 2017, Uchino 2013).  
DED is broadly attributed to either impaired tear film production or excessive tear film 
evaporation. Either of these changes to the tear film can compromise the health of the ocular 
surface with associated epithelial damage, which can adversely affect visual function. 
This can be experienced as blurred vision and ocular surface discomfort, often described as a 
feeling of dryness, burning, itchiness, or a sandy/gritty sensation. 
Treatment of DED is mainly symptomatic and very few specific pharmacologic therapies are 
currently approved (Jones 2017). Artificial tear preparations are generally the first therapy 
considered. Artificial tears are based on lubricating or viscosity-increasing agents and there is 
limited evidence suggesting that any one type of artificial tear is markedly better than others 
(Doughty 2009). With respect to pharmaceuticals, various strategies exist for targeting the 
underlying ocular inflammation associated with DED with two products (Restasis® [0.05% 
cyclosporine ophthalmic emulsion] and Cequa™ [0.09% cyclosporine ophthalmic solution]) 
indicated for increased tear production in patients with DED and a third, Xiidra® (5.0% 
lifitegrast ophthalmic solution), indicated for the treatment of the signs and symptoms of 
DED. In addition, a novel cholinergic agonist, delivered nasally (varenicline solution, nasal 
spray 0.03mg [Tyrvaya™]), is approved for the treatment of signs and symptoms of DED. 
The short-term application of topical ocular steroids is also used for acute management of 
DED. 
In recent years, increased attention has been placed on the neuronal regulation of tear 
production. The trigeminal nerve provides the pathway for parasympathetic stimulation of 
the lacrimal functional unit and sensory stimulation of the cornea and conjunctiva is essential 
for initiating basal tear production (Belmonte 2015; Belmonte 2017). Reduced corneal 
neuron density and / or dysfunction of the corneal sensory nerves have been hypothesized to 
contribute to the pathogenesis of DED. The functional types of sensory nerve fibers of the 
cornea are distinguished by their selective expression of different transient receptor potential 
channels, each of which confers a specific sensitivity to mechanical, thermal, or chemical 
stimuli. 

 
 
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Branches of the trigeminal nerve innervating the cornea and lids selectively express cold 
sensitive thermoreceptors, called TRPM8 receptors (Belmonte 2017, Viana 2011). TRPM8 
receptors are associated with the detection of ocular surface dryness and are activated by 
evaporative cooling and hyperosmolarity leading to regulation of tear production and blink 
rate (Belmonte 2017, Yang 2017, Yang 2018). In addition, agonists of TRPM8 promote a 
cooling sensation that may be beneficial for reducing ocular discomfort and pain. Taken 
together, TRMP8 agonists may have a dual role in the potential treatment of DED by both 
stimulation of tear production and reduction of discomfort (Abelson 2013). 
AR-15512 is a potent and selective agonist of TRPM8 that has been used as a flavoring agent 
or adjuvant in the food industry and as cooling agent for chewing gum and candies for 
several years. AR-15512 was acquired by Aerie in connection with the acquisition of 
Avizorex Pharma S.L. (“Avizorex”), who began the development of AR-15512 ophthalmic 
solution.  
When applied topically to the eye, AR-15512 activates cold thermoreceptor nerve terminals 
of the cornea leading to regulation of tear production and blink rate. In addition, a cooling 
sensation may be produced which could be beneficial for reduction of ocular discomfort. 
Preclinical and clinical evidence to date support the mechanism of AR-15512 as an agonist of 
TRPM8 and the ability of AR-15512 to modulate corneal nerve impulse activity leading to 
increased tear production and a reduction of DED symptoms. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of AR-15512 is 
provided in the investigator’s brochure (IB). A summary of the clinical studies can be found 
in Section 1.2 below.  

 
 
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1.3 
Risk/Benefit Assessment 
AR-15512 has been used as a flavoring agent or adjuvant in the food industry and as a 
cooling agent for chewing gum and candies for more than a decade. AR-15512 (FL-no. 
16.123) is generally recognized as safe (GRAS) as a flavoring agent or adjuvant 
(USFDA/FEMA GRAS No. 4681) in or on human food products with no safety concerns at 
specified use levels (EU/EFSA 2014; WHO/JECFA No. 2079). 
In vitro, in vivo and ex vivo studies have also been performed on AR-15512 to demonstrate 
safety, tolerability and negligible systemic exposure and to characterize the effective dose 
and the regimen of ocular administration of AR-15512 ophthalmic solution. In addition, 
Aerie has conducted two good laboratory practice (GLP) 3-month repeated-dose topical 

 
 
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3.3 
Study Duration and Dates 
The duration of subject participation is approximately 15 weeks (2 weeks vehicle run-in 
period before randomization followed by 13 weeks of randomized study intervention 
administration). 
4. STUDY POPULATION SELECTION 
4.1 
Study Population 
This study is anticipated to enroll approximately 460 subjects with DED as defined below in 
Sections 4.2 and 4.3 so as approximately 414 subjects complete Day 90. The anticipated 
dropout rate is 10%. To achieve this goal, approximately 1500 subjects may be screened.  
4.2 
Inclusion Criteria 
Subjects must meet all of the following criteria to enter into the study: 
1. Male or female, 30 years of age or older at the Screening visit 
2. Have a previous history of DED, clinician diagnosed or patient reported, within the 
previous 6 months prior to the Screening visit 
3. Have used, and/or desired to use artificial tears for DED symptoms within 2 months 
prior to the Screening visit 
8. Corrected visual acuity equal to or better than logMar +0.7 (Snellen equivalent equal 
to or better than 20/100), as assessed by Early Treatment of Diabetic Retinopathy 
Study (ETDRS) scale in both eyes at both the Screening and Baseline visits  

 
 
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9. Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol 
10. Written informed consent from the subject has been obtained prior to any study 
related procedures 
11. Able, as assessed by the investigator, and willing to follow study instructions and 
likely to complete all required study visits 
4.3 
Exclusion Criteria 
Subjects meeting any of the following criteria during Screening and/or Baseline visits 
(i.e., qualification visits) will be excluded from entry into the study: 
1. History or presence of any ocular disorder or condition (other than DED) in either 
eye that would, in the opinion of the investigator, interfere with the interpretation of 
the study results or subject safety, such as: significant corneal or conjunctival 
scarring; pterygium or nodular pinguecula; conjunctivitis, or inflammation not 
associated with DED; anterior (epithelial) basement membrane corneal dystrophy or 
other clinically significant corneal dystrophy or degeneration; evidence of 
keratoconus; etc. (Note: Blepharitis and/or Meibomian gland disease not requiring 
treatment are allowed.) 
2. Current evidence of other significant ophthalmic disease requiring topical medication 
(e.g. glaucoma or ocular hypertension), which may interfere with vision (e.g., 
cataract, macular degeneration) or other disease which the investigator believes may 
interfere with study findings or interpretation 
3. Diagnosis of recurrent, ongoing, or active ocular infection including, but not limited 
to herpes simplex or zoster, vaccinia, varicella, tuberculosis of the eye, 
acanthamoeba, or fungal disease 
4. History of ocular surgery within 1 year prior to the Screening visit, including punctal 
cautery, corneal refractive, or anterior segment surgeries that affect corneal sensitivity 
(e.g., cataract surgery or any surgery involving limbal or corneal incision) 
5. Have had a corneal transplant in either or both eyes 
6. Use of contact lenses in either eye within 7 days prior to the Screening visit or 
planned use during the study 
7. Punctal or intracanalicular plug present in either eyelid at the Screening visit or 
anticipated plug insertion or occlusion at any time during the study. If a subject had 
plugs, they must have been removed at least 14 days prior to the screening visit 
8. Regular use of lid hygiene within 14 days prior to the Screening visit or any planned 
use during the study 
9. Use of lid heating therapy (i.e., LipiFlow®, iLUX®, TearCare®) or Meibomian gland 
probing/therapeutic expression within 1 year prior to the Screening visit or 
anticipated during the study 

 
 
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10. Use of artificial tears within 2 hours prior to the Screening visit or anticipated use 
during the study 
11. Use of any topical ocular anti-inflammatory medication within 30 days prior to the 
Screening visit or anticipated use during the study (e.g., ocular cyclosporine 
[Restasis®, Cequa™], lifitegrast [Xiidra®], any other prescription ophthalmic product 
for DED, topical ocular corticosteroid- or non-steroidal-anti-inflammatory agents, or 
autologous serum  
12. Use of any topical ocular glaucoma medication within 30 days prior to the Screening 
visit or anticipated use during the study 
13. Regular use of any other topical ocular medication (i.e., in addition to medications 
excluded by exclusion criterion #11 or #12) within 14 days prior to the Screening 
visit or anticipated use during the study (e.g., eye whitening products [Visine®, 
Lumify®], topical ocular antibiotics, topical ocular antihistamines, mast cell 
stabilizers, age-related blurry near vision (presbyopia) drops [Vuity™], or other over-
the-counter [OTC], herbal, prescription, or nutritional supplements). Note: Occasional 
short-term use of these topical ocular medications will be permitted provided that no 
drops were used within 24 hours of the Screening visit or anticipated use within 
24 hours of any study visit 
14. Use of Tyrvaya™ (varenicline solution, nasal spray 0.03mg) within 30 days prior to 
the Screening visit or anticipated use during the study 
15. Use of medications for the treatment of severe DED and/or Meibomian gland disease 
such as oral pilocarpine, oral cevimeline, oral macrolides, oral tetracyclines, oral 
tetracycline derivatives, and oral retinoids within 30 days prior to the Screening visit 
or anticipated use during the study 
16. Initiation, discontinuation, or change in dose of a systemic medication known to 
cause ocular drying (e.g., antihistamines or tricyclic antidepressants) less than 14 days 
prior to the Screening visit or a change in dosage is anticipated during the study. 
Note: Occasional short-term use of medications such as systemic antihistamines will 
be permitted provided that use was not within 24 hours of the Screening visit or 
anticipated use within 24 hours of any study visit 
17. Initiation, discontinuation, or change in dose of a systemic corticosteroid less than 
60 days prior to the Screening visit or a change in dosage is anticipated during the 
study. Note: Non-ocular topically applied corticosteroids (including topical creams, 
nasal sprays and inhalers) will be permitted during the study and the dose is not 
required to be stable 
18. Initiation, discontinuation, or change in dose of a systemic immunomodulator 
(e.g., hydroxychloroquine, methotrexate, cyclosporine) less than 60 days prior to the 
Screening visit or a change in dosage is anticipated during the study  
19. Have received any vaccine within 3 days prior to the Screening or Baseline visit  
20. Use of an investigational product or device within 30 days prior to the Screening visit 
21. Randomization to a study arm in Phase 2b AR-15512-CS201 (COMET-1) study  
22. At the Screening visit, at the investigator’s discretion, have uncontrolled or severe: 

