A Phase 3b Open-Label Study Designed to Evaluate Tear Production Stimulated by 0.003% AR-15512
Phase: PHASE3
Conditions: Dry Eye Disease
Sponsor: Alcon Research

 
 
 
 
 
A Phase 3b Open-Label Study Designed to Evaluate Tear 
Production Stimulated by 0.003% AR-15512 
 
STUDY ID: 
DEF512-E002 
 
 
PROTOCOL v.2 
15 Jan 2025 
 
 
NCT06544707 

AR-15512 ophthalmic solution 0.003%  
 
 
 
 
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Clinical Trial Protocol: DEF512-E002 
 
 
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Confidential 
 
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Clinical Trial Protocol: DEF512-E002 
Protocol Title: 
A Phase 3b Open-Label Study Designed to 
Evaluate Tear Production Stimulated by 0.003% 
AR-15512 
Protocol Number: 
DEF512-E002 
Study Phase: 
Phase 3b 
Investigational Product 
Name: 
AR-15512 ophthalmic solution 0.003%  
IND Number: 
147005 
Indication: 
Dry Eye Disease 
Investigators: 
Single-center 
Sponsor: 
Alcon Research, LLC and its affiliates (“Alcon”) 
6201 South Freeway 
Fort Worth, Texas 76134-2099 
Contract Research 
Organization: 
Ora, Inc. 
138 Haverhill Street 
Suite 102 
Andover, MA 01810, U.S.A 
Phone: +1-978-685-8900 
 
CONFIDENTIAL STATEMENT 
This protocol contains confidential, proprietary information of Ora, Inc. and/or Alcon Research, 
LLC, and its affiliates (“Alcon”). Further dissemination, distribution, or copying of this protocol 
or its contents is strictly prohibited. 
 
 

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AR-15512 ophthalmic solution 0.003%  
 
 
 
 
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Clinical Trial Protocol: DEF512-E002 
 
 
                                Version 2.0, 15 Jan 2025 
 
Confidential 
 
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1 
SYNOPSIS 
Protocol Title: 
A Phase 3b Open-Label Study Designed to Evaluate Tear 
Production Stimulated by 0.003% AR-15512 
Protocol Number: 
DEF512-E002 
Investigational Product: 
AR-15512 ophthalmic solution 0.003% 
Study Phase: 
Phase 3b 
Primary Objective(s): 
Stage 1 and Stage 2: To evaluate tear production, via tear 
meniscus height (TMH) as measured by optical coherence 
tomography (OCT), following acute administration of AR-
15512 ophthalmic solution 0.003% (hereafter 0.003% AR-
15512) in subjects with dry eye disease (DED). 
Overall Study Design: 
Structure: 
Single-center, open-label, single-arm, two-stage acute 
dosing 
Duration: 
This study will consist of 1 day at single visit (acute). 
Dosage/Dose Regimen/ 
Instillation/Application/Use: 
Qualified subjects will be dosed in clinic by site staff once 
at Visit 1 with 0.003% AR-15512 (1 drop in each eye) in a 
staggered cadence (left eye followed by dosing of the right 
eye approximately 2 - 4 hours after completion of post-drop 
OCT). 
Summary of Visit Schedule: 
The study consists of 1 Visit (Screening, Enrollment and 
Assessments). 
Study Population Characteristics: 
Number of Subjects: 
Approximately 80 subjects will be enrolled with 
approximately 40 subjects enrolled in Stage 1 and 
approximately 40 subjects in Stage 2 

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Condition/Disease: 
Dry Eye Disease 
Inclusion Criteria: 
To be eligible to participate in either stage of this trial, an 
individual must meet all the following criteria: 
1. Male or female, 18 years of age or older. 
2. Within the last 12 months, have a previous history 
of DED, either clinician diagnosed, or patient 
reported. 
3. Within the last 6 months, have used, or desired to 
use artificial tears for DED symptoms. 
4. Within the last 6 months, have a documented 
Schirmer test with or without topical anesthesia 
VFRUHDQGPPPLQ 
5. Have a total corneal sodium fluorescein staining 
VFRUHDQGEDVHGRQWKHPRGLILHG1DWLRQDO
(\H,QVWLWXWH1(,JUDGLQJVFKHPHZLWKQRRQH
region scoring > 3. 
6. Have an Ocular Surface Disease Index (OSDI)© 
score > 12. 
7. Corrected Visual Acuity (Snellen) 20/200 or better 
in both eyes. 
8. Good general and ocular health, as determined by 
the investigator using medical history, ophthalmic 
examination and history. 
9. Capable of giving signed informed consent, which 
includes compliance with the requirements and 
restrictions listed in the informed consent form 
(ICF) and in this protocol. 
10. Written informed consent from the subject has been 
obtained prior to any study related procedures. 
11. Able, as assessed by the investigator, and willing to 
follow study instructions. 
Exclusion Criteria: 
Subjects meeting any of the following criteria will be 
excluded from entry into either stage of the study: 
Ophthalmic: 
1. Current evidence of other clinically significant 
ophthalmic disease other than dry eye (e.g., 
glaucoma or macular degeneration).  
Note: Blepharitis and/or Meibomian gland disease 
not requiring treatment are allowed. 
2. Use of artificial tears within 2 hours of the Study 
Visit. 
3. History of ocular surgery within 1 year of the Study 
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). 

