A Long-Term Safety Study Evaluating the Safety and Systemic Exposure of AR-15512, a Cold Thermoreceptor Modulator, for the Treatment of Dry Eye Disease (COMET-4)
Phase: PHASE3
Conditions: Dry Eye Disease
Sponsor: Aerie Pharmaceuticals

 
 
 
 
 
A Long-Term Safety Study Evaluating the Safety and Systemic 
Exposure of AR-15512, a Cold Thermoreceptor Modulator, for the 
Treatment of Dry Eye Disease (COMET-4) 
 
STUDY ID: 
AR-15512-LTSS 
 
 
PROTOCOL 
 
 
NCT05493111 
 

 
 
AR-15512 Ophthalmic Solution 
Clinical Study Protocol: AR-15512-LTSS 
Aerie Pharmaceuticals, Inc.
 
 
 
 
 
Confidential 
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Clinical Study Protocol  
Study Title: 
A Long-Term Safety Study Evaluating the Safety and Systemic 
Exposure of AR-15512, a Cold Thermoreceptor Modulator, for the 
Treatment of Dry Eye Disease (COMET-4) 
Study Number: 
AR-15512-LTSS 
Study Phase: 
3 
Product Name: 
AR-15512 
Indication: 
Dry Eye Disease 
Investigators: 
Multicenter 
 
 
Sponsor: 
Aerie Pharmaceuticals, Inc. 
Sponsor 
Contact: 
4301 Emperor Boulevard Suite 400 
Durham, NC 27703 
+1-919-237-5300 
NCT Number: 
05493111 
 
 
Date 
Original Protocol (Rev 0): 
22 August 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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CLINICAL PROTOCOL CONTACT INFORMATION 
 
 
 
 
 

 
 
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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 Long-Term Safety Study Evaluating the Safety and Systemic Exposure of AR-15512, a Cold 
Thermoreceptor Modulator, for the Treatment of Dry Eye Disease (COMET-4) 
Study Number: 
AR-15512-LTSS 
Study Phase: 
3 
Primary Objective: 
To evaluate the safety of topical ophthalmic 0.003% AR-15512 compared to its vehicle dosed twice daily 
(BID) in subjects with dry eye disease (DED) for 12 months 
Study Design: 
This will be a 12 month, multicenter, vehicle-controlled, double-masked, randomized study conducted at 
approximately 10 sites in the United States. All subjects enrolled will have DED. The study will consist of a 
Baseline (Day 1) visit as well as visits on Day 14, Day 90, Day 180, Day 270, and Day 365 (Study Exit). In 
addition, there will be dispensing visits on Days 45, 135, 225, and 315. 
Subjects who qualify at the Baseline visit, based on inclusion/exclusion criteria, will be enrolled in the study 
and randomized in a 2:1 ratio within each site, to receive either 0.003% AR-15512 or AR-15512 vehicle to 
be administered BID as 1 drop in each eye for 12 months. Systemic pharmacokinetic (PK) evaluation will be 
performed in a subset of subjects (n=35).     
Study Population: 
This study is anticipated to randomize approximately 270 subjects with DED. Approximately 108 subjects 
out of 180 subjects randomized to receive 0.003% AR-15512 and 54 subjects out of 90 subjects randomized 
to receive vehicle are expected to reach the Day 365 visit. The anticipated dropout rate is 40%. To achieve 
this goal, approximately 360 subjects may be screened. 
Key Inclusion Criteria  
Subjects must meet all of the following criteria to enter into the study: 
 
Have a previous history of DED, clinician diagnosed or patient reported, within the previous 12 
months of the Baseline visit 
 
Have used or desired to use artificial tears for DED symptoms within 3 months prior to the Baseline 
visit 
 
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 the Baseline visit 

 
 
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 
Good general and ocular health, as determined by the investigator using medical history, ophthalmic 
examination and history, and vital signs (heart rate and blood pressure) at the Baseline visit 
Key Exclusion Criteria 
Subjects meeting any of the following criteria at the Baseline visit (i.e., qualification visit) will be excluded 
from entry into the study: 
 
History or presence of any severe ocular disorder or condition (other than DED) in either eye that is, 
in the opinion of the investigator, likely to interfere with subject safety or evaluation, 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 
 
Use of contact lenses in either eye within 7 days prior to the Baseline visit or planned use during the 
study 
 
Use of any topical ocular anti-inflammatory medication within 30 days prior to the Baseline 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 
 
Use of artificial tears within 2 hours prior to the Baseline visit 
 
Use of topical ocular autologous serum within 30 days prior to the Baseline visit or anticipated use 
during the study 
 
Use of any topical ocular glaucoma medication within 30 days prior to the Baseline visit or 
anticipated use during the study 
 
Use of Tyrvara™ (varenicline solution, nasal spray 0.03mg) within 30 days prior to the Baseline 
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 Baseline visit or anticipated use during the study 
 
Use of lid heating therapy (i.e., LipiFlow®, iLUX®) or Meibomian gland probing/therapeutic 
expression within 6 months prior to the Baseline visit or anticipated during the study 
 
Randomization to a study arm in Phase 2b AR-15512-CS201 (COMET-1) study, Phase 3 
AR-15512-CS301 (COMET-2) study or Phase 3 AR-15512-CS302 (COMET-3) study. 
Study Interventions and Dosing Regimens: 
Randomization (2:1) 
 
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 12 months (365 days) 
Safety Assessments: 
 
Adverse events 
 
Vital signs (heart rate and blood pressure) 
 
Endothelial cell counts 
 
Hematology, chemistry, and urinalysis 
 
Best corrected visual acuity (Baseline and Exit visits only) 
 
Corrected visual acuity   

 
 
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 
Biomicroscopy 
 
Total ocular staining 
 
Intraocular pressure (IOP) 
 