 
 
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a. Systemic allergy 
b. Rhinitis or sinusitis 
23. History or presence of significant systemic disease (i.e.: cardiovascular, pulmonary, 
hepatic, renal, hematologic, immunologic). Significant is defined as any disease that, 
in the assessment of the Investigator, would put the safety of the subject at risk 
through participation, or which would prevent or confound protocol-specified 
assessments (e.g., severe Sjögren’s syndrome, severe rheumatoid arthritis, severe 
systemic lupus erythematosus, uncontrolled immunodeficiency disease, etc.) 
24. Known allergies or sensitivity to the study interventions or study diagnostic agents 
including sodium fluorescein, lissamine green, etc. 
25. Positive pregnancy test at Screening or Baseline visits or currently breastfeeding or 
plans to become pregnant or breastfeed during the study 
26. Women of childbearing potential who are not using a medically acceptable form of 
birth control  
27. The subject has a condition or is in a situation that, in the Investigator’s opinion, may 
put the subject at significant risk, may confound the study results, or may interfere 
significantly with the subject’s participation in the study 
28. Employees directly involved in the AR-15512-CS301 trial at the clinical site  
4.4 
Screen Failures 
A screen failure occurs when a participant who consents to participate in the clinical study is 
not subsequently randomized. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAEs. Individuals who do not meet the criteria for participation in 
this study (screen failures) may be rescreened for eligibility up to one time if there is a 
reasonable possibility, in the Investigator’s opinion, that the patient might meet the eligibility 
criteria. It is encouraged for the investigator to discuss potential rescreening with the 
Sponsor. Rescreened participants should be assigned a new participant number for every 
screening/rescreening event. 
4.5 
During-Study Restrictions 
4.5.1 
Prior and Concomitant Therapy 
Pharmacologic and non-pharmacologic therapies and surgeries/procedures will be queried as 
described in Sections 6.3 and 6.2. 
4.5.1.1 
Prohibited Prior and Concomitant Therapies 
The table below outlines all prohibited prior and concomitant therapies. Additional details 
can be found in the Supplemental Medication Guide. Subjects must discontinue the use of 
any of the therapies or interventions listed in Table 1 for the specified period prior to the 

 
 
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Screening visit and these therapies or interventions must not be used during the course of the 
study. Use of any of these therapies or interventions during the course of the study must be 
documented as a protocol deviation unless otherwise specified in a “Note” or Section 4.5.1.3. 
4.5.1.2 
Prior and Concomitant Therapies Requiring Stability 
Table 2 below outlines all prior and concomitant therapies requiring stability. Additional 
details can be found in the Supplemental Medication Guide. Subjects using these therapies 
prior to the study must have been on a stable dose or treatment for the time period specified 
in the table. Initiation, change in dose, or discontinuation of any of these therapies during the 
study must be documented as a protocol deviation unless otherwise specified in a “Note” or 
Section 4.5.1.3. 

 
 
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Table 2 
Prior and Concomitant Therapies Requiring Stability 
Treatment/Intervention 
Required Period of Stability Prior to 
the Screening Visit 
Any systemic medication known to cause ocular drying (e.g., 
antihistamines, tricyclic antidepressants)  
Note: Occasional short-term use of medications such as systemic 
antihistamines will be permitted provided that use was not within 24 
hours of any Study visit 
14 days1  
Systemic immunomodulators (e.g., hydroxychloroquine, 
methotrexate, cyclosporine) 
60 days1 
Systemic corticosteroids (e.g., IV and oral)  
60 days1 
1  The use of these medications is allowed during the study provided that the dosing regimen is stable for the 
time specified in the table (prior to the Screening visit).  The total time for washout if one of these 
medications is discontinued prior to the Screening visit is the same duration required for stability.  
4.5.1.3 
Permitted Prior and Concomitant Therapies 
Therapy considered necessary for the subject’s welfare may be given at the discretion of the 
investigator. Additional details can be found in the Supplemental Medication Guide. If the 
use of a specific therapy or intervention is in question, please contact Aerie (see Section 
10.2). 
Use of the following is permitted during the study: 
 Any systemic medication not itemized as an exclusion in Section 4.3 is permitted. 
 Occasional (as needed) use of medications such as non-prescription anti-
inflammatories / pain relievers (e.g. aspirin, acetaminophen etc.), and acid-
reflux/heartburn medications will be permitted. 
 Occasional short-term use of medications such as systemic antihistamines will be 
permitted but should be discouraged. Use is not allowed within 24 hours of any 
Study visit 
 For example, as needed (short-term) use of and cold/flu medications that do 
not contain antihistamines is permitted and these medications are preferred. 
Cold/flu medications that do contain antihistamines are discouraged but will 
be permitted (please refer to the Prohibited and Permitted Concomitant 
Medication List).  
 Vaccines are permitted during the study provided that they are not administered 
within 3 days of any study visit 
 Occasional short-term use of topical ocular medications not described in exclusion 
criteria #11 and #12 are permitted  
 Examples of topical ocular medications that may be used on an occasional 
short-term bases include: eye whitening products [Visine®, Lumify®], topical 
ocular antibiotics, topical ocular antihistamines, mast cell stabilizers or other 
OTC, herbal, prescription, or nutritional supplements 
 These topical ocular medications must not be used within 24 hours of any 
study visit 

 
 
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 Although occasional short-term use is permitted, use of these topical ocular 
medications should be discouraged 
 Non-ocular topical or other (non-ocular) locally acting corticosteroids (e.g., topical 
creams, nasal sprays, inhalers etc.) are permitted. 
 Skin care products containing retinoids are permitted.  
4.5.2 
Fluid and Food Intake 
No requirements or restrictions. 
4.5.3 
Subject Activity Restrictions 
Subjects are not to administer the evening dose of the randomized study intervention on 
Days 1, 7, 14, 28 and 90 since this dose will be administered during the clinic visit instead. 
4.5.4 
Women of Childbearing Potential and Acceptable Contraceptive Methods 
An adult woman is considered to be of childbearing potential unless she is at least 1-year 
post-menopause (no menses for 12 months or more without an alternative medical cause) 
or at least 3 months post-surgical sterilization. Subjects must not intend to become pregnant 
during the study and must properly use an acceptable effective method of contraception.  
If a woman is of childbearing potential, she must have a pregnancy test performed at the 
visits specified in the Schedule of Visits and Procedures (Appendix 1). Additional pregnancy 
tests may also be required per local regulatory guidelines. Subjects with positive pregnancy 
test result must be excluded from the study. Subjects with negative pregnancy test must agree 
to use an acceptable effective contraception method during the study.  
Acceptable contraceptive methods when used consistently and in accordance with both the 
product label and the instructions of the physician (Clinical Trials Facilitation Group 2020), 
include: 
1. Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, or transdermal) 
2. Progestogen-only hormonal contraception (oral, injectable, or implantable) 
3. Intrauterine device (IUD) 
4. Intrauterine hormone-releasing system (IUS) 
5. Bilateral tubal occlusion  

 
 
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6. Vasectomized partner1  
7. Sexual abstinence2  
8. Male or female condom with or without spermicide 
9. Cap, diaphragm, or sponge with spermicide 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method are not acceptable 
methods of contraception. 
4.5.4.1 
Pregnancy Reporting 
If pregnancy of a subject occurs during the study, the Investigator will notify the Sponsor 
within 24 hours of learning of the pregnancy. Any subject who becomes pregnant while 
participating in the study will discontinue study intervention.  
Every attempt will be made to collect data on the pregnancy with subject permission. 
The investigator will collect follow-up information on the subject and the neonate and the 
information will be forwarded to the Sponsor. Abnormal pregnancy outcomes 
(e.g., spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) 
are considered SAEs and will be reported as such. 
5. STUDY INTERVENTIONS 
Study intervention is defined as any investigational product(s), marketed product(s), placebo, 
vehicle(s), or medical device(s) intended to be administered to a study participant according 
to the study protocol. 
5.1 
Description of Study Interventions 
5.1.1 
Investigational Product 
AR-15512 ophthalmic solution is a sterile, preservative-free, isotonic, buffered aqueous 
solution containing 0.003% AR-15512, hypromellose, polyoxyl 35 castor oil, sodium 
dihydrogen phosphate dihydrate, and sodium chloride in water (either purified water or water 
for injection). The product formulations are adjusted to a pH of approximately 7 with sodium 
hydroxide and are packaged in blow-fill-seal containers of extruded polyethylene. 
 