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4. Current evidence of other significant ophthalmic 
disease requiring topical medication (e.g., 
glaucoma, ocular hypertension) or other ophthalmic 
disease which the investigator believes may 
interfere with study findings or interpretation. 
5. History of corneal transplant in one or both eyes. 
6. 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. 
7. Use of contact lenses in either eye within 7 days of 
the Study Visit. 
8. Punctal or intracanalicular plug present in either 
eyelid within 14 days of the Study Visit. 
9. Use of lid hygiene (all forms of lid care including 
lid wipes, scrubs and purposeful cleansing of lids 
with soap or medicated shampoos, etc.) or heat 
masks within 7 days of the Study Visit. 
10. Use of lid heating therapy (i.e., LipiFlow®, iLUX®, 
TearCare®) or Meibomian gland 
probing/therapeutic expression within 3 months of 
the Study Visit. 
11. Use of Intense Pulsed Light (IPL) therapy on 
eyelids within 3 months of the Study Visit. 
12. Use of any topical ocular anti-inflammatory 
medications (e.g., ocular cyclosporine [Restasis®, 
Cequa™, Vevye™, generics], lifitegrast [Xiidra®]) 
or any other prescription ophthalmic product for 
DED (e.g., perfluorohexyloctane [Meibo™]), any 
topical ocular corticosteroid, or any non-steroidal-
anti-inflammatory agents within 30 days of the 
Study Visit. 
13. Use of topical ocular autologous serum within 30 
days of the Study Visit. 
14. Use of any other topical ocular drop (prescription or 
OTC, including artificial tears) within 2 hours of the 
Study Visit. 
15. Use of Tyrvaya™ (varenicline solution, nasal spray 
0.03mg) within 30 days of the Study Visit. 
16. 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 of the Study Visit. 
General/Systemic: 
17. Initiation, discontinuation, or change in dose of a 
systemic medication known to cause ocular drying 

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(e.g., antihistamines or tricyclic antidepressants) 
within 14 days of the Study Visit. 
18. Initiation, discontinuation, or change in dose of a 
systemic corticosteroid within 30 days of the Study 
Visit.  
Note: 1RQ-ocular topically applied corticosteroids 
(including topical creams, nasal sprays and inhalers) 
are not applicable to this exclusion. 
 
19. Initiation, discontinuation, or change in dose of a 
systemic immunomodulator (e.g., 
hydroxychloroquine, methotrexate, cyclosporine) 
within 60 days of the Study Visit. 
20. Have received any vaccine within 3 days prior to 
the Study Visit. 
21. Use of an investigational product or device within 
30 days of the Study Visit. 
22. At the Study Visit, at the investigator’s discretion, 
have uncontrolled or severe: 
a. Systemic allergy 
b. Rhinitis or sinusitis 
23. History or presence of significant systemic disease 
(i.e., cardiovascular, pulmonary, hepatic, renal, 
hematologic, immunologic). Significant is defined 
as any disease that, in the assessment of the 
Investigator, would put the safety of the subject at 
risk through participation, or would prevent or 
confound protocol-specified assessments (e.g., 
severe Sjögren’s syndrome, severe rheumatoid 
arthritis, severe systemic lupus erythematosus, 
uncontrolled immunodeficiency disease, etc.). 
24. Known allergies or sensitivity to the study 
interventions or study diagnostic agents. 
25. Positive pregnancy test or currently breastfeeding. 
26. 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. 
Study Formulations and 
Formulation Numbers: 
AR-15512 ophthalmic solution 0.003% 