Dilated fundus exam 
Pharmacokinetics 
 
Systemic exposure (plasma pharmacokinetic parameters (selected sites)) 
 
 
 
 
 
 
 
 
 
 
Statistical Methods: 
Determination of Sample Size 
This study is designed to determine the long-term safety of 0.003% AR-15512. Approximately 270 subjects 
will be randomized in a 2:1 ratio to receive 0.003% AR-15512 (180 subjects) or AR-15512 vehicle (90 
subjects). Assuming a dropout rate of 40%, approximately 108 subjects randomized to receive 0.003% and 
54 subjects randomized to receive vehicle are expected to reach the Day 365 visit.   
With 108 subjects completing 1 year (365 days) on 0.003% AR-15512, the study will have 96% probability 
to detect adverse events that occur at a true rate of 3% or greater. That is, with 108 subjects completing 1 
year (365 days) on the investigational product, if a specific adverse event is not observed, then with 96% 
confidence, that adverse event occurs at a true rate of <3%. 
 
Analysis methods 
Frequencies and percentages of treatment-emergent adverse events (TEAEs) will be summarized for 0.003% 
AR-15512 and vehicle. 
Other safety endpoints including vital signs, endothelial cell counts, laboratory parameters (hematology, 
chemistry, and urinalysis), corrected visual acuity, best corrected visual acuity, biomicroscopy, total ocular 
staining, IOP, and dilated fundoscopy will be summarized by treatment group and visit using descriptive 
statistics. For assessments performed by eye, each eye will be summarized separately.  
Plasma pharmacokinetic parameters including AR-15512 area under the plasma concentration time curve 
(AUC), maximum recorded concentration (Cmax), minimum recorded concentration (Cmin), time of maximum 
concentration (Tmax) will be summarized. RCmax and RAUC (where R represents an accumulation factor) will 
be calculated.  
 
Date of Original Approved Protocol (Rev 0): 22 August 2022 
 
 

 
 
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TABLE OF CONTENTS 
SYNOPSIS ..........................................................................................................................5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..............................12 
1. 
INTRODUCTION ....................................................................................................14 
1.1 
Background ..........................................................................................................14 
1.2 
Clinical Development of AR-15512 ....................................................................15 
1.3 
Risk/Benefit Assessment ......................................................................................16 
2. 
STUDY OBJECTIVES ............................................................................................18 
2.1 
Primary Objective ................................................................................................18 
3. 
INVESTIGATIONAL PLAN ..................................................................................18 
3.1 
Overall Study Design and Plan ...........................................................................18 
3.2 
Rationale for Study Design and Control Group ...............................................19 
3.3 
Study Duration and Dates ...................................................................................19 
4. 
STUDY POPULATION SELECTION ...................................................................20 
4.1 
Study Population ..................................................................................................20 
4.2 
Inclusion Criteria .................................................................................................20 
4.3 
Exclusion Criteria ................................................................................................21 
4.4 
Screen Failures .....................................................................................................23 
4.5 
During Study Restrictions ...................................................................................23 
4.5.1 
Prior and Concomitant Therapy ..................................................................23 
4.5.2 
Fluid and Food Intake ...................................................................................25 
4.5.3 
Subject Activity Restrictions .........................................................................25 
4.5.4 
Women of Childbearing Potential and Acceptable Contraceptive 
Methods ...........................................................................................................25 
5. 
STUDY INTERVENTION ......................................................................................27 
5.1 
Description of Study Interventions.....................................................................27 
5.1.1 
Investigational Product .................................................................................27 
5.1.2 
Vehicle (Control) ............................................................................................27 
5.2 
Selection and Timing of Dose for Each Patient .................................................27 
5.3 
Method of Assigning Patients to Study Intervention Groups ..........................28 
5.4 
Masking .................................................................................................................28 
5.5 
Unmasking ............................................................................................................28 
5.6 
Study Intervention Compliance ..........................................................................29 
5.7 
Packaging and Labeling ......................................................................................29 
5.8 
Storage and Dispensation ....................................................................................29 
5.9 
Accountability ......................................................................................................30 
5.9.1 
Receipt and Disposition of Study Medication .............................................30 
5.9.2 
Return of Study Intervention ........................................................................30 
6. 
STUDY PROCEDURES ..........................................................................................30 
6.1 
Informed Consent ................................................................................................30 
6.2 
Demographics, Medical and Surgical History...................................................31 
6.3 
Prior and Concomitant Medication Assessments .............................................31 
6.4 
Vital Signs .............................................................................................................31 
6.5 
Clinical Laboratory Tests....................................................................................31 

 
 
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6.5.1 
Laboratory Parameters .................................................................................31 
6.5.2 
Sample Collection, Storage and Shipping ....................................................32 
6.5.3 
Pregnancy Testing ..........................................................................................32 
6.6 
Systemic Pharmacokinetic Analysis ...................................................................32 
6.7 
Dispensing Study Intervention............................................................................32 
6.8 
Safety Assessments ...............................................................................................33 
6.8.1 
Corrected Visual Acuity ................................................................................33 
6.8.2 
Best Corrected Visual Acuity ........................................................................33 
6.8.3 
Specular Microscopy to Assess Corneal Endothelial Cell Counts.............33 
6.8.4 
Biomicroscopy ................................................................................................33 
6.8.5 
Ocular Surface Staining ................................................................................34 
6.8.6 
Intraocular Pressure ......................................................................................35 
6.8.7 
Dilated Fundus Exam by Slit Lamp .............................................................36 
6.10 
Adverse Events Assessments ...............................................................................37 
6.10.1 
Performing Adverse Event Assessments ......................................................37 
6.10.2 
Adverse Event Definitions .............................................................................38 
6.10.3 
Reporting Adverse Events .............................................................................38 
6.10.4 
Severity............................................................................................................39 
6.10.5 
Relationship ....................................................................................................40 
6.10.6 
Expectedness ...................................................................................................41 
6.10.7 
Clinical Laboratory Adverse Events ............................................................41 
6.10.8 
Serious Adverse Events, Serious Adverse Reactions or Suspected 
Unexpected Serious Adverse Reactions .......................................................41 
6.11 
Participant Discontinuation/Withdrawal from the Study ................................42 
6.11.1 
Actions after Discontinuation .......................................................................42 
6.11.2 
Discontinuation of the Entire Study .............................................................43 
6.11.3 
Completed Study ............................................................................................43 
7. 
STUDY ACTIVITIES ..............................................................................................43 
7.1 
Day 1 (Baseline) Procedures ...............................................................................43 
7.2 
Day 14 ....................................................................................................................44 
7.3 
Day 45 ....................................................................................................................45 
7.4 
Day 90 ....................................................................................................................45 
7.5 
Day 135 ..................................................................................................................46 
7.6 
Day 180 ..................................................................................................................46 
7.7 
Day 225 ..................................................................................................................47 
7.8 
Day 270 ..................................................................................................................47 
7.9 
Day 315 ..................................................................................................................48 
7.10 
Day 365 ..................................................................................................................48 
7.11 
Early Termination ...............................................................................................49 
8. 
QUALITY CONTROL AND ASSURANCE .........................................................50 