1 Vasectomized partner is considered to be a highly effective birth control method providing that the partner is 
the sole sexual partner of the women of childbearing potential and that the vasectomized partner has received a 
medical assessment of the surgical success 
 
2 Sexual abstinence is considered to be an acceptable method of contraception when defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study interventions. The reliability 
of sexual abstinence needs to be evaluated in relation to the duration of the trial and the preferred and usual 
lifestyle of the subject 

 
 
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The investigational product will be provided in masked identical kits. 
5.1.2 
Vehicle (Control) 
AR-15512 ophthalmic solution vehicle is a sterile, preservative-free, isotonic, buffered 
aqueous solution containing hypromellose, polyoxyl 35 castor oil, sodium dihydrogen 
phosphate dihydrate, sodium chloride in water (either purified water or water for injection). 
The product formulation is adjusted to a pH of approximately 7 with sodium hydroxide and 
is packaged in blow-fill-seal containers of extruded polyethylene. 
AR-15512 vehicle will be provided in masked identical kits, identical to the investigational 
product. 
5.2 
Selection and Timing of Dose for Each Patient 
Subjects who qualify at the Screening visit will be instructed on proper administration 
procedure to instill 1 drop of AR-15512 vehicle BID to both eyes on Days -14 to -1 
(vehicle run-in period) as follows: 1 drop in each eye in the morning (from approximately 
7:00h to 10:00h) and 1 drop in each eye in the evening (from approximately 19:00h to 
22:00h). A new vial should be used for each administration time (both eyes dosed from one 
vial). 
Following the vehicle run-in period, those subjects who requalify at the Baseline visit, will be 
randomized into two groups, in a 1:1 ratio within each site, as follows: 
 0.003% AR-15512 (n = 230) 
 AR-15512 vehicle (n = 230) 
Subjects will be re-instructed on proper administration procedures at the Baseline visit. 
Subjects will be instructed to administer their randomized study intervention BID to both 
eyes as follows: 1 drop in each eye in the morning (from approximately 7:00h to 10:00h) and 
1 drop in each eye in the evening (from approximately 19:00h to 22:00h). A new vial should 
be used for each administration time (both eyes dosed from one vial). At the Screening visit, 
the morning dose of AR-15512 vehicle will be administered in clinic by the subject under 
site staff supervision. At the Day 1, Day 7, Day 14, Day 28 and Day 90 visits, the “evening” 
(or second) dose of randomized study intervention will be administered by the site staff, 
thus there will be no “evening” (or second) dose administered by the subjects on these days. 
All office visits must be arranged at approximately the same time of day ± 1 hour.  
5.3 
Method of Assigning Patients to Study Intervention Groups 
All subjects will be centrally assigned to randomized study intervention using interactive 
response technology (IRT). Before the study is initiated, the log-in information and directions 
for the IRT will be provided to qualified personnel at each site. 

 
 
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All qualified subjects will be assigned to receive AR-15512 vehicle BID to both eyes 
for approximately 14 days during the vehicle run-in period. Following the run-in period, 
all subjects who requalify at the Baseline visit (Day 1), will be randomized in a 1:1 ratio, 
within each site, to receive 0.003% AR-15512 or AR-15512 vehicle. The IRT will provide 
the site with the specific kit number(s) for each randomized subject at the time of 
randomization. Sites will dispense the study intervention according to the IRT instructions 
and the Schedule of Visits and Assessments (Appendix 1).  
5.4 
Masking 
During the vehicle run-in period, the subject will be masked. During the randomized study 
intervention period, the investigator and site staff performing eligibility / efficacy and safety 
assessments and the subjects will be masked. Subjects will remain masked during the 
randomized phase. Subjects will be informed that they all will receive vehicle at some point 
in the study, but the exact timing will not be specified.   
AR-15512 (0.003%) and AR-15512 vehicle will be provided in identical single-use blow-fill-
seal containers.  
5.5 
Unmasking 
A randomization schedule for allocating the study interventions within a site will be prepared 
by an unmasked statistician who is not involved in the day-to-day conduct of the study. 
Study intervention assignments will be masked to the Investigator, the clinical study team 
(Sponsor, personnel involved in day-to-day study management, Monitors, Data Managers, 
and Statisticians), and the subjects. Only in case of medical emergency or occurrence of 
adverse events that warrant unmasking in the opinion of the investigator, will the study 
intervention assignment(s) be unmasked and made available to the Investigator and the 
Medical Monitor. In the absence of medical need, the randomization code will not be 
available to the above personnel until after the study is completed and the database is locked. 
If the Investigator feels it is necessary to unmask a subject’s study intervention assignment 
after an emergency situation, the Investigator should contact the Medical Monitor. Only after 
consultation with the Medical Monitor will a decision be made as to whether or not the study 
intervention for the subject should be unmasked. The study intervention assignment will be 
revealed on a subject-by-subject basis, thus leaving the masking on the remaining subjects 
intact. 
5.6 
Study Intervention Compliance 
At the Screening visit, the morning dose will be administered in clinic by the subject under 
supervision from site personnel. For the Day 1, Day 7, Day 14, Day 28 and Day 90 visits, 
the “evening” dose will be administered by designated site personnel; all other doses will be 
administered by the subject. Study intervention compliance will be assessed by site records 
for these treatments. 

 
 
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The subjects’ used and unused study intervention vials will be collected at each visit from the 
Baseline visit up to and including the Day 90 (Exit) visit to assess dosing compliance. Dosing 
compliance will be based off the used and unused vial count. If the subject is less than 80% 
or more than 125% compliant with dosing based on the expected number of used and unused 
vials, then the subject will be deemed non-compliant and a protocol deviation must be 
recorded. Subjects will be instructed on instillation and storage of study intervention at the 
end of each visit (excluding the exit visit), as well as provided written instructions. 
These guidelines will be used by the Investigator for determining the subject’s necessary 
compliance for the study and for recording deviations from this compliance. 
The study centers will keep an accurate accountability record that specifies the amount of 
study intervention dispensed to each subject, the amount of study intervention returned to the 
site, and the dates of each. 
5.7 
Packaging and Labeling 
Each packaged unit will be labeled with an investigational label with the information 
required per applicable regulations. 
The products for each study intervention assignment will be packaged into identical 
randomized intervention kits; each randomized intervention kit will contain one of 2 study 
interventions: 0.003% AR-15512 ophthalmic solution or AR-15512 ophthalmic solution 
vehicle. 
Additional detail is provided in the Pharmacy Manual.  
5.8 
Storage 
The study intervention must be dispensed and administered according to the procedures 
prescribed in this protocol and Pharmacy Manual. Only qualified subjects may receive study 
intervention, in accordance with all the applicable regulatory requirements. Only authorized 
staff is allowed to dispense these study interventions. Under normal conditions of handling 
and administration, the study interventions are not expected to pose significant safety risk to 
site staff. Adequate precautions must be taken to avoid direct contact with the study 
intervention. The study interventions will be stored in a secure area under the appropriate 
physical conditions for the product. Access to the study intervention will be limited to 
authorized site staff only. The study interventions will be stored as directed on the 
investigational label. The study interventions must be stored in clinic refrigerated (2°C to 
8°C/36°F to 46°F) until dispensed to the subject. Temperature of the study intervention 
storage location at the site is to be monitored using a calibrated monitoring device and 
documented. Study intervention should be removed from the refrigerator at least 30 minutes 
before use. At time of dispensing, the subject will be instructed to store the study intervention 
per details in the Pharmacy Manual and to protect from light (store in carton) as directed on 
the investigational label. Subjects should be instructed not to freeze the study intervention.  

 
 
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5.9 
Accountability 
5.9.1 
Receipt and Disposition of Study Medication  
Study interventions will be shipped to the Investigator’s site from a central depot. If a 
discrepancy is noted, the appropriate individual at the Sponsor or designee must be notified 
immediately, in accordance with the Pharmacy Manual. The responsible person(s) for 
dispensing study intervention at the Investigator’s site is the only site staff member(s) 
permitted to distribute study intervention and also has sole responsibility to account for all 
returned used, partially used and unused vials of study intervention. The study intervention(s) 
must not be used outside this protocol. An Investigational Product Accountability Log will be 
kept at each clinical site.  
5.9.2 
Return of Study Intervention 
When the study is completed or is terminated by the Sponsor, all study materials including 
used and unused study intervention kits / vials will be returned to the Sponsor or their 
designee. Subjects should be instructed to retain all vials (used, partially used or unused) of 
study intervention and return them to the clinical site. All study intervention accounting 
procedures must be completed before the study is considered to be concluded. 
The responsible person(s) at the Investigator’s site has the sole responsibility to account for 
all used, partially used, and unused study intervention. This site staff member at the 
Investigator’s site will complete a study intervention returns form or equivalent that will be 
signed by the Investigator or designee prior to returning the used and unused study 
intervention vials to the Sponsor or their designee. 
6. STUDY PROCEDURES 
6.1 
Informed Consent 
Prior to any study procedures, the study will be discussed with each subject, and subjects 
wishing to participate must give written informed consent. The verbal explanation of the 
study will cover all the elements specified in the written information provided for the subject. 
The Investigator will inform the subject of the aims, methods, anticipated benefits, and 
potential hazards of the study, including any discomfort it may entail. The subject must be 
given every opportunity to clarify any points he/she does not understand and, if necessary, 
may ask for more information. At the end of the interview, the subject should be given time 
to reflect. Subjects and/or a legally authorized representative then will be required to sign and 
date the ICF. 
The ICF must have received approval/favorable review by a properly constituted Institutional 
Review Board (IRB) prior to use. A copy of the signed and dated consent document will be 
given to each subject. The original signed and dated ICF must be maintained in the study 
files at the Investigator’s site. 

 
 
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The Investigator or staff is responsible for ensuring that no subject is exposed to any study 
related examination or activity before the subject has given written informed consent. 
It should be emphasized that the subject is at liberty to withdraw consent to participate at any 
time, without penalty or loss of benefits to which the subject is otherwise entitled. Subjects 
who refuse to give, or withdraw, written informed consent may not be included or continued 
in this study, and should be notified that discontinuation from the study will not impact their 
subsequent care. 
6.2 
Demographics, Medical and Surgical History 
Demographic data will be collected and recorded. Significant medical and ophthalmic history 
will be collected and any current underlying medical/ophthalmic conditions, including those 
that may have resolved before the Screening visit, must also be recorded. All relevant 
medical and ophthalmic surgical procedures should be recorded. 
6.3 
Prior and Concomitant Medication Assessments 
Any medication (including vaccines, OTC, prescription medicines, vitamins, and/or herbal 
supplements) that the participant is receiving at the time of enrollment or receives during the 
study must be recorded. Prior medications taken up to at least 90 days prior to the Screening 
visit must also be recorded. Additional details on prohibited and allowable medications can 
be found in the Supplemental Medication Guide. 
6.4 
Clinical Laboratory Tests 
6.4.1 
Laboratory Parameters 
A chemistry panel, a complete blood count (hematology and differential), and urinalysis will 
be performed as described in the Laboratory Manual.  
6.4.2 
Sample Collection, Storage and Shipping 
The site staff responsible for collecting the laboratory samples will be identified on the Site 
Authorization and Delegation Log. Details for the preparation and shipment of samples and 
reference ranges will be provided in the Laboratory Manual. 
6.4.3 
Pregnancy Testing  
Urine pregnancy tests for women of childbearing potential (WOCBP; defined in 
Section 4.5.4) are required at Screening, Baseline and Day 90 (Study Exit) visits. Pregnancy 
tests must be negative for the subject to receive study intervention. 
6.5 
Dispensing Study Intervention 
Masked study-related site personnel will be cautioned that any used or unused study 
intervention kits are not to be opened at the clinical site by the site staff involved in efficacy 
or safety assessments. 