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Evaluation Criteria: 
Efficacy Measures and 
Endpoints: 
Stage 1: 
Primary Endpoint: 
x 
Change from baseline (pre-drop compared to 3 
minutes post-drop) in TMH as measured by OCT. 
Stage 2: 
Primary Endpoint: 
x 
Change from baseline (pre-drop compared to 3 
minutes post-drop) in TMH as measured by OCT. 
Safety Measures: 
Stage 1 and Stage 2 
x 
Corrected Visual Acuity 
x 
Slit-lamp biomicroscopy 
x 
Adverse Events (AE) 
General Statistical Methods and Types of Analyses 
Analysis Sets: 
x 
Safety Analysis set: The safety analysis set will include all subjects who have received 
at least one dose of 0.003% AR-15512. 
x 
Full Analysis Set (FAS): The FAS will include all subjects who have received at least 
one dose of 0.003% AR-15512 and have pre-drop and 3-minute post-drop TMH 
measurements. 
x 
Per Protocol Set (PPS): The PPS will include all subjects who are part of the FAS and 
have no major protocol deviations that could potentially influence the primary efficacy 
endpoint. 
Analyses supporting Primary Objective: 
The primary analysis will assess the change from baseline (pre-drop compared to 3 minutes 
post-drop) in TMH using OCT. A paired t-test using the FAS will be performed to test the pre-
drop and post-drop difference in TMH. Descriptive statistics such as the mean, standard 
deviation, minimum, and maximum, as well as 90% confidence intervals, will be reported for 
the observed and change from baseline results. 
Statistical Hypotheses: 

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2 
TABLE OF CONTENTS 
1 6<1236,6 ............................................................................................................................ 3 
2 7$%/(2)&217(176 .................................................................................................... 10 
3 /,672)$%%5(9,$7,216 ............................................................................................. 14 
4 ,1752'8&7,21 .............................................................................................................. 16 
4.1 Dry Eye Disease ........................................................................................................ 16 
5 STUDY OBJECTIVES ....................................................................................................... 17 
5.1 Primary Objective(s) ................................................................................................. 17 
 
6 &/,1,&$/+<327+(6(6 ............................................................................................... 18 
7 29(5$//678'<'(6,*1 ............................................................................................ 18 
8 678'<3238/$7,21 ..................................................................................................... 19 
8.1 1XPEHURI6XEMHFWVDSSUR[LPDWH ........................................................................... 19 
8.2 Study Population Characteristics .............................................................................. 19 
8.3 Inclusion Criteria ....................................................................................................... 19 
8.4 Exclusion Criteria ...................................................................................................... 20 
8.5 Withdrawal Criteria (if applicable) ........................................................................... 23 
9 STUDY PARAMETERS .................................................................................................... 23 
9.1 Efficacy Measures and Endpoints ............................................................................. 23 
9.1.1 Primary Efficacy Measure(s) ......................................................................... 23 
 
9.2 Safety Measures (Stage 1 and Stage 2) ..................................................................... 24 
10 STUDY MATERIALS ...................................................................................................... 24 
10.1 Study Treatment(s) .................................................................................................... 24 
10.1.1 
Study Treatment/Formulation .................................................................. 24 
10.1.2 
Instructions for Use and Administration .................................................. 24 
10.2 Other Study Supplies ................................................................................................. 24 
11 678'<0(7+2'6$1'352&('85(6 ..................................................................... 25 
11.1 Subject Entry Procedures .......................................................................................... 25 
11.1.1 
Overview .................................................................................................. 25 
11.1.2 
Informed Consent ..................................................................................... 25 
11.1.3 
Washout Intervals ..................................................................................... 26 
11.1.4 
Procedures for Final Study Entry ............................................................. 26 
11.1.5 
Methods for Assignment to Treatment Groups ........................................ 26 
11.2 Demographics ........................................................................................................... 26 
11.3 Medical and Surgical History .................................................................................... 26 

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11.4 Prior and Concomitant Medications .......................................................................... 26 
11.4.1 
Prohibited Medications/Treatments.......................................................... 27 
11.4.2 
Escape Medications .................................................................................. 27 
11.4.3 
Special Diet or Activities ......................................................................... 27 
11.5 Clinical Laboratory Tests .......................................................................................... 27 
11.5.1 
Pregnancy Testing .................................................................................... 27 
11.6 Dispensing Study Intervention .................................................................................. 27 
11.7 Efficacy Assessment ................................................................................................. 27 
11.7.1 
OCT .......................................................................................................... 27 
11.8 Safety Assessments ................................................................................................... 28 
11.8.1 
Corrected Visual Acuity ........................................................................... 28 
11.8.2 
Biomicroscopy.......................................................................................... 28 
 