 
 
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9. 
PLANNED STATISTICAL METHODS ................................................................50 
9.1 
General Considerations .......................................................................................50 
9.2 
Unit of Analysis ....................................................................................................51 
9.3 
Study Eye Selection ..............................................................................................51 
9.4 
Missing Data .........................................................................................................51 
9.5 
Hypotheses ............................................................................................................51 
9.7 
Determination of Sample Size .............................................................................51 
9.8 
Analysis Populations ............................................................................................52 
9.8.1 
Safety Population ...........................................................................................52 
9.9 
Demographics and Baseline Characteristics .....................................................52 
9.10 
Safety Analysis .....................................................................................................52 
9.11 
Analysis of Pharmacokinetic Data .....................................................................53 
9.13 
Interim Analysis ...................................................................................................54 
10.  ADMINISTRATIVE CONSIDERATIONS ...........................................................54 
10.1 
Investigators .........................................................................................................54 
10.2 
Medical Monitor ...................................................................................................54 
10.3 
Institutional Review Board .................................................................................54 
10.4 
Ethical Conduct of the Study ..............................................................................55 
10.5 
Subject Information and Consent ......................................................................55 
10.6 
Subject Confidentiality ........................................................................................55 
10.7 
Study Monitoring .................................................................................................56 
10.8 
Interactive Response Technology .......................................................................56 
10.9 
Case Report Forms and Study Records .............................................................57 
10.10  Protocol Deviations ..............................................................................................57 
10.11  Access to Source Documentation ........................................................................58 
10.12  Data Generation and Analysis ............................................................................58 
10.13  Retention of Data .................................................................................................59 
10.14  Financial Disclosure .............................................................................................59 
10.15  Publication and Disclosure Policy ......................................................................59 
11.  REFERENCES .........................................................................................................60 
12.  APPENDICES ...........................................................................................................62 
Appendix 1 
Schedule of Visits and Procedure ...........................................................62 
TABLE OF TABLES 
Table 1 
Required Washout Periods for Prohibited Prior and Concomitant  
Therapies ..................................................................................................24 
Table 2 
Study Intervention Dispensing Schedule ...............................................32 
TABLE OF FIGURES 
Figure 1 
Study Design .............................................................................................19 
Figure 2 
Oxford Ocular Grading Scheme.............................................................35 

 
 
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LIST OF APPENDICES 
Appendix 1 
Schedule of Visits and Procedure ...........................................................62 
 

 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse Event 
AR 
Adverse Reaction 
AUC 
Area Under the Curve 
BCVA 
Best Corrected Visual Acuity 
BID 
Twice Daily 
BPM 
Beats Per Minute 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
Cmax 
Maximum Plasma Concentration 
Cmin 
Minimum Plasma Concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
CRO 
Contract Research Organization 
CS 
Clinically Significant 
DED 
Dry Eye Disease 
eCRF       
Electronic Case Report Form 
EDC   
Electronic Data Capture 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GRAS 
Generally Recognized as Safe 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 

 
 
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IND 
Investigational New Drug 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LogMAR 
Logarithmic Minimum Angle of Resolution 
LS 
Least Square 
NCS 
Not Clinically Significant 
NDA 
New Drug Application 
ODS 
Ocular Discomfort Score 
PK 
Pharmacokinetic 
RAUC 
Accumulation Ratio Based Upon Area Under the Curve 
RCmax 
Accumulation Ratio Based Upon Maximum Plasma Concentration 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
TID 
Three Times a Day 
Tmax 
Time of Maximum Concentration 
TRPM8 
Transient Receptor Potential Melastatin 8 
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). 
 
  

 
 
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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 

 
 
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(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 
ocular toxicity studies of AR-15512 ophthalmic solution in rabbits on clinical formulations 
and higher dose regimens then reflected in this Phase 3 study.  
DED represents a significant health care burden, contributing to approximately 25% of visits 
to ophthalmic clinics (Gayton 2009, Reddy 2004, Yu 2011), and can significantly affect a 
patient’s daily activities and quality of life. Studies have shown that DED interferes with 
reading, driving ability, computer use, work productivity and is associated with increased 
anxiety, stress, and depression (Noor 2018).  
Currently there are few effective treatments for DED. Artificial tears, which are comprised of 
various polymers and buffering excipients are formulated to soothe and lubricate the ocular 
surface and are usually the initial option for all DED patients. Artificial tears are generally 
palliative in nature and do not halt disease progression. With respect to pharmaceuticals, 
various strategies exist for targeting the underlying ocular inflammation associated with 
DED, but only one (5% lifitegrast [Xiidra®]), is 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.   
Thus, there is a significant unmet need for an effective topical ocular therapeutic to 
effectively treat the signs and symptoms of DED. This unmet need in combination with all 
pre-clinical and clinical data collected to date support continued development of AR-15512 
as a potential new treatment for DED with a high overall positive benefit-risk ratio to 
humans. 
 