 
 
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Study staff responsible for dispensing study intervention will be listed on the Site 
Authorization and Delegation Log. When a subject meets all criteria for enrollment, 
the subject will be randomly assigned to a study intervention according to the IRT. 
The responsible study staff will account for all used, partially used and unused study kits / 
vials by maintaining a Study Intervention Accountability log. 
See Table 3 for the study intervention dispensing schedule. Details of timing and procedures 
for dispensing study intervention are found in the Pharmacy Manual.  
Table 3 
Study Intervention Dispensing Schedule 
Study Day 
Quantity Dispensed to Subject 
-14 
1 Run-In kit (40 vials) 
1 
1 Randomized Intervention Kit (40 vials) 
7 
1 vial administered in-office from the Day 7 Kit 
14 
1 Randomized Intervention Kit (40 vials) 
28 
2 Randomized Intervention Kits (80 vials) 
601 
2 Randomized Intervention Kits (80 vials) 
90 
Study Exit 
1. Dispensation and collection of study intervention only. No other procedures 
are scheduled on this day. 
6.6 
Efficacy Assessments  
6.6.1 
Symptom Questionnaire (Visual Analog Scale (VAS)) 
Subjects will be asked to rate each of the following DED symptoms (both eyes together), 
over the last 24 hours, each on a separate VAS: ocular discomfort (ODS), eye dryness (EDS), 
. For each VAS, subjects will be asked to place a vertical mark on the horizontal 
line to indicate the level of each symptom, with 0 corresponding to “no symptom” and 100 
corresponding to “maximal symptom”. The assessment line length of each scale will be 
100 mm (Figure 2). Instructions for measuring each subject’s response on each VAS can be 
found in the Manual of Procedures.  

 
 
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Figure 2 
Ocular Discomfort: Visual Analog Scale  
 
 
 
Eye Dryness: Visual Analog Scale 
 
 
6.6.2 
Symptom Assessment in Dry Eye Questionnaire 
The SANDE questionnaire (Schaumberg 2007) is comprised of 2 unique VASs to assess the 
frequency and severity of DED symptoms. Subjects will be asked to complete the SANDE to 
rate both the frequency and severity of DED symptoms for both eyes together. Each of the 
two questions will be accompanied by a VAS. The assessment line length of the scale will be 
100 mm and will be similar to the following depiction (Figure 3). Higher scores indicate 
greater frequency or severity.  
Instructions for measuring each subject’s response on each VAS can be found in the Manual 
of Procedures. The SANDE score will be calculated by multiplying the frequency score by 
the severity score and obtaining the square root. The final value must be rounded to the 
nearest whole number.  
__________________________________________ 
0 
 
 
 
 
 
100 
 
       (No Ocular Discomfort)  
  
  
      (Maximum Ocular Discomfort) 

 
 
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Figure 3 
SANDE Questionnaire  
 

 
 
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6.6.7 
Unanesthetized Schirmer Test 
Two unanesthetized Schirmer tests will be performed on both eyes at each of the Baseline 
(Day 1), Day 7, Day 14, Day 28 and Day 90 visits.  
Placement and removal of the strips should be performed by the Investigator, sub-
Investigator or designated trained personnel. Reading of the strips post-test, should be 
performed by only the Investigator or sub-Investigator. Every effort should be made to 
ensure the same individual(s) performs this assessment for a given subject at each applicable 
visit. 
Additional details can be found in the Manual of Procedures.   

 
 
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6.8.2 
Corrected Visual Acuity  
Logarithmic minimum angle of resolution (LogMAR) visual acuity in both eyes must be 
assessed using an ETDRS Series 2000 chart. Visual acuity should be evaluated prior to 
ocular examinations as specified in the Schedule of Visits and Procedures (Appendix 1). 
Additional procedural details can be found in the Manual of Procedures.  
6.8.3 
Biomicroscopy  
Slit lamp biomicroscopic observations will be graded as Normal or Abnormal. Abnormal 
findings will be categorized as clinically significant (findings that may interfere with study 
parameters or otherwise confound the data as determined by the investigator) or not clinically 
significant (NCS). The following will be examined in both eyes: 
 Cornea  
 Conjunctiva 
 Anterior Chamber 
 Iris 
 Lens 
 Eyelid 
Additional procedural details can be found in the Manual of Procedures. 
6.8.4 
Intraocular Pressure 
The IOP must be measured in both eyes only after the biomicroscopic exam is completed and 
must be measured prior to pupil dilation. IOP will be taken by qualified study site personnel 
with the subject seated. Every effort should be made to ensure that the same study site 
personnel use the same device for IOP measurement for a given subject. A Goldmann 
applanation tonometer affixed to a slit lamp is the preferred device for IOP measurement. 
6.8.5 
Dilated Fundoscopy 
Dilated fundus exams will be performed in both eyes using indirect ophthalmoscopy. 
The Investigator will make observations of the vitreous, retina, macula, choroid and optic 
nerve. 
Observations will be graded as Normal or Abnormal. Abnormal findings that are clinically 
significant (as determined by the Investigator that may interfere with study parameters or 
otherwise confound the data) and those that are not clinically significant will be described. 
An indirect Fundoscopy examination should be performed if retinal disease is detected. 
 Vitreous: Examination should emphasize the visual axis. 
 Retina, Macula, Choroid: Include an observation of the retina and its blood vessels. 
Eyes should be excluded from the study if active inflammation is present. 
 Optic Nerve: Significant damage or cupping to the optic nerve should be noted. 

 
 
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It is recommended that tropicamide 1% ophthalmic solution be used to dilate subjects. 
6.9 
Adverse Events Assessments 
6.9.1 
Performing Adverse Event Assessments 
All AEs occurring during the study, regardless of the assumption of causal relationship, must 
be documented on the respective eCRF.  
Qualified study staff responsible for assessing AEs will be listed on the Site Authorization 
and Delegation Log. This includes assessment of AE severity and relationship to treatment. 
AE information may be volunteered by the subject or solicited by study personnel through 
non-leading questions.  
Documentation of AEs/adverse reactions will include AE description, start date and stop 
date, severity, relationship, action(s) taken, seriousness, and outcome. 
If a disease is known at the time an AE is reported, this diagnosis should be recorded rather 
than listing of individual symptoms. However, if a cluster of symptoms cannot be identified 
as a single diagnosis, each individual event should be reported separately. If a diagnosis is 
subsequently known, it should be reported as follow-up information. 
When recording an AE, the following information should be provided on the study AE 
eCRF: 
1. Action Taken with Study Intervention: 
 None 
 Study Intervention Discontinued 
 Study Intervention Interrupted 
2. AE Outcome: 
 Fatal 
 Not Recovered/Not Resolved 
 Recovered/Resolved 
 Recovered/Resolved with sequelae 
 Recovering/Resolving 
 Unknown/Lost to follow-up 
6.9.2 
Adverse Event Definitions 
The following definitions of terms apply to this section:  
 Adverse event (AE): any untoward medical occurrence associated with the administration 
of the study intervention in humans, whether or not considered to be related to the study 
intervention.  

 
 
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 Adverse reaction (AR): any AE for which there is a reasonable possibility that the 
administration of the drug caused the AE. For the purposes of Investigational New Drug 
(IND) safety reporting, “reasonable possibility” means there is evidence to suggest a 
causal relationship between the administration of the drug and the AE. See Section 6.9.5. 
 Life-threatening AE or life-threatening AR: an AE or AR is considered “life-threatening” 
if, in the view of either the Investigator or Sponsor, its occurrence places the subject at 
immediate risk of death. It does not include an AE or AR that, had it occurred in a more 
severe form, might have caused death.  
 Serious adverse event (SAE) or serious adverse reaction (SAR): an AE or AR is 
considered “serious” if, in the view of either the Investigator or Sponsor, it results in any 
of the following outcomes: Death, a life-threatening or sight-threatening AE, subject 
hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias, or convulsions that do not 
result in subject hospitalization, or the development of drug dependency or drug abuse. 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported 
as a serious adverse event when the hospitalization or prolonged hospitalization was for 
an elective surgical procedure or for a preexisting condition (with no increase in 
severity).  
 Unexpected AE or unexpected AR: an AE or AR is considered “unexpected” if it is not 
listed in the Investigator’s Brochure or is not listed at the specificity or severity that has 
been observed; or, if an Investigator’s Brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application, as amended. See section 6.9.6. 
6.9.3 
Reporting Adverse Events 
AEs should be documented from the time the subject provides informed consent until subject 
participation in the study has been completed. If a serious or non-serious AE or adverse 
reaction is unresolved at the time of exit, efforts will be made to follow up until the AE or 
adverse reaction is resolved or stabilized, the subject is lost to follow-up, or there is other 
resolution to the event. These follow-up visits will be documented.  
If an event occurs after informed consent but prior to subject enrollment and the 
commencement of study medication, it should be recorded as an AE. Any change in the 
health status after commencement of study medication should be recorded as treatment 
emergent adverse events (TEAEs). 