11.9.1 
Ocular Surface Disease Index (OSDI)©.................................................... 28 
 
 
11.9.3 
Sodium Fluorescein Staining of the Cornea Based on the Modified 
1DWLRQDO(\H,QVWLWXWH1(,*UDGLQJ6FKHPH .............................................. 29 
11.10 Examination Procedures ........................................................................................ 29 
11.10.1 
Procedures to be Performed at Study Visit with Regard to Study 
Objective(s) .................................................................................................... 29 
11.11 Schedule of Visits, Measurements, and Dosing ..................................................... 29 
11.11.1 
Scheduled Visits ..................................................................................... 29 
11.11.2 
Unscheduled Visits ................................................................................. 29 
11.12 Compliance with Protocol ...................................................................................... 30 
11.13 Subject Disposition ................................................................................................ 30 
11.13.1 
Completed Subjects ................................................................................ 30 
11.13.2 
Discontinued Subjects ............................................................................ 30 
11.13.3 
Screen Failures ....................................................................................... 30 
11.14 Study Termination ................................................................................................. 31 
11.15 Study Duration ....................................................................................................... 31 
11.16 Monitoring and Quality Assurance ........................................................................ 31 
11.17 Quality Tolerance Limits ....................................................................................... 31 
12 $'9(56((9(176 ........................................................................................................ 32 
12.1 Performing Adverse Event Assessments ................................................................... 32 
12.2 Adverse Event Definitions ........................................................................................ 33 
12.3 Reporting Adverse Events ......................................................................................... 34 
12.3.1 
AEs and Prior Medical History ................................................................ 34 
12.3.2 
Severity ..................................................................................................... 35 

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14.7 Handling of Biological Specimens ............................................................................ 49 
14.8 Publications 49 
15 5()(5(1&(6 .................................................................................................................. 50 
16 $33(1',&(6 ................................................................................................................... 51 
Appendix 1: Schedule of Visits and PROCEDURES (Stage 1 and STage 2) ........................ 51 
Appendix 2: Handling of Biological Specimens .................................................................... 52 
 
 
 
 
 
 
 

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3 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AR 
Adverse Reaction 
BID 
Twice Daily 
CRO 
Clinical Research Organization 
DED 
Dry Eye Disease 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
 
 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GRAS 
Generally Recognized as Safe 
H0 
1XOO+\SRWKHVLV 
HA 
Alternative Hypothesis 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
,1' 
,QYHVWLJDWLRQDO1HZ'UXJ 
IEC 
Independent Ethics Committee 
IP 
Investigational Product 
IPL 
Intense Pulsed Light 
IRB 
Institutional Review Board 
LogMAR 
Logarithmic Minimum Angle of Resolution 
1&6 
1RWClinically Significant 
1(, 
1DWLRQDO(\H,QVWLWXWH 
OCT 
Optical Coherence Tomography 
 
 
OSDI 
Ocular Surface Disease Index 
OTC 
Over-the-Counter 
PT 
Preferred Terms 
SAE 
Serious Adverse Event 

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SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SD 
Standard Deviation 
SOC 
System Organ Class 
SUSAR 
Serious Adverse Reactions 
TEAE 
Treatment-Emergent adverse events 
 
 
TMH 
Tear Meniscus Height 
TOST 
Two One-Sided Tests 
TRPM8 
Transient Receptor Potential Melastatin 8 
WOCBP 
women of childbearing potential 
 
 

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4 
INTRODUCTION 
4.1 
Dry Eye Disease 
Dry eye disease (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 (&UDLJ1LFKROVHWDO). 
Despite the availability of several pharmaceutical products, there remains a significant 
unmet need for an effective topical ocular therapeutic to effectively treat the signs and 
symptoms of DED. 
In recent years, increased attention has been placed on the neuronal regulation of tear 
production. 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 DED. 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 that 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. 
 

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5 
STUDY OBJECTIVES 
5.1 
Primary Objective(s) 
x Stage 1 and Stage 2: To evaluate tear production, via tear meniscus height 
(TMH) as measured by Optical Coherence Tomography (OCT), following acute 
administration of 0.003% AR-15512 in subjects with DED. 