 

 
 
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2. STUDY OBJECTIVES 
2.1 
Primary Objective 
To evaluate the safety of topical ophthalmic 0.003% AR-15512 compared to its vehicle 
dosed BID in subjects with DED for 12 months. 
3. INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This will be a 12 month, multicenter, vehicle-controlled, double-masked, randomized study 
conducted at approximately 10 sites in the United States. All subjects enrolled will have 
DED. The study will consist of a Baseline (Day 1) visit as well as follow-up visits on Days 
14, 90, 180, 270, and 365 (Study Exit). In addition, there will be dispensing visits on Days 
45, 135, 225, and 315. A schematic of the overall study design can be found in Figure 1.  
Subjects who qualify at the Baseline visit, based on inclusion/exclusion criteria, will be 
enrolled in the study and randomized in a 2:1 ratio within each site, to receive either 0.003% 
AR-15512 or AR-15512 vehicle to be administered BID as 1 drop in each eye for 12 months 
(365 days). Safety assessments will be conducted at each scheduled study visit. Systemic 
pharmacokinetic (PK) evaluation will be performed in a subset of subjects (n=35). 
Blood samples for systemic PK will be collected at the Baseline visit (Day 1) as well as the 
Day 14 and Day 90 visits
 
A summary of all study assessments per visit can be found in Appendix 1 
(Schedule of Visits and Procedures). 

 
 
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4. STUDY POPULATION SELECTION 
4.1 
Study Population 
This study is anticipated to enroll approximately 270 subjects with DED as defined below in 
Sections 4.2 and 4.3 so that approximately 108 subjects randomized to receive 0.003% and 
54 subjects randomized to receive vehicle are expected to reach the Day 365 visit. 
The anticipated dropout rate is 40%.  To achieve this goal, approximately 360 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, 18 years of age or older at the Baseline visit 
2. Have a previous history of DED, clinician diagnosed or patient reported, within the 
previous 12 months of the Baseline visit 
3. Have used or desired to use artificial tears for DED symptoms within 3 months prior 
to the Baseline visit 
6. 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 the Baseline visit 
7. Good general and ocular health, as determined by the investigator using medical 
history, ophthalmic examination and history, and vital signs (heart rate and blood 
pressure) at the Baseline visit 
8. 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 
9. Written informed consent from the subject has been obtained prior to any study 
related procedures 
10. Able, as assessed by the investigator, and willing to follow study instructions and 
likely to complete all required study visits 

 
 
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4.3 
Exclusion Criteria 
Subjects meeting any of the following criteria during the Baseline visit will be excluded from 
entry into the study: 
1. History or presence of any severe ocular disorder or condition (other than DED) in 
either eye that is, in the opinion of the investigator, likely to interfere with subject 
safety or evaluation, 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, 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. Punctal or intracanalicular plug present in either eyelid at the Baseline 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 Baseline visit 
5. History of ocular surgery within 6 months prior to the Baseline 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) 
6. Have had a corneal transplant in either or both eyes 
7. Use of contact lenses in either eye within 7 days prior to the Baseline visit or planned 
use during the study 
8. Use of any topical ocular anti-inflammatory medication within 30 days prior to the 
Baseline 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 
9. Use of artificial tears within 2 hours prior to the Baseline visit 
10. Use of topical ocular autologous serum within 30 days prior to the Baseline visit or 
anticipated use during the study 

 
 
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11. Use of any topical ocular glaucoma medication within 30 days prior to the Baseline 
visit or anticipated use during the study  
12. Use of any other topical ocular medication not listed in Exclusions 8, 9, 10 or 11 
within 24 hours prior to the Baseline visit. 
13. Use of Tyrvaya™ (varenicline solution, nasal spray 0.03mg) within 30 days prior to 
the Baseline visit or anticipated use during the study 
14. 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 Baseline visit or 
anticipated use during the study 
15. Use of a systemic medication containing an antihistamine within 24 hours prior to the 
Baseline visit  
16. Use of lid heating therapy (i.e., LipiFlow®, iLUX®) or Meibomian gland 
probing/therapeutic expression within 6 months prior to the Baseline visit or 
anticipated during the study 
17. Use of an investigational product or device within 30 days prior to the Baseline visit 
18. Have received any vaccine within 3 days prior to the Baseline visit  
19. At the Baseline visit, at the investigator’s discretion, have uncontrolled or severe. 
a. Systemic allergy 
b. Rhinitis or sinusitis 
20. 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.) 
21. Known allergies or sensitivity to the study interventions or study diagnostic agents 
including sodium fluorescein, lissamine green, etc. 
22. Positive pregnancy test at the Baseline visit or currently breastfeeding or plans to 
become pregnant or breastfeed during the study 
23. Women of childbearing potential who are not using a medically acceptable form of 
birth control  

 
 
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24. Randomization to a study arm in Phase 2b AR-15512-CS201 (COMET-1) study, 
Phase 3 AR-15512-CS301 (COMET-2) study or Phase 3 AR-15512-CS302 
(COMET-3) study 
25. 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 
26. Employees directly involved in any prior or ongoing AR-15512 study 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 Section 6.3.  
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 
Baseline 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 should be 
documented as a protocol deviation unless otherwise specified in a “Note” or Section 4.5.1.2. 