 
 
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Surgery should not be reported as an outcome of an adverse event if the purpose of the 
surgery was diagnostic and the outcome was uneventful. 
6.9.3.1 
AEs and Prior Medical History  
Any medical condition present prior to informed consent which remains unchanged or 
improved should not be recorded as an AE at subsequent visits. However, an AE should be 
recorded if the frequency, intensity, or the character of a pre-existing condition worsens 
during the study period beyond what would be expected from the natural progression of that 
condition.  
Symptoms and signs that are consistent with the natural history of DED are not considered 
reportable adverse events. Such developments are recorded but are not reportable adverse 
events. Worsening of symptoms and signs of DED should be recorded as an AE or SAE only 
if judged by the investigator to have unexpectedly worsened in severity and/or frequency or 
changed in nature at any time during the study. When recording an unanticipated worsening 
of DED, it is important to convey why the development was unexpected.   
If there is a question as to whether a medical development should be reported as an adverse 
event, the Investigator is recommended to contact the Sponsor for guidance. 
6.9.4 
Severity 
Severity of an AE is defined as a qualitative assessment of the level of discomfort or the 
degree of intensity of an AE as determined by the Investigator or reported to them by the 
subject. The assessment of severity is made irrespective of study medication relationship or 
seriousness of the event and should be evaluated according to the following scale: 
 1 = Mild: present and noticeable, but not distressing, and no disruption of normal daily 
activities 
 2 = Moderate: bothersome, discomfort sufficient to possibly reduce or affect normal daily 
activity 
 3 = Severe: incapacitating, with inability to work or perform normal daily activity 
A change in increased severity for a reported AE will require a stop date for the previous 
severity and a new start and stop date for the new severity. For example, a change in severity 
may go from mild to moderate, or from moderate to severe. In either case, the start and stop 
dates should be recorded. 
Note: A severe AE is not the same as a serious AE. Seriousness of an AE (NOT severity) 
serves as a guide for defining regulatory reporting obligations (see Section 6.9.8 for further 
information on SAEs, SARs, and suspected unexpected serious adverse reactions 
[SUSARs]).  

 
 
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6.9.5 
Relationship 
A relationship between the AE and the study intervention or study procedure will be 
determined by the Investigator, as applicable, for each AE using these explanations:  
 Not Related: The event is clearly related to other factors such as subject’s clinical 
condition, therapeutic interventions, concomitant disease, or therapy administered to the 
subject and does not follow a known response pattern to the product, device, or 
procedure.  
 Unlikely Related: The event is most probably caused by other etiologies such as subject’s 
underlying condition, therapeutic intervention, or concomitant therapy; or the delay 
between administration and the onset of the AE is incompatible with a causal 
relationship. Therefore, there is not a reasonable possibility that the AE was caused by 
the product, device, or procedure.  
 Possibly Related: The event follows a reasonable, temporal sequence from the time of 
study medication administration or study procedure and/or follows a known response 
pattern to the product, device or procedure but could have been produced by other factors 
such as the subject’s clinical state, therapeutic interventions, or concomitant therapy 
administered to the subject.  
 Related: The event follows a reasonable, temporal sequence from the time of study 
medication administration or study procedure and/or follows a known response pattern to 
the product, device or procedure and cannot be reasonably explained by other factors 
such as subject’s clinical state, therapeutic interventions or concomitant therapy 
administered to the subject, and either occurs immediately following study medication 
administration or procedure, or improves on stopping the study medication, or reappears 
on repeat exposure, or there is a positive reaction at the application site.  
6.9.6 
Expectedness 
 AEs or ARs are considered “unexpected” if they are not listed in the Reference Safety 
Information section of the Investigator’s Brochure for AR-15512 or are not listed at the 
specificity or severity that has been observed. “Unexpected,” as used in this definition, 
also refers to AEs or ARs that are mentioned in the Investigator’s Brochure as occurring 
with this class of drugs or as anticipated from the pharmacological properties of 
AR-15512 and are not specifically mentioned as occurring with the study drug.  
For example, under this definition, hepatic necrosis would be unexpected (by virtue of 
greater severity) if the Investigator’s Brochure referred only to elevated hepatic enzymes 
or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be 
unexpected (by virtue of greater specificity) if the Investigator’s Brochure listed only 
cerebral vascular accidents. “Unexpected,” as used in this definition, also refers to AEs or 

 
 
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ARs that are mentioned in the Investigator’s Brochure as occurring with a class of drugs 
or as anticipated from the pharmacological properties of the drug but are not specifically 
mentioned as occurring with the particular drug under investigation. 
 An Investigator must immediately (i.e., within 24 hours from time of awareness) report 
any SAE or SAR (see Section 6.9.2 for definitions) to the Sponsor or its clinical research 
organization (CRO) representative, whether or not considered drug-related, including 
those listed in the protocol or Investigator’s Brochure. 
6.9.7 
Clinical Laboratory Adverse Events 
Clinical laboratory values (other than pregnancy tests results) that are noted as abnormal and 
clinically significant at study exit and that are changes from Screening values will be 
documented as AEs. 
6.9.8 
Serious Adverse Events, Serious Adverse Reactions or Suspected Unexpected 
Serious Adverse Reactions 
6.9.8.1 
Reporting SAEs or SARs  
An Investigator must immediately (i.e., within 24 hours) report any SAE or SAR 
(see Section 6.9.2 for definitions) to the Sponsor or its CRO representative, whether or not 
considered study intervention-related, including those listed in the protocol or Investigator’s 
Brochure. The Investigator must use the SAE report form and include an assessment of 
whether there is a reasonable possibility that the drug caused the event. The Investigator must 
report any SAE or SAR that occurs or is observed during the study. In case of incomplete 
information, the Investigator must provide follow-up information as soon as possible, again 
using the SAE report form. The email or fax to submit the SAE report is found in Section 
6.9.8.3.  
SAE reports will be evaluated by the Medical Monitor. Regulatory authorities, IRB, and 
Investigators at each of the study sites will be informed as required.   
6.9.8.2 
Reporting Suspected Unexpected Serious Adverse Reactions (SUSARs)  
The Investigator must immediately (i.e., within 24 hours) report SUSARs. In the event of 
SUSAR, the site must notify the Medical Monitor (Section 10.2) for the study and submit an 
SAE report form within 24 hours of notification, observation, or occurrence of the SUSAR, 
whether or not complete information is available. In the case of incomplete information, 
the Investigator must provide follow-up information as soon as possible using the SAE report 
form. 

 
 
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6.9.8.3 
SAE Report Contact Information  
Safety Email: aeriesmb@continuumindia.com  
Safety Fax: +91 1724106300 
6.10 
Participant Discontinuation/Withdrawal from the Study 
A subject may exit the study by their own volition or at the discretion of the Investigator or 
the Medical Monitor. Any subject may decide to voluntarily withdraw from the study at any 
time without prejudice.  
The subject may also be discontinued from the study for the following reasons:  
 
AEs (AEs including, in the opinion of the Investigator, clinically relevant laboratory 
abnormalities, and intercurrent diseases reported by the subject or observed by the 
Investigator with documentation on the eCRF)  
 
Withdrawal of Consent  
 
Non-compliance (e.g., non-adherence to scheduled follow-up visits or use of study 
intervention)  
 
Lost to Follow-up  
 
Disallowed Concurrent Treatment 
 
Investigator Decision  
 
Protocol Deviation  
 
Death  
 
Does not meet entry criteria 
 
Other  
6.10.1 
Actions after Discontinuation 
Also see Early Termination Procedures (Section 7.3). 
All subjects who discontinue study intervention due to a report of an AE must be followed 
and provided appropriate medical care until their signs and symptoms have remitted or 
stabilized or until clinically meaningful abnormal laboratory findings have returned to 
acceptable or pre-study limits.  
For subjects who choose to withdraw consent or who are discontinued for non-compliance 
prior to completing the study, every possible effort should be made by the Investigator to 
assure there is a final visit that includes all examinations listed for the Early Termination 
Visit. 

 
 
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6.10.2 
Discontinuation of the Entire Study 
The entire study may be discontinued at any given site by the Investigator or the Sponsor or 
Sponsor representative, or at all sites by the Sponsor. Prompt, written notice of reasonable 
cause to all other relevant parties (Sponsor or Investigator) is required. Prompt notice to the 
IRB and to regulatory authorities is also required. 
6.10.3 
Completed Study  
The study is completed when the last visit of the last subject has been completed at the last 
site taking part in the study. The Sponsor or Sponsor representative will be in communication 
with the investigational sites regarding enrollment completion. 
7. STUDY ACTIVITIES 
7.1 
Screening and Run-In Period 
7.1.1 
Screening Visit (Day -14 [+3* days]) 
 Informed consent 
 Demographics 
 Medical, ophthalmic, and surgical history 
 Prior or concomitant medication review 
 Vital signs (heart rate and blood pressure) 
 Urine pregnancy test (WOCBP only) 
 Symptom Questionnaire (VAS) (Ocular Discomfort, Eye Dryness 
 
 SANDE Questionnaire (VAS) 
 Corrected visual acuity 
 Slit-lamp biomicroscopy 
 At least 5-minute rest period 
 
 
 
  
 
 

 
 
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 CAE exposure  
 
 
 
 
 Inclusion and exclusion criteria 
 AE Review 
 Dispensing of the study intervention 
 In office administration of study intervention by subject under site staff supervision 
 Intraocular pressure 
 Dilated fundus exam 
* The Baseline visit is requested to be scheduled between 11 and 14 days after the Screening 
visit. If absolutely necessary, the Baseline visit may be delayed up to 7 days (extending the 
run-in period to a maximum of 21 days).   
7.2 
Randomized Intervention Period 
7.2.1 
Baseline (Day 1) Procedures 
 Collection of used and unused study intervention  
 Concomitant medication review 
 AE review 
 Vital signs (heart rate and blood pressure) 
 Urine pregnancy test (WOCBP only) 
 Symptom Questionnaire (VAS) (Ocular Discomfort, Eye Dryness 
 
 SANDE Questionnaire (VAS) 

 
 
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 Corrected visual acuity  
 Slit-lamp biomicroscopy  
 
  
 
  
 
 
 
  
 
  
 
  
 