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6 
CLINICAL HYPOTHESES 
The clinical hypothesis for this study is that administration of 0.003% AR-15512 leads to 
an increase in tear production. 
7 
OVERALL STUDY DESIGN 
This is a Phase 3b, single center, open-label, single-arm, two-stage, acute dosing study 
conducted in the United States. 
Approximately 80 male and female subjects at least 18 years of age with a previous 
history of DED and meeting all study eligibility criteria will be enrolled. Enrollment will 
take place in two stages; with approximately 40 subjects being enrolled in each stage. 
While identical in design, the two stages of the study will be considered independent. 
Each of the stages will consist of 1 Visit (Screening, Enrollment, and Assessments). All 
subjects will be exited from the study at the end of the Study Visit. All qualified subjects 
post Screening will be dosed once in clinic by site staff with 0.003% AR-15512 in both 
eyes. The dosing will be in a staggered cadence, starting with the left eye followed by 
dosing of the right eye approximately 2 - 4 hours after completion of post-drop OCT. All 
subjects will undergo both baseline (pre-drop) and post-drop OCT imaging in the left eye 
and tear collection in the right eye at designated intervals. A study diagram is provided in 
Figure 1. 
Details of assessments performed can be found in Appendix 1 (Schedule of Visits and 
Procedures) as well as the Manual of Procedures. 

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Figure 1 Study Design (Stage 1 and Stage 2) 
8
STUDY POPULATION
8.1
Number of Subjects (approximate) 
This study is anticipated to enroll approximately 40 subjects with DED into each stage. 
To achieve this goal, approximately 80 subjects may be screened for each of Stage 1 and 
Stage 2. 
8.2
Study Population Characteristics 
All subjects must be at least 18 years of age, of either gender, and of any race, and must 
meet all inclusion criteria and none of the exclusion criteria.
8.3
Inclusion Criteria
To be eligible to participate in either stage of this trial, an individual must meet all the 
following criteria:
1. Male or female, 18 years of age or older. 
2. Within the last 12 months, have a previous history of DED, either clinician
diagnosed or patient reported. 
3. Within the last 6 months, have used, or desired to use artificial tears
for DED symptoms. 
4. Within the last 6 months, have a documented Schirmer test with or without 
topical anesthesia VFRUHDQGPPPLQ. 
5. Have a total corneal sodium fluorescein staining score  1 and  15 based
on the modified 1DWLRQDO(\H,QVWLWXWH (1(,) grading scheme, with no 
one region scoring > 3. 
6. Have an Ocular Surface Disease Index (OSDI)© score > 12. 
7. Corrected Visual Acuity (Snellen) 20/200 or better in both eyes Good general and

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ocular health, as determined by the investigator using medical history, ophthalmic 
examination and history. 
8. Good general and ocular health, as determined by the investigator using medical 
history, ophthalmic examination and history. 
9. Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol. 
10. Written informed consent from the subject has been obtained prior to any study 
related procedures. 
11. Able, as assessed by the investigator, and willing to follow study instructions. 
8.4 
Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from entry into either 
stage of the study: 
Ophthalmic: 
1. Current evidence of other clinically significant ophthalmic disease other than dry 
eye (e.g., JODXFRPDRUPDFXODUGHJHQHUDWLRQ1RWH%OHSKDULWLVDQGRU
Meibomian gland disease not requiring treatment are allowed. 
2. Use of artificial tears within 2 hours of the Study Visit. 
3. History of ocular surgery within 1 year of the Study 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). 
4. Current evidence of other significant ophthalmic disease requiring topical 
medication (e.g., glaucoma, ocular hypertension) or other ophthalmic disease 
which the investigator believes may interfere with study findings or interpretation. 
5. History of corneal transplant in one or both eyes. 

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6. 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. 
7. Use of contact lenses in either eye within 7 days of the Study Visit. 
8. Punctal or intracanalicular plug present in either eyelid within 14 days of the 
Study Visit. 
9. Use of lid hygiene (all forms of lid care including lid wipes, scrubs and 
purposeful cleansing of lids with soap or medicated shampoos, etc.) or heat masks 
within 7 days of the Study Visit. 
10. Use of lid heating therapy (i.e., LipiFlow®, iLUX®, TearCare®) or Meibomian 
gland probing/therapeutic expression within 3 months of the Study Visit. 
11. Use of Intense Pulsed Light (IPL) therapy on eyelids within 3 months of the Study 
Visit. 
12. Use of any topical ocular anti-inflammatory medications (e.g., ocular 
cyclosporine [Restasis®, Cequa™, Vevye™, generics], lifitegrast [Xiidra®]) or 
any other prescription ophthalmic product for DED (e.g., perfluorohexyloctane 
[Meibo™]), any topical ocular corticosteroid, or any non-steroidal-anti-
inflammatory agents within 30 days of the Study Visit. 
13. Use of topical ocular autologous serum within 30 days of the Study Visit. 
14. Use of any other topical ocular drop (prescription or over-the-counter [OTC], 
including artificial tears) within 2 hours of the Study Visit. 
15. Use of Tyrvaya™ (varenicline solution, nasal spray 0.03mg) within 30 days of the 
Study Visit. 
16. 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 of the 
Study Visit. 
 