 
 
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Table 1 
Required Washout Periods for Prohibited Prior and Concomitant Therapies 
Treatment/Intervention 
Washout Required Prior to the 
Baseline Visit 
Use of any of topical ocular anti-inflammatory medication (e.g., 
ocular cyclosporine [Restasis®, Cequa™], lifitegrast [Xiidra®], any 
other prescription ophthalmic solution for DED, topical ocular 
corticosteroid- or non-steroidal-anti-inflammatory agents, topical 
ocular glaucoma or topical ocular IOP lowering medications) 
30 days 
Use of topical ocular autologous serum 
30 days 
Use of Tyrvaya™ (varenicline solution, nasal spray 0.03mg) 
30 days 
Use of any 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 
30 days 
Any investigational product or device  
30 days 
Lid-heating therapy, Meibomian gland probing, or therapeutic 
Meibomian gland expression 
6 months 
Contact lenses 
7 days 
4.5.1.2 
Permitted Prior and Concomitant Therapies 
Therapy considered necessary for the subject’s welfare may be given at the discretion of the 
investigator. If the use of a specific therapy or intervention is in question, please contact 
Aerie according to the Medical Monitoring Plan. 
Use of the following is permitted during the study: 
 Artificial tears (must not be used within 2 hours prior to any study visit) 
 Any other topical ocular medication (other than artificial tears) not itemized as an 
exclusion in Section 4.3 (must not be used within 24 hours of any study visit) 
 Any systemic medication not itemized as an exclusion in Section 4.3 is permitted 
(any systemic medication containing an antihistamine must not be used within 
24 hours of any study visit) 
 Vaccines are permitted during the study provided that they are not administered 
within 3 days of any study visit 
 Skin care products containing retinoids are permitted 
 Lid hygiene (all forms) is permitted 
 

 
 
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4.5.2 
Fluid and Food Intake 
No requirements or restrictions. 
4.5.3 
Subject Activity Restrictions 
Subjects are not to administer their morning dose of study intervention on Day 14, Day 90, 
Day 180, Day 270, and Day 365 (Exit visit). If a subject inadvertently doses their morning 
drop on the day of a clinic visit, at least 90 minutes must elapse between the time of drop 
administration reported by the subject and the start of the study visit. NOTE – If the subject 
is participating in the Systemic PK assessment and inadvertently doses their morning drop on 
the day of a clinic visit at either Day 14 or 90, then the visit needs to be rescheduled.  
 
 
Subjects are not to administer artificial tears within 2 hours of any study visit 
 
Subjects are not to administer any allowed topical ocular medication (other than artificial 
tears) within 24 hours of any study visit. 
 
Subjects are not to administer any medication (topical or systemic) that includes an 
antihistamine within 24 hours of any study visit.  
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. Enrolled subjects 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) 

 
 
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5. Bilateral tubal occlusion  
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/guardian 
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. 
 
 
 
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 
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5. STUDY INTERVENTION 
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. 
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 Baseline visit will be randomized into two groups, in a 2:1 ratio 
within each site, as follows: 
 0.003% AR-15512 (n = 180) 
 AR-15512 vehicle (n = 90) 
Subjects will be instructed to instill 1 drop of 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 Baseline visit (Day 1), as well as all follow up visits (Day 14, 90, 180, 270 and 365), 
the morning dose of randomized study intervention will be administered in clinic by study 
staff. All other doses will be administered by the subject. If a subject inadvertently doses 
their morning drop on the day of a clinic visit, at least 90 minutes must elapse between the 

 
 
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time of drop administration reported by the subject and the start of the study visit. 
NOTE -- If the subject is participating in the Systemic PK assessment and inadvertently 
doses their morning drop on the day of a clinic visit at either Day 14 or 90, then the visit 
needs to be rescheduled.  
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. 
All qualified subjects will be randomized in a 2:1 ratio within each site to receive 0.003% 
AR-15512 or AR-15512 vehicle at the Baseline visit. 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 study, the investigator and site staff performing eligibility, safety, PK 
 
 assessments and the subjects will be masked. Subjects will be informed 
that there is a 1 in 3 chance they will receive vehicle.   
AR-15512 (0.003%) and AR-15512 vehicle will be provided in identical single-use blow-fill-
seal containers.  
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. 
The Sponsor clinical study team (e.g., personnel involved in day-to-day study management, 
monitors, data managers, and statisticians) will be masked. 
5.5 
Unmasking 
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 or 
designee. The Medical Monitor will decide whether 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. 

 
 
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5.6 
Study Intervention Compliance 
Study intervention compliance will be assessed by site records for treatments administered in 
the clinic. At all visits, the “morning” dose of randomized study intervention will be 
administered by the site staff. All other doses will be administered by the subject. 
Subjects will be instructed on instillation and storage of study intervention at each visit 
(excluding the Exit visit), as well as provided written instructions.  
Study compliance will be monitored by counting the number of returned unused vials 
compared to the total number of vials dispensed. The subject’s unused study intervention 
vials will be collected throughout the study to assess dosing compliance.  
If the subject is less than 80% or more than 125% compliant with dosing based on the 
expected number of unused vials, then the subject will be deemed non-compliant and a 
protocol deviation must be recorded.  
The study centers will keep an accurate accountability record that specifies the amount of 
study intervention dispensed to each subject, the amount of unused 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 subject 
kits; each subject 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 and Dispensation 
The study intervention must be dispensed or administered according to the procedures 
prescribed in this protocol and the 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 should 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 

 
 
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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 Subject Dosing Instructions. Study intervention 
should be protected from light (store in carton) as directed on the investigational label. 
Subjects should be instructed not to freeze the study intervention. 
5.9 
Accountability 
5.9.1 
Receipt and Disposition of Study Medication  
Study intervention 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 permitted 
to distribute study intervention and also has sole responsibility to account for all returned 
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 unused study intervention 
kits / vials will be returned to the Sponsor or their designee. Subjects should be instructed to 
retain all unused vials of study intervention and return them to the clinical site starting with 
the Day 14 visit up to and including the Day 365 (Study Exit). 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 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 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. 
 