  
 Inclusion and exclusion criteria review 
 Randomization 
 Dispensing of study intervention 
 At least 30 and up to 45-minute rest period 
 Pre-drop unanesthetized Schirmer test  
 At least 15 and up to 20-minute rest period 
 In office administration of study intervention by site staff  
 Post-drop unanesthetized Schirmer test  
 Hematology, chemistry, and urinalysis 
 Intraocular pressure 
 Dilated fundus exam 
 

 
 
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7.2.2 
Day 7 (± 2 days) Procedures 
 Concomitant medication review 
 AE review 
 Symptom Questionnaire (VAS) (Ocular Discomfort, Eye Dryness 
) 
 SANDE Questionnaire (VAS) 
 
 
 
 
 Corrected visual acuity  
 Slit-lamp biomicroscopy  

 
 
 
 
 
  
 
  
 
  
 
 
 Pre-drop unanesthetized Schirmer test  
 At least 15 and up to 20-minute rest period 
 In office administration of study intervention by site staff 
 Post-drop unanesthetized Schirmer test 
7.2.3 
Day 14 (± 2 days) Procedures 
 Collection of used and unused study intervention  
 Concomitant medication review 
 AE review 

 
 
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 Symptom Questionnaire (VAS) (Ocular Discomfort, Eye Dryness
 
 SANDE Questionnaire (VAS) 
 
 
 
 
 Corrected visual acuity  
 Slit-lamp biomicroscopy  
 
  
 
 
 
 
 
 
 
  
 Dispensing of study intervention 
 At least 30 and up to 45-minute rest period 
 Pre-drop unanesthetized Schirmer test  
 At least 15 and up to 20-minute rest period 
 In office administration of study intervention by site staff 
 Post-drop unanesthetized Schirmer test  
7.2.4 
Day 28 (± 2 days) Procedures 
 Collection of used and unused study intervention  
 Concomitant medication review 
 AE review 
 Symptom Questionnaire (VAS) (Ocular Discomfort, Eye Dryness 
) 
 SANDE Questionnaire (VAS) 

 
 
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 Corrected visual acuity  
 Slit-lamp biomicroscopy  
 
  
 
  
 
 
 
  
 
  
 Dispensing of study intervention 
 At least 30 and up to 45-minute rest period 
 Pre-drop unanesthetized Schirmer test  
 At least 15 and up to 20-minute rest period 
 In office administration of study intervention by site staff 
 Post-drop unanesthetized Schirmer  
7.2.5 
Day 60 (± 5 days) Procedures 
 Collection of used and unused study intervention  
 Dispensing of study intervention 
7.2.6 
Day 90 (-2 / +5 days) Procedures 
 Collection of used and unused study intervention  
 Concomitant medication review 
 AE review 
 Vital signs (heart rate and blood pressure) 

 
 
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 Urine Pregnancy test (WOCBP only) 
 Symptom Questionnaire (VAS) (Ocular Discomfort, Eye Dryness 
 
 SANDE Questionnaire (VAS) 
 
 
 
 
 
 
 Corrected visual acuity  
 Slit-lamp biomicroscopy  
 
  
 
  
 
  
 
  
 
  
 
 
 Pre-drop unanesthetized Schirmer test  
 At least 15 and up to 20-minute rest period 
 In office administration of study intervention by site staff 
 Post-drop unanesthetized Schirmer test  
 Hematology, chemistry, and urinalysis 
 Intraocular pressure  
 Dilated fundus exam  
 Study Exit 

 
 
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7.3 
Early Termination Procedures 
Every effort should be made to perform the following procedures at the Early Termination 
visit. 
 Collection of used and unused study intervention 
 Concomitant medication review 
 AE review 
 Vital signs (heart rate and blood pressure) 
 Urine pregnancy test (WOCBP only) 
 Corrected visual acuity  
 Slit-lamp biomicroscopy  
 Hematology, chemistry, and urinalysis 
 Intraocular Pressure  
 Dilated Fundus Exam  
 Study Exit 
7.4 
Unscheduled Visits 
An unscheduled visit may be any visit to the Investigator other than the visits specified in the 
protocol as possibly required for the subject’s ophthalmic condition. 
The investigator will perform all procedures necessary to evaluate the study participant at 
these visits and record any AEs in the eCRF. 
8. QUALITY CONTROL AND ASSURANCE 
The progress of the study will be monitored by on-site, written, and telephone 
communications between personnel at the Investigator’s site and the Study Monitor. 
The Investigator will allow the Sponsor or designee and/or representatives of Health 
Regulatory Agencies to inspect all eCRFs, subject records (source documents), signed 
consent forms, study medication records (receipt, storage, preparation, and disposition), 
and regulatory files related to this study at mutually convenient times at regular intervals 
during the study and upon request after the study has been completed.  

 
 
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The purpose of these visits is to provide the Sponsor and/or Health Regulatory Agency the 
opportunity to evaluate the progress of the study, document compliance with the protocol and 
with regulatory requirements, verify the accuracy and completeness of subject eCRFs, 
resolve any apparent discrepancies or inconsistencies in the study records, and account for all 
investigational supplies. 
9. PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
Quantitative variables will be summarized using number of subjects (n), mean, median, 
standard deviation (SD), minimum and maximum. Qualitative variables will be summarized 
using counts and percentages.  
All summaries will be presented by treatment group. 
For the purpose of summarization, medical history, concurrent medications, and AEs will be 
coded to MedDRA and WHO Drug dictionaries, as appropriate. 
Baseline measures are defined as the last non-missing measure prior to the initiation of 
randomized study treatment unless otherwise defined in the SAP.  
Change from Baseline (CFB) will be calculated as post-Baseline result – Baseline; treatment 
comparisons will be calculated as AR-15512 – vehicle. 
All primary and secondary analyses will be two-sided at a significance level of 0.05. 
9.1.1 
Unit of Analysis 
Safety endpoints will be analyzed for both eyes. For efficacy endpoints assessed at the eye 
level, the unit of analysis will be the “study eye” as defined in Section 9.1.2. For efficacy 
endpoints assessed OU, the unit of analysis with be the subject. 
9.1.2 
Study Eye Selection 
The study subject must have at least one eye (the same eye) meeting all the inclusion criteria 
(Section 4.2) and none of the exclusion criteria (Section 4.3) at both Screening and Baseline 
visits where applicable. Study subjects will be dosed in both eyes. If both eyes are eligible at 
the time of randomization, the study eye will be defined as the eye with the lower pre-drop 
unanesthetized Schirmer score to be performed at the Baseline visit. If both eyes still qualify 
and have the same pre-drop unanesthetized Schirmer score, the right eye will be designated 
as the study eye 

 
 
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9.1.3 
Missing Data 
The primary analysis will be completed with available data per subject as specified in 
Estimand 1 from the intent-to-treat (ITT) population, assuming the overall study 
discontinuation rate is <5% in each arm. If the study discontinuation rate is ≥ 5% in each arm 
then the primary analysis will be based on multiple imputation methodology as specified in 
Estimand 2, and the available data analyses will become robustness analyses.  
Additional robustness analyses will include repeating the primary analysis on the ITT 
population imputing missing data as failures for the proportion of subjects with ≥ 10 mm 
increase in unanesthetized Schirmer score on Day 14 endpoint; using multiple imputation 
methodology under different assumptions of missingness (at random and not at random) each 
using 30 imputed values; the ITT population imputing missing data using last observation 
carried forward (LOCF); the ITT population using trimmed means; and the per-protocol (PP) 
population with available data per subject. 
9.1.4 
Hypotheses 
The primary endpoints will be tested as follows: 
H01: The difference between study eyes treated with AR-15512 (0.003%) and study eyes 
treated with vehicle, in the proportion of subjects with ≥ 10 mm increase in unanesthetized 
Schirmer score on Day 14 = 0. 
H11: The difference between study eyes treated with AR-15512 (0.003%) and study eyes 
treated with vehicle, in the proportion of subjects with ≥ 10 mm increase in unanesthetized 
Schirmer score on Day 14 ≠ 0. 

 
 
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9.2 
Determination of Sample Size 
Two hundred two (202) ITT population subjects (study eyes) per treatment group yields 99% 
power to conclude superiority of 0.003% AR-15512 over vehicle in the proportion of 
subjects with ≥ 10 mm increase in unanesthetized Schirmer score on Day 14, assuming a true 
difference of proportions (AR-15512 vs vehicle) of 80% vs 30% and a two-sided alpha 
= 0.05. 

 
 
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Additionally, 202 ITT population subjects (study eyes) per treatment group yields 99% 
power to conclude superiority of 0.003% AR-15512 over vehicle in the mean change from 
Baseline in SANDE score on Day 28 assuming a true difference (AR-15512 minus vehicle) 
of -7.9, a common SD of 17.72, and a two-sided alpha = 0.05.  
Accounting for subject discontinuations, approximately 460 total subjects (230 per treatment 
arm) will be randomized assuming a dropout rate of 10%. 
9.3 
Analysis Populations 
The following analysis population will be considered. 
9.3.1 
Intent-to-Treat Population 
The intent-to-treat (ITT) population includes all randomized subjects. The primary efficacy 
analysis will be performed on the ITT population. Subjects in the ITT will be analyzed as 
randomized. 
9.3.2 
Per Protocol Population 
The per protocol (PP) population includes subjects in the ITT population who do not have 
significant protocol deviations likely to seriously affect the primary outcome of the study and 
who complete the trial through Day 90. Protocol deviations will be assessed prior to database 
lock and unmasking. The PP population will be analyzed using observed data only for 
efficacy variables. Subjects in the PP population will be analyzed as treated. 
9.3.3 
Safety Population 
The safety population includes all randomized subjects who have received at least one dose 
of the investigational product. The safety population will be analyzed for all safety 
assessments. Subjects in the safety population will be analyzed as treated. 
9.4 
Demographics and Baseline Characteristics 
Subject demographics including age, sex, race, ethnicity, and iris color will be presented 
using summary statistics (mean, SD, minimum, maximum, and median) or frequency counts 
and percentages as appropriate. 