 

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General/Systemic: 
17. Initiation, discontinuation, or change in dose of a systemic medication known to 
cause ocular drying (e.g., antihistamines or tricyclic antidepressants) within 14 
days of the Study Visit. 
18. Initiation, discontinuation, or change in dose of a systemic corticosteroid within 
GD\VRIWKH6WXG\9LVLW1RWH1RQ-ocular topically applied corticosteroids 
(including topical creams, nasal sprays and inhalers) are not applicable to this 
exclusion. 
19. Initiation, discontinuation, or change in dose of a systemic immunomodulator 
(e.g., hydroxychloroquine, methotrexate, cyclosporine) within 60 days of the 
Study Visit. 
20. Have received any vaccine within 3 days prior to the Study Visit. 
21. Use of an investigational product or device within 30 days of the Study Visit. 
22. At the Study Visit, at the investigator’s discretion, have uncontrolled or severe: 
a. Systemic allergy 
b. Rhinitis or sinusitis 
23. History or presence of significant systemic disease (i.e., cardiovascular, 
pulmonary, hepatic, renal, hematologic, immunologic). Significant is defined as 
any disease that, in the assessment of the Investigator, would put the safety of the 
subject at risk through participation, or would prevent or confound 
protocol-specified assessments (e.g., severe Sjögren’s syndrome, severe 
rheumatoid arthritis, severe systemic lupus erythematosus, uncontrolled 
immunodeficiency disease, etc.). 
24. Known allergies or sensitivity to the study interventions or study diagnostic 
agents. 
25. Positive pregnancy test or currently breastfeeding. 
26. 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. 

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8.5 
Withdrawal Criteria (if applicable) 
If at any time during the study the investigator determines that a subject’s safety has been 
compromised, the subject may be withdrawn from the study.  
Subjects may withdraw consent from the study at any time. 
The sponsor and/or investigator may discontinue any subject for non-compliance or any 
valid medical reason (see Section 11.13.2). 
9 
STUDY PARAMETERS 
9.1 
Efficacy Measures and Endpoints 
9.1.1 
Primary Efficacy Measure(s) 
Stage 1, the primary efficacy endpoint will be evaluated: 
x Change from baseline (pre-drop compared to 3 minutes post-drop) in TMH as 
measured by OCT 
Stage 2, the primary efficacy endpoint will be evaluated: 
x Change from baseline (pre-drop compared to 3 minutes post-drop) in TMH as 
measured by OCT 

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9.2 
Safety Measures (Stage 1 and Stage 2) 
x Corrected Visual Acuity 
x Slit-lamp biomicroscopy 
x Adverse Events (AE) 
10 
STUDY MATERIALS 
10.1 
Study Treatment(s) 
10.1.1 
Study Treatment/Formulation 
x AR-15512 ophthalmic solution 0.003% 
10.1.2 
Instructions for Use and Administration 
AR-15512 Ophthalmic Solution 0.003%, administered once in clinic by site staff to both 
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right eye approximately 2 - 4 hours after completion of post-drop OCT). 
Study intervention will be administered once only at the Study Visit. Details of dosing 
can be found in the Manual of Procedures. 
10.2 
Other Study Supplies 
Details of other study supplies can be found in the Manual of Procedures. 