 
 
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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. 
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 Baseline 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, over the counter, prescription medicines, vitamins, 
and/or herbal supplements) that the subject is receiving at the time of enrollment or receives 
during the study must be recorded. Prior medications taken within 90 days prior to the 
Baseline visit must also be recorded. Details regarding artificial tear use (if applicable), 
such as brand, frequency, start / end date will be recorded at each visit.  
6.4 
Vital Signs 
Systolic and diastolic blood pressure will be measured using an appropriate 
sphygmomanometer after subjects have been at rest (seated) for at least 5 minutes. 
Blood pressure will be recorded in mmHg. 
Heart rate will be measured using manual or automated methods in beats per minute (bpm) 
after the subject has been in a resting state (seated) for at least 5 minutes. If measured 
manually, pulse will be counted for 30 seconds, multiplied by 2, and recorded in bpm. 
6.5 
Clinical Laboratory Tests 
6.5.1 
Laboratory Parameters 
A chemistry panel, a complete blood count (hematology and differential), and urinalysis will 
be performed as described in the Laboratory Manual.  

 
 
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6.5.2 
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. 
6.5.3 
Pregnancy Testing  
Urine pregnancy tests for women of childbearing potential (WOCBP; defined in 
Section 4.5.4) are required at Baseline and Exit visits. Pregnancy tests must be negative for 
the subject to receive study treatment. 
6.6 
Systemic Pharmacokinetic Analysis 
Blood draw for systemic pharmacokinetic measures will be performed at selected sites to 
include approximately 35 subjects. Given 2:1 randomization, this is expected to yield 
approximately 20 subjects exposed to AR-15512 and 10 subjects exposed to AR-15512 
vehicle. Samples collected from subjects will be analyzed for AR-15512 concentration. 
Six blood samples per visit will be collected at Day 1, Day 14, and Day 90. On these visits, 
one PK sample will be collected pre-drop and 5 samples will be collected post-drop at the 
following time points: t=15 minutes, 30 minutes, 1 hour, 4 hours, and 8 hours. 
Additional details of procedures are described in the Laboratory Manual. 
6.7 
Dispensing Study Intervention 
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 unused vials by maintaining an 
Investigational Product Accountability log. 
See Table 2 for the study intervention dispensing schedule. Details of timing and procedures 
for dispensing study intervention are found in the Pharmacy Manual. 
Table 2 
Study Intervention Dispensing Schedule 
Study Day 
Quantity Dispensed to Subject 
Day 1 (Baseline) 
1 kit (40 vials) 
14 
2 kits (80 vials) 
45 
3 kits (120 vials) 
90 
3 kits (120 vials) 
135 
3 kits (120 vials) 
180 
3 kits (120 vials) 
225 
3 kits (120 vials) 
270 
3 kits (120 vials) 
315 
3 kits (120 vials) 
365 
Study Exit 
 

 
 
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6.8 
Safety Assessments 
6.8.1 
Corrected Visual Acuity  
Logarithmic minimum angle of resolution (LogMAR) visual acuity in both eyes will be 
assessed at all visits 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. 
6.8.2 
Best Corrected Visual Acuity  
This assessment will only be performed at Baseline and Exit visit.  Best Corrected Visual 
Acuity (BCVA) will be assessed by the ETDRS method. Subjects will have their visual 
acuity measured in a 4-meter lane under standard illumination by a certified examiner 
reading a standard ETDRS chart. Subjects will undergo manifest refraction at each visit. 
The visual acuity lane will be certified, as will the visual acuity examiner prior to study 
initiation. Specifications for the visual acuity lane, illumination, charts, light box, refraction 
lens, and the technician certification process are detailed in the Manual of Procedures. 
6.8.3 
Specular Microscopy to Assess Corneal Endothelial Cell Counts  
Specular microscopy of the central cornea will be performed at the Baseline and Exit visit.  
Three images of the central corneal endothelium will be taken at each of the specified visits 
for each eye.  Average cell density for each image will be generated by a built-in algorithm 
and recorded in the electronic case report forms (eCRFs).  The overall average cell density of 
the central corneal endothelium will be calculated by electronic data capture (EDC) system.  
The presence or absence of abnormal cellular morphology (polymegethism) will be 
determined by visual inspection of images and noted in the eCRF. See the Manual of 
Procedures for additional details. 
6.8.4 
Biomicroscopy 
Slit lamp biomicroscopy will be performed at all in-clinic study visits. Observations will be 
graded as Normal or Abnormal. Abnormal findings will be categorized as clinically 
significant (CS; 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: 
 Cornea  
 Conjunctiva 
 Anterior Chamber 
 Iris 

 
 