 
 
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9.5 
Efficacy Analyses 
9.5.1 
Primary Efficacy Endpoints 
 Proportion of subjects ≥ 10 mm increase in unanesthetized Schirmer score on Day 14 
9.5.2 
Primary Efficacy Analyses 
The primary comparison in this trial will be between AR-15512 (0.003%) and vehicle in the 
ITT population with available data per subject using Estimand 1 below if the overall study 
discontinuation rate is < 5%. If the discontinuation rate is ≥ 5%, this analysis will be a 
sensitivity analysis. 
Estimand 1: 
 Population: subjects in the ITT population with DED defined through enrollment 
criteria  
 Endpoint:  
o Proportion of subjects with ≥ 10 mm increase in unanesthetized Schirmer 
score on Day 14 
 Intercurrent event:  
o Discontinuation of investigational products is ignored. [treatment policy 
strategy]  
o Non-optimal compliance is ignored. [treatment policy strategy]  
o Withdrawal due to any reason. Missing data not imputed. [hypothetical 
strategy] 
 Population-level summary:  
o Difference in the proportion of subjects ≥ 10 mm increase in unanesthetized 
Schirmer score on Day 14 between AR-15512 (0.003%) and vehicle  
If the overall study discontinuation rate is ≥ 5% in each arm then the primary analysis will be 
based on multiple imputation methodology using Estimand 2 below. If the discontinuation 
rate is < 5% in each arm, this analysis will be a sensitivity analysis. 

 
 
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9.5.3 
Secondary Efficacy Endpoints 
 Change from Baseline in SANDE score on Day 28 
 Change from Baseline in unanesthetized Schirmer score on Day 14 
 Change from Baseline in SANDE Score on Day 90 
 Change from Baseline in ODS - VAS on Day 90 
 Change from Baseline in Eye Dryness - VAS Day 90 

 
 
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9.6 
Safety Endpoints and Analyses 
Adverse events will be coded using the MedDRA dictionary. Frequencies and percentages of 
treatment-emergent adverse events will be summarized at the subject level by system organ 
class and preferred term for all TEAEs, treatment related TEAEs, serious TEAEs, 
and TEAEs causing premature discontinuation of study drug by treatment group. An AE is 
treatment emergent if it occurs or worsens after the first dose of trial treatment. Similar 
summaries will be presented for all TEAEs by maximal severity. Separate summaries will be 
performed for ocular and non-ocular TEAEs. 
Other safety endpoints including visual acuity, slit-lamp biomicroscopy, and dilated 
fundoscopy will be summarized by treatment group and visit using descriptive statistics. 
Changes or shifts from Baseline will also be summarized where appropriate. For assessments 
performed by eye, study eye and fellow eye will be summarized separately.  
In addition, changes from Baseline to worst on-treatment value for ocular safety assessments 
will be summarized. 
10. ADMINISTRATIVE CONSIDERATIONS 
10.1 
Investigators 
The Principal Investigator is responsible for all site medical-related decisions.  
10.2 
Medical Monitor 
The Sponsor Lead shall serve as the primary point of contact for sites for all medical monitor 
queries. The Sponsor Lead will work with and / or elevate actions / site questions to the 
medical monitor, to ensure complete and accurate transfer of information, documentation of 
all queries and continued appropriate conduct of study. The Sponsor Lead contact 
information is: 

 
 
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The medical monitor should be contacted for urgent medical queries that require immediate 
(24 hour) response. 
10.3 
Institutional Review Board Approval 
This protocol, materials used to recruit subjects, and materials used to document consent 
must be approved by the IRB prior to initiation of the study. The name and address of each 
reviewing IRB will be documented in the Trial Master File for each participating country. 
Written IRB approval must adequately identify the protocol and informed consent. 
In addition to approving the protocol, the IRB must also approve the Subject Information and 
Consent Form, as well as any advertising tools that will be used for the study.  
Written approval also must indicate whether approval was granted based on full committee 
review or expedited review. Copies of all approved materials, all correspondence with the 
IRB and written approval from the IRB must be made available to the Sponsor, prior to the 
start of subject enrollment into the study. The investigator will report promptly to the IRB 
any new information that may adversely affect the safety of the subjects or the conduct of the 
study. The investigator will submit written summaries of the study to the IRB as required. 
On completion of the study the IRB will be notified that the study has ended. 
10.4 
Ethical Conduct of the Study 
The study will be conducted according to this clinical protocol and will be governed by all 
applicable governmental rules and regulations concerning the conduct of clinical trials on 
human subjects. This includes, but is not limited to:  
 The approval of IRBs 
 The Helsinki Declaration (World Medical Association 2013)  
 US Code of Federal Regulations, Title 21 
 International Conference on Harmonization (ICH) Consolidated Good Clinical Practice 
Guideline (E6 R2) 
 SOPs of the Sponsor and any other vendors participating in the conduct of the study 
 Obtaining prospective informed consent 

 
 
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10.5 
Subject Information and Consent 
Informed consent must take place before any study specific procedures are initiated. Signed 
and dated written informed consent must be obtained from each subject and/or from the 
subject’s legal representative prior to enrollment into the study. 
All informed consent forms must be approved for use by the Sponsor and receive 
approval/favorable opinion from an IRB prior to their use. If the consent form requires 
revision (e.g., due to a protocol amendment or significant new safety information), it is the 
Investigator’s responsibility to ensure that the amended informed consent is reviewed and 
approved by the Sponsor prior to submission to the governing IRB and that it is read, signed 
and dated by all subjects subsequently enrolled in the study as well as those currently 
enrolled in the study if directed by the IRB. 
10.6 
Subject Confidentiality 
The Investigator and his/her staff will maintain all personal subject data collected and 
processed for the purposes of this study using adequate precautions to ensure confidentiality, 
in accordance with local, state, and country laws and regulations.  
Monitors, auditors and other authorized representatives of Aerie, the IRB approving this 
study, and government regulatory authorities (e.g., FDA) may be granted direct access to the 
study subject’s original medical and study records for verification of the data or clinical study 
procedures. Access to this information will be permitted to representatives of the 
aforementioned organizations to the extent permitted by law.  
A report of this study’s results may be published or sent to the appropriate health authorities 
in any country in which the study drug may ultimately be marketed, but subject identities will 
not be disclosed in these documents. 
10.7 
Study Monitoring 
Clinical research associates will be responsible for monitoring the study sites and study 
activities. They will contact and visit the Investigator regularly. The actual frequency of 
monitoring visits depends on subject enrollment and on study site performance. Among 
others, the following items will be reviewed: 
 Study progress 
 Compliance with the protocol 
 Completion of eCRFs 
 Storage and accountability of study intervention 
 Source data verification 
 AE and SAE reporting 
 Essential documents contained within the regulatory binder 

 
 
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For source data verification (i.e., comparison of eCRF entries with subject records), critical 
data points will be source verified and will include, but not be limited to: subject 
identification, informed consent and assent, if applicable (procedure, signature, and date), 
selection criteria, and primary efficacy and safety parameters (i.e., AEs). All other data will 
be subject to risk-based source verification, with specific details outlined in a Monitoring 
Plan. 
10.8 
Interactive Response Technology 
Interactive response technology (IRT) is a validated touch-tone phone or web-based system 
that can be used for subject randomization/study intervention request, drug inventory 
management, emergency unmasking, and by study subjects for recording diary responses. 
Interactive response technology activities will be performed as described in the IRT User 
Manual. 
10.9 
Case Report Forms and Study Records 
An investigator is required to prepare and maintain adequate and accurate case histories that 
record all observations and other data pertinent to the investigation on each individual 
administered the study intervention or employed as a control in the investigation. Case 
histories include the case report forms and supporting data including, for example, signed 
and dated consent forms and medical records including, for example, progress notes of the 
physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the 
study. 
Study data will be recorded via electronic case report forms (eCRFs). Each authorized study 
staff member will receive a unique access account in order to use the Electronic Data Capture 
(EDC) system. Access accounts will not be shared among study staff. Authorized users will 
make entries and/or changes to the eCRF via a secure internet access. Each completed set of 
eCRFs will be reviewed by the Investigator who will then electronically sign and date the 
eCRF confirming that data for the subjects are complete and accurate. 
Source document information should be legible. Recorded data should only be corrected by 
drawing a single line through the incorrect entry and writing the revision next to the 
corrected data. The person who has made the correction should place his or her initials as 
well as the date of the correction next to the correction. Data may not be obliterated by 
erasure, redaction, or with correction fluid. 
The study records must include a copy of each Investigator's curriculum vitae and medical 
license, completed FDA Form 1572 / Statement of Investigator, each eCRF, subject 
charts/source documents, Investigator's Brochure, Investigator’s Brochure amendments, 
protocol, protocol amendments, correspondence with the Sponsor and the IRB, IP storage, 
receipts, returns and dispensing records, Delegation of Responsibilities Log, site training 
records, records of site monitoring, unmasking documentation, AE and SAE reporting, IRB 
approvals, advertisements, written information provided to subjects, and subject completed 

 
 
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ICFs. If the Investigator moves, withdraws from an investigation, or retires, the responsibility 
for maintaining the records may be transferred to another person (e.g., Sponsor, other 
Investigator) who will accept the responsibility. Notice of this transfer, including written 
acceptance, must be made to and agreed upon by the Sponsor. 
10.10 Protocol Deviations 
Per ICH E6 (Good Clinical Practice [GCP]) R2 Section 4.5.1 the Investigator/institution 
should conduct the trial in compliance with the protocol agreed with the Sponsor and, 
if required, by the Regulatory Authority and which was given approval/favorable opinion by 
IRB.  
Protocol waivers or deviations from the protocol inclusion and exclusion criteria are not 
allowed because they can potentially jeopardize the scientific integrity of the study regulatory 
acceptability or subject safety. Therefore, adherence to the criteria as specified in the 
protocol is essential.  
The site will contact the Sponsor for clarification of inclusion and/or exclusion criteria as 
needed prior to enrollment of the study subject. The Sponsor or their representative will 
document clarification requests and responses. If a subject does not meet any of the 
eligibility criteria, that subject may not be enrolled into the study. 
If the Investigator feels that in his/her clinical judgment, it is necessary to promptly 
implement reasonable alternatives to, or deviations from, the protocol in consideration of the 
safety of study subjects, the Sponsor is to be notified of these alternatives and deviations, 
and the reasons for such changes are to be documented in the study records. The Investigator 
is to also notify his/her IRB of any such changes. 
If a significant protocol deviation is identified by the Investigator or through site monitoring 
activities an immediate submission to the IRB may be required e.g., 24 or 48 hours (as per 
IRB guidelines). The Sponsor will assess any protocol deviation and decide whether any of 
these non-compliances should be reported to the relevant regulatory authority as a serious 
breach of GCP and the protocol. If per the relevant regulatory authorities’ requirements, 
the protocol deviation is not required to be reported immediately but is still required to be 
notified to the IRB, the specific protocol deviation will be added to the annual progress 
report. 
The Sponsor will review, designate, and/or approve all protocol deviations prior to the 
database lock. 
10.11 Access to Source Documentation 
Monitors, auditors, and other authorized representatives of the Sponsor, the governing 
IRB(s), the FDA, the Department of Health and Human Services (DHHS), and other 
domestic government agencies will be granted direct access to the study subject’s original 
medical and study records for verification of the data and/or clinical study procedures. 