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11 
STUDY METHODS AND PROCEDURES 
11.1 
Subject Entry Procedures 
11.1.1 
Overview 
Subjects, as defined by the criteria in Sections 8.2, 8.3, and 8.4, will be considered for 
entry into this study. 
11.1.2 
Informed Consent 
Written informed consent will be obtained from each subject. A copy of the signed and 
dated consent document will be given to each subject. The original signed and dated 
informed consent document must be maintained in the study files at the Investigator’s 
site. 
The investigator is responsible for ensuring that no patient is subject to any study-related 
examination or activity before that patient has given informed consent. The patient must 
give written consent after the receipt of detailed information. The verbal explanation will 
cover all the elements specified in the written information provided for the patient. 
It should be emphasized that the patient is at liberty to withdraw consent to participate at 
any time, without penalty or loss of benefits to which the patient is otherwise entitled. 
Patients who refuse to give, or withdraw, written informed consent may not be included 
or continued in this study, but this will not impact their subsequent care. 
The investigator will inform the patient of the aims, methods, anticipated benefits, and 
potential hazards of the study, including any discomfort it may entail. The patient must be 
given every opportunity to clarify any points he/she does not understand and if necessary, 
ask for more information. At the end of the interview, the patient may be given time to 
reflect if this is required, or if the patient requests more time. Patients and/or legal 
guardian will be required to sign and date the informed consent form. 
A copy of the signed and dated consent document will be given to each subject. The 
original signed and dated informed consent document must be maintained in the study 
files at the Investigator’s site. Signed informed consent must be attained prior to the 
conductance of any study procedures. 

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11.1.3 
Washout Intervals 
Prohibited medications, treatments, and activities are outlined in Exclusion Criteria 
(Section 8.4) 
11.1.4 
Procedures for Final Study Entry 
Subjects must meet all inclusion and none of the exclusions criteria. 
11.1.5 
Methods for Assignment to Treatment Groups 
Each subject who signs an ICF will be assigned a screening number. Screening numbers 
will be assigned in sequential order at each site beginning with 001 and will follow the 
two-GLJLWVLWHQXPEHUHJVXEMHFWDW6LWHZLOOKDYH6FUHHQLQJ1XPEHU-001). 
All screening numbers will be assigned in strict numerical sequence at a site and no 
numbers will be skipped or omitted. Inclusion and exclusion criteria will be reviewed, 
and qualifying subjects will be enrolled into the study. 
11.2 
Demographics 
Demographic data including age, sex, race, and ethnicity will be collected and recorded. 
11.3 
Medical and Surgical History 
Significant medical and ophthalmic history will be collected and any current underlying 
medical/ophthalmic conditions, including those that may have resolved before the Study 
Visit, must also be recorded. All relevant medical and ophthalmic surgical procedures 
must be recorded. 
11.4 
Prior and Concomitant Medications 
Any medication (including vaccines, OTC, prescription medicines, vitamins, and/or 
herbal supplements) that the participant is receiving at the time of the Study Visit must be 
recorded on the subject’s source document and corresponding electronic case report form 
(eCRF) along with the reason the medication was taken. Prior medications taken up to at 
least 30 days prior to the Study Visit must also be recorded. 
Concurrent enrollment in another investigational drug or medical device study is not 
permitted. 

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11.4.1 
Prohibited Medications/Treatments 
Disallowed medications/treatments during the study are outlined in the Exclusion Criteria 
(Section 8.4). 
11.4.2 
Escape Medications 
1RHVFDSHPHGLFDWLRQVDUHrequired for this study. 
11.4.3 
Special Diet or Activities 
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11.5 
Clinical Laboratory Tests 
11.5.1 
Pregnancy Testing 
Urine pregnancy tests for women of childbearing are required. Pregnancy tests must be 
negative for the subject to receive study intervention. 
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 effective method of contraception. 
11.6 
Dispensing Study Intervention 
Study intervention will be administered once only at the Study Visit. Details of dosing 
can be found in the Manual of Procedures. 
11.7 
Efficacy Assessment 
11.7.1 
OCT 
Only the left eye of subjects will be imaged with OCT and this assessment should be 
performed by the Investigator, designated sub-Investigator or trained research personnel 
only. Details will be provided in the OCT Procedures Manual. 
In brief, subject is seated in a comfortable position in front of the OCT. OCT imaging 
will occur: 
a. Before 0.003% AR-15512 drop administration 