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 Lens 
 Eyelid 
 Anterior Vitreous 
Additional procedural details can be found in the Manual of Procedures. 
6.8.5 
Ocular Surface Staining  
Ocular surface staining will be performed at each visit, starting with sodium fluorescein 
staining of the cornea. Care should be taken when using sodium fluorescein strips to avoid 
causing ocular surface discomfort or irritation.  
The subject should be instructed to look up such that 1 drop of sodium fluorescein can be 
applied to the right eye by gently pulling down on the lower lid and touching the droplet 
from a moistened (2 drops of normal sterile saline) strip onto the bulbar conjunctiva, 
releasing the droplet. The paper strip must not touch the bulbar conjunctiva. Repeat for the 
left eye with a new moistened strip. To thoroughly mix the sodium fluorescein with the tear 
film, the subject will be instructed to blink several times over approximately 15 seconds. 
Approximately 3 minutes after instillation of sodium fluorescein to both eyes, the entire 
corneal surface will be evaluated for sodium fluorescein staining, starting with the right eye. 
The examination will be performed with the slit lamp at approximately 16X magnification 
using the slit lamp’s cobalt blue filter to illuminate the ocular surface and a yellow barrier 
filter placed directly in front of the objective lens of the slit lamp.  
Grading of the resulting corneal staining will be based on the Oxford ocular grading scheme 
(cornea portion only) (Figure 2), which grades the entire cornea from 0 to 5. Half (0.5) grade 
increments may be used. The upper eyelid may be lifted slightly to visualize the entire 
corneal surface.  
Following sodium fluorescein staining of the cornea, conjunctival staining with lissamine 
green will be performed as follows. Care should be taken when using lissmaine green strips 
to avoid causing ocular surface discomfort or irritation. 
The subject should be instructed to look up such that 1 drop of lissamine green can be 
applied to the right eye by gently pulling down on the lower lid and touching the droplet 
from a moistened (2 drops of normal sterile saline) strip onto the bulbar conjunctiva, 
releasing the droplet. The paper strip must not touch the bulbar conjunctiva. Repeat for the 
left eye with a new moistened strip. To thoroughly mix the lissamine green with the tear film, 
the subject will be instructed to blink several times over approximately 15 seconds. 
Approximately 1 minute after instillation of lissamine green to both eyes and starting with 
the right eye, grading of the resulting conjunctival staining can begin. The 2 conjunctival 
regions (nasal and temporal) will each be graded (0 to 5) using the Oxford ocular grading 
scheme (Figure 2). Half (0.5) grade increments may be used. To grade the temporal zone, 
the subject should be instructed to look nasally; to grade the nasal zone, the subject should be 

 
 
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instructed to look temporally. The total conjunctival staining score is calculated as the sum of 
the 2 regions (maximum possible score 10). 
Total ocular staining is then calculated as the sum of total corneal staining (0-5) and total 
conjunctival staining (0-10) for a maximum possible score of 15 per eye. 
Figure 2 
Oxford Ocular Grading Scheme  
 
6.8.6 
Intraocular Pressure 
IOP must be measured only after the biomicroscopic exam is completed and must be 
measured prior to pupil dilation. IOP will be measured at all in-clinic study visits by qualified 
study site personnel with the subject seated. Every effort should be made to ensure that the 
same study site personnel uses 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. 

 
 
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6.8.7 
Dilated Fundus Exam by Slit Lamp 
Dilated fundus exams will be performed at each visit 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 NCS will be described. An indirect 
Fundoscopy (peripheral retinal), 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. 
It is recommended that tropicamide 1% ophthalmic solution be used to dilate subjects. 

 
 
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6.10 
Adverse Events Assessments 
6.10.1 
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 

 
 
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6.10.2 
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.  
 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 6.10.5.  
 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.  
 Unexpected AE or unexpected AR: an AE or AR is considered “unexpected” if it is 
not listed in the IB or is not listed at the specificity or severity that has been observed; 
or, if an IB 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 6.10.6. 
6.10.3 
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 AR is 

 
 
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unresolved at the time of exit, efforts will be made to follow up until the AE or AR 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 a treatment 
emergent adverse event (TEAE). 
Surgery should not be reported as an outcome of an AE if the purpose of the surgery was 
diagnostic and the outcome was uneventful. 
6.10.3.1 
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 AEs. Such developments are recorded but are not reportable AEs. 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 AE, 
the Investigator is recommended to contact the Sponsor for guidance. 
6.10.4 
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 
 

 
 
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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 6.10.8 for further 
information on SAEs, SARs, and suspected unexpected serious adverse reactions 
[SUSARs]).  
6.10.5 
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.  

 
 
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6.10.6 
Expectedness 
AEs or ARs are considered “unexpected” if they are not listed in the Reference Safety 
Information section of the IB 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 IB 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 IB referred only to elevated hepatic enzymes or hepatitis. Similarly, 
cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the IB listed only cerebral vascular accidents. “Unexpected,” as used in this 
definition, also refers to AEs or SARs that are mentioned in the IB 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 6.10.2 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 IB (see Section 6.10.8).  
6.10.7 
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 Baseline values will be 
documented as AEs. 
6.10.8 
Serious Adverse Events, Serious Adverse Reactions or Suspected Unexpected 
Serious Adverse Reactions 
6.10.8.1 
Reporting SAEs or SARs  
An Investigator must immediately (i.e., within 24 hours) report any SAE or SAR (see 
Section 6.10.2 for definitions) to the Sponsor or its CRO representative, whether or not 
considered drug-related, including those listed in the protocol or IB. 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 6.10.8.3. 
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.   

 
 
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6.10.8.2 
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. 
6.10.8.3 
SAE Report Contact Information  
 
 
6.11 
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  
 Other  
6.11.1 
Actions after Discontinuation 
Also see Early Termination Procedures (Section 7.11). 

 
 
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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 Exit or Early 
Termination Visit. 
6.11.2 
Discontinuation of the Entire Study 
The entire study may be discontinued at any given site by the Investigator the Sponsor / 
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. 
6.11.3 
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 
Day 1 (Baseline) Procedures 
 Informed consent 
 Demographics 
 Medical, ophthalmic, and surgical history 
 Prior and concomitant medication review 
 Adverse events 
 Vital signs (heart rate and blood pressure) 
 Urine pregnancy test (women of child-bearing potential only) 
 Corrected visual acuity 
 Best corrected visual acuity 
 Slit lamp biomicroscopy 

 
 
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 Adverse events 
 Vital signs (heart rate and blood pressure) 
 Corrected visual acuity 
 Slit lamp biomicroscopy 
 At least 5-minute rest 
 Total ocular staining  
 Pre-dose blood draw for PK Samples (selected sites only) 
 Dispensing of study intervention  
 
 
 
 
 
 
 In-office administration of study intervention 
 
 
 Post-dose blood draws for PK Samples (selected sites only) 
 
 
 
 
 
 
 Intraocular pressure 
 Dilated fundus exam 
7.3 
Day 45 
 Collection of unused study intervention 
 Dispensing of study intervention 
7.4 
Day 90 
 Collection of unused study intervention  