 
 
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Access to this information will be permitted to representatives of the aforementioned 
organizations to the extent permitted by law. 
10.12 Data Generation and Analysis 
A system of computerized data validation checks will be implemented and applied to the 
database on an ongoing basis. Query reports pertaining to data omissions and discrepancies 
will be forwarded to the clinical Investigator and the Sponsor for resolution. The study 
database will be updated by the clinical investigator or their staff, in accordance with the 
resolved query reports. All changes to the study database will be documented. 
Data will be checked per CRO’s SOPs. The database will be locked, and a biostatistician will 
complete the analyses of the data in accordance with the SAP. 
10.13 Retention of Data 
The Investigator’s site and clinical laboratory will retain all records related to the study in 
compliance with ICH GCP Guidelines E6 (R2) sections 4.9.4 and 4.9.5, and appliable local 
regulations. 
Archived versions of the database will be saved by the Sponsor consistent with ICH Good 
Clinical Practices Guidelines E6 (R2) section 5.5.11, complying with whichever of the 
requirements is longer.  
If for any reason custody of the records must be transferred, the Sponsor is to be notified in 
writing of any such transfer. 
10.14 Financial Disclosure 
The Principal Investigator and sub-Investigators (as listed on Form FDA 1572) will provide 
financial disclosure information prior to participation in the study. The Principal Investigator 
and any sub-Investigators will notify the Sponsor promptly of any required revision to their 
financial disclosure status (if applicable) during the term of this study, annually, or at the end 
of the study.  
Under 21 CFR 54 the Investigator/Sub investigator is required to provide the sponsor with 
sufficient accurate financial information to allow for complete disclosure or certification and 
to update this information if any relevant changes occur during the study and for one year 
following its completion. 

 
 
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10.15 Publication and Disclosure Policy 
Study information for this protocol will be posted on publicly available clinical trial registers 
before enrollment of Subjects begins.  
Where required by applicable regulatory requirements, an Investigator signatory will be 
identified for the approval of the clinical study report. 
Aerie Pharmaceuticals, as the Sponsor, has proprietary interest in the study. Authorship and 
manuscript composition will reflect joint cooperation between multiple Investigators and 
sites and Aerie Pharmaceuticals personnel. For studies with multiple centers, no individual 
publications will be allowed prior to completion of the final report of the multicenter study 
except as agreed with Aerie Pharmaceuticals. 
 
 

 
 
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11. REFERENCES 
1. 
Abelson MBG, Daniel. Cool Opportunities to Modulate Nociception. Review of 
Ophthalmology.2013;20(12):48-50. 
2. 
Baudouin C, Aragona P, Van Setten G, Rolando M, Irkeç M, Benítez del Castillo J, et 
al; ODISSEY European Consensus Group members. Diagnosing the severity of dry eye: 
a clear and practical algorithm. Br J Ophthalmol. 2014;98(9):1168-1176. 
3. 
Belmonte C, Acosta MC, Merayo-Lloves J, Gallar J. What Causes Eye Pain? Current 
ophthalmology reports. 2015;3(2):111-21. 
4. 
Belmonte C, Nichols JJ, Cox SM, Brock JA, et al; TFOS DEWS II pain and sensation 
report. Ocul Surf. 2017; (15):404-447. 
5. 
Bron AJ, Tomlinson A, Foulks GN, Pepose JS, Baudouin C, Geerling G, et al. 
Rethinking dry eye disease: a perspective on clinical implications. Ocul Surf. 2014;12(2 
Suppl):S1-S31. 
6. 
Clinical Trials Facilitation and Coordination Group (CTFG). Recommendations related 
to contraception and pregnancy testing in clinical trials. Version 1.1. 
https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2020_09_HMA_CTFG_Contraception_guidance
_Version_1.1_updated.pdf. Published September 21, 2020. Accessed March 2, 2004.  
7. 
Craig JP, Nichols KK, Akpek,EK, Caffery B, et al. TFOS DEWS II Definition and 
classification report. Ocul Surf. 2017; (15): 276-283. 
8. 
Doughty MJ, Glavin S. Efficacy of different dry eye treatments with artificial tears or 
ocular lubricants: a systematic review. Ophthalmic & physiological optics. Journal of 
the British College of Ophthalmic Opticians (Optometrists). 2009;29(6):573-83. 
9. 
European Food Safety Authority (EFSA). Scientific Opinion on Flavouring Group 
Evaluation 304, Revision 1 (FGE.304Rev1): Four carboxamides from Chemical Groups 
30. EFSA Journal 2014; 12(7):3769. 
10. 
Gayton JL. Etiology, prevalence, and treatment of dry eye disease. Clin Ophthalmol. 
2009;3:405-412. 
11. 
Jones L, Downie LE, Korb D, Benitez-del-Castillo JM, et al. TFOS DEWS II 
Management and Therapy Report. Ocul Surf. 2017; (15):575-628. 
12. 
Nichols KK, Evans DG, Karpecki PM. A comprehensive review of the clinical trials 
conducted for dry eye disease and the impact of the vehicle comparators in these trials. 
Curr Eye Res. 2021;46(5):609-614. 
13. 
Noor NA. Dry Eye Disease: The Undervalued Impact on Quality of Life. World 
J.Ophthal. Vis. Res. 2018; (1-1):1-2. 
14. 
Reddy P, Grad O, Rajagopalan K. The Economic Burden of Dry Eye: A Conceptual 
Framework and Preliminary Assessment. Cornea. 2004; 23:751–761.  

 
 
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15. 
Rolando M, Geerling G, Dua HS, Benítez-del-Castillo JM, Creuzot-Garcher C. 
Emerging treatment paradigms of ocular surface disease: proceedings of the Ocular 
Surface Workshop. Br J Ophthalmol. 2010;94 Suppl 1:i1-9. 
16. 
Schaumberg DA, Gulati A, Mathers WD, Clinch T, Lemp MA, Nelson JD, Foulks GN, 
Dana R, Development and Validation of a Short Global Dry Eye Symptom Index. 2007. 
Ocul. Surf. (5:1):50-57. 
17. 
Smith JA, AlbeitzJ, Begley C, Caffery B, et al. The epidemiology of dry eye disease: 
Report of the epidemiology subcommittee of the International Dry Eye Workshop 
(2007). Ocul Surf.  2007a;5(2):93-107. 
18. 
Stapleton F, Alves M, Bunya VY, Jalbert I, et al; TFOS DEWS II epidemiology report. 
Ocul Surf. 2017; (15):334-365. 
19. 
Uchino M, Schaumberg DA. Dry Eye Disease: Impact on Quality of Life and Vision. 
Curr Ophthalmol Rep. 2013; 1(2): 51–57. 
20. 
USFDA/FEMA, Smith RL, Waddell WJ, Cohen SM, et al. GRAS Flavoring Substances 
25: The 25th publication by the Expert Panel of the Flavor and Extract Manufactures 
Association provides an update on recent progress in consideration of flavoring 
ingredients generally recognized as safe under the Food Additive Amendment. Food 
Technology 2011; 65(7), 44-75. 
21. 
Viana F. Chemosensory Properties of the Trigeminal System. 2011. ACS Chem. 
Neurosci. (2): 38–50. 
22. 
WHO Food Additives Series: 67. Safety Evaluation of Certain Food Additives. 
Prepared by the Seventy-sixth meeting of the Joint FAO/WHO Expert Committee on 
Food Additives (JECFA), World Health Organization, Geneva, 2012. 
23. 
World Medical Association. World Medical Association Declaration of Helsinki: 
Ethical Principles for Medical Research Involving Human Subjects. JAMA. 
2013;310(20):2191–2194. 
24. 
Yang JM, Li F, Liu Q, Rüedi M, Tak E, et al. A novel TRPM8 agonist relieves dry eye 
discomfort. BMC Ophthalmology. 2017; (17):101-115. 
25. 
Yang JM, Wei ET, Kim SJ, Yoon KC. TRPM8 Channels and Dry Eye. Pharmaceuticals 
2018; (11): 125-131. 
26. 
Yu J, Asche CV, Fairchild CJ. The Economic Burden of Dry Eye Disease in the United 
States: A Decision Tree Analysis. Cornea. 2011; 30:379–387. 
 
 

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Clinical Study Protocol: AR-15512-CS301, Amendment 2 
Aerie Pharmaceuticals, Inc.  
 
Confidential  
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AR-15512 Ophthalmic Solution 
Clinical Study Protocol: AR-15512-CS301, Amendment 2 
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Confidential  
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AR-15512 Ophthalmic Solution 
Clinical Study Protocol: AR-15512-CS301, Amendment 2 
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Confidential  
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AR-15512 Ophthalmic Solution 
Clinical Study Protocol: AR-15512-CS301, Amendment 2 
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Confidential  
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AR-15512 Ophthalmic Solution 
Clinical Study Protocol: AR-15512-CS301, Amendment 2 
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Confidential  
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AR-15512 Ophthalmic Solution 
Clinical Study Protocol: AR-15512-CS301, Amendment 2 
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Confidential  
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