 
 
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 Concomitant medication review 
 Adverse events 
 Vital signs (heart rate and blood pressure) 
 Corrected visual acuity 
 Slit lamp biomicroscopy 
 At least 5-minute rest 
 Total ocular staining  
 Pre-dose blood draw for PK Samples (selected sites only) 
 Dispensing of study intervention  
 
 
 
 
 
 
 In-office administration of study intervention 
 
 
 Post-dose blood draws for PK Samples (selected sites only) 
 
 
 
 
 Intraocular pressure 
 Dilated fundus exam 
7.5 
Day 135 
 Collection of unused study intervention 
 Dispensing of study intervention 
7.6 
Day 180 
 Collection of unused study intervention 

 
 
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 Concomitant medication review 
 Adverse events 
 Vital signs (heart rate and blood pressure) 
 Corrected visual acuity 
 Slit lamp biomicroscopy 
 At least 5-minute rest 
 Total ocular staining  
 Hematology, chemistry, and urinalysis  
 Dispensing of study intervention  
 
 
 
 
 
 
 In-office administration of study intervention 
 
 
 
 
 
 
 
 
 Intraocular pressure 
 Dilated fundus exam 
7.7 
Day 225 
 Collection of unused study intervention 
 Dispensing of study intervention 
7.8 
Day 270 
 Collection of unused study intervention 

 
 
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 Concomitant medication review 
 Adverse events 
 Vital signs (heart rate and blood pressure) 
 Corrected visual acuity 
 Slit lamp biomicroscopy 
 At least 5-minute rest 
 Total ocular staining  
 Dispensing of study intervention  
 
 
 
 
 
) 
 In-office administration of study intervention 
 
 
 
 
 
 
 Intraocular pressure 
 Dilated fundus exam 
7.9 
Day 315 
 Collection of unused study intervention 
 Dispensing of study intervention 
7.10 
Day 365  
 Collection of unused study intervention  
 Concomitant medication review 
 Adverse events 

 
 
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 Vital signs (heart rate and blood pressure) 
 Urine pregnancy test (women of child-bearing potential only) 
 Corrected visual acuity 
 Best corrected visual acuity 
 Slit lamp biomicroscopy 
 At least 5-minute rest 
 Total ocular staining  
 At least 10-minute rest 
 Specular microscopy to assess corneal endothelial cell counts 
 Hematology, chemistry, and urinalysis  
 
 
 
 
 
 
 In-office administration of study intervention 
 
 
 
 
 
 
 
 
 Intraocular pressure 
 Dilated fundus exam 
 Study exit 
7.11 
Early Termination 
 Collection of unused study intervention  

 
 
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 Concomitant medication review 
 Adverse events 
 Vital signs (blood pressure and heart rate) 
 Urine pregnancy test (women of child-bearing potential only) 
 Corrected visual acuity  
 Best corrected visual acuity 
 Slit lamp biomicroscopy  
 Specular microscopy to assess corneal endothelial cell counts 
 Hematology, chemistry, and urinalysis 
 Intraocular pressure  
 Dilated fundus exam  
 Study exit 
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.  
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 
This is a study with safety assessments only and no formal comparisons will be made 
between 0.003% AR-15512 and vehicle.  

 
 
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 Treatment-Emergent AESIs 
 TEAEs by maximal severity 
 TEAEs by study day of onset 
Separate analyses will be performed for ocular and non-ocular AEs. 
Other safety endpoints including vital signs, endothelial cell counts, laboratory parameters 
(hematology, chemistry, and urinalysis), corrected visual acuity, best corrected visual acuity, 
biomicroscopy, total ocular staining, IOP, and dilated fundoscopy will be summarized by 
treatment group and visit using descriptive statistics. 
9.11 
Analysis of Pharmacokinetic Data 
Plasma pharmacokinetic parameters including AR-15512 area under the plasma 
concentration time curve (AUC), maximum recorded concentration (Cmax), minimum 
recorded concentration (Cmin), time of maximum concentration (Tmax) will be summarized. 
RCmax and RAUC (where R represents an accumulation factor) will be calculated. Details will 
be outlined in the SAP and Laboratory Manual. 

 
 
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9.13 
Interim Analysis 
An interim analysis will be conducted after all subjects have completed the Day 180 visit or 
discontinued. Details will be provided in the SAP. 
10. ADMINISTRATIVE CONSIDERATIONS 
10.1 
Investigators 
The Principal Investigator must be a physician duly qualified to practice medicine and 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: 
The medical monitor should be contacted for urgent medical queries that require immediate 
(24 hour) response. 
 
10.3 
Institutional Review Board 
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 

 
 
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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 (CFR), Title 21 
 International Conference on Harmonization (ICH) Consolidated Good Clinical 
Practice Guideline (E6 R2) 
 Standard Operating Procedures (SOPs) of the Sponsor and any other vendors 
participating in the conduct of the study 
 Obtaining prospective informed consent 
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 

 
 
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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 
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 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. 
IRT activities will be performed as described in the IRT User Manual. 

 
 
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10.9 
Case Report Forms and Study Records 
Investigators are 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 investigational drug 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 CRFs (eCRFs). Each authorized study staff 
member will receive a unique access account in order to use the 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, medical 
license, completed FDA Form 1572 / Statement of Investigator, each eCRF, subject 
charts/source documents, IB, protocol, protocol amendments, correspondence with the 
Sponsor and the IRB, study intervention 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 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 Practices [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.  

 
 
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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 competent authority as a serious 
breach of GCP and the protocol. If per the relevant competent 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 and designate 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, European Medicines 
Agency, other domestic government agencies, and other foreign regulatory 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. 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. 

 
 
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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 Statistical Analysis Plan. 
10.13 Retention of Data 
The Investigator’s site and clinical laboratory will retain all records related to the study in 
compliance with ICH Good Clinical Practices 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. 
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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