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b. 3 minutes ± 15 seconds after 0.003% AR-15512 drop administration 
Images are recorded in the central plane of the lower eye lid, directly underneath the 
pupil. 
11.8 
Safety Assessments 
11.8.1 
Corrected Visual Acuity 
Logarithmic minimum angle of resolution (LogMAR) visual acuity in both eyes must be 
assessed using an Early Treatment of Diabetic Retinopathy Study (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. 
11.8.2 
Biomicroscopy 
6OLWODPSELRPLFURVFRSLFREVHUYDWLRQVZLOOEHJUDGHGDV1RUPDORU$EQRUPDO$EQRUPDO
findings will be categorized as clinically significant (findings that may interfere with 
study parameters or otherwise confound the data as determined by the investigator) or not 
FOLQLFDOO\VLJQLILFDQW1&67KHIROORZLQJZLOOEHH[DPLQHGLQERWKH\HV 
x Eyelid 
x Conjunctiva 
x Cornea 
x Anterior Chamber 
x Iris 
x Lens 
Additional procedural details can be found in the Manual of Procedures. 
11.9 
Other Assessments 
11.9.1 
Ocular Surface Disease Index (OSDI)© 
The OSDI© questionnaire consists of 12 questions regarding ocular symptoms, 
environmental triggers, and vision-related functioning in patients with DED (Schiffman, 

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Christianson et al. 2000). Additional procedural details can be found in the Manual of 
Procedures. 
11.10 Examination Procedures 
11.10.1 Procedures to be Performed at Study Visit with Regard to Study 
Objective(s) 
Details of examination procedures can be found in the Manual of Procedures. 
11.11 Schedule of Visits, Measurements, and Dosing 
11.11.1 Scheduled Visits 
Refer to Appendix 1 for a schedule of visits and procedures. 
11.11.2 Unscheduled Visits 
These visits may be performed in order to ensure subject safety. All procedures 
performed at an unscheduled visit will be recorded in the source documents and on the 

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Unscheduled Visit eCRF pages. Any procedure indicated in the eCRF that is not 
SHUIRUPHGVKRXOGEHLQGLFDWHGDV³1RWGRQH´ 
11.12 Compliance with Protocol 
A protocol deviation occurs when there is any non-adherence to a study procedure or 
schedule that is specified by the protocol. The term “protocol deviation” includes those 
departures from the protocol previously described by the term “protocol violation”; all 
departures from the protocol are now described as protocol deviations, regardless of the 
potential impact on subject safety. A Protocol Deviation Log shall be maintained by the 
site(s). Protocol deviations will be summarized in the final clinical study report. 
11.13 Subject Disposition 
11.13.1 Completed Subjects 
A completed subject is one who has not been discontinued from the study. 
11.13.2 Discontinued Subjects 
Subjects may be discontinued prior to their completion of the study due to: 
x subject request/withdrawal 
x AEs 
x protocol violations 
x administrative reasons (e.g., inability to continue, lost to follow up) 
x sponsor termination of the study 
x other 
1RWH,QDGGLWLRQDQ\VXEMHFWPD\EHGLVFRQWLQXHGIRUDQ\VRXQGPHGLFDOUHDVRQ 
1RWLILFDWLRQRIDVXEMHFWGLVFRQWLQXDWLRQDQGWKHUHDVRQIRUGLVFRQWLQXDWLRQZLOOEHPDGH
to Ora and/or the sponsor and will be clearly documented on the CRF. 
11.13.3 Screen Failures 
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 

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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. 
11.14 Study Termination 
The study may be stopped at any time by the investigator, the sponsor, and/or Ora with 
appropriate notification. 
11.15 Study Duration 
An individual subject’s participation will involve 1 visit. 
11.16 Monitoring and Quality Assurance 
During the course of the study, an Ora monitor or designee will make routine site visits to 
review protocol compliance, assess investigational product (IP) accountability, and 
ensure the study is being conducted according to the pertinent regulatory requirements. 
The review of the subjects’ medical records will be performed in a manner that 
adequately maintains subject confidentiality. Further details of the study monitoring will 
be outlined in a monitoring plan. 
Regulatory authorities of domestic and foreign agencies, quality assurance and or its 
designees may carry out on-site inspections and/or audits which may include source data 
checks. Therefore, direct access to the original source data will be required for 
inspections and/or audits. All inspections and audits will be carried out giving 
consideration to data protection as well as subject confidentiality to the extent that local, 
state, and federal laws apply. 
11.17 Quality Tolerance Limits 
Quality tolerance limits (QTLs) will be predefined through an internal risk management 
process and monitored on an ongoing basis, with documentation of QTLs that are met 
summarized in the clinical study report. 

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12 
ADVERSE EVENTS 
12.1 
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:  
x 1RQH 
x Study Intervention Discontinued  
x Study Intervention Interrupted  
2. AE Outcome:  
x Fatal  
x 1RW5HFRYHUHG1RW5HVROYHG 
x Recovered/Resolved  
x Recovered/Resolved with sequelae  
x Recovering/Resolving  

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x Unknown/Lost to follow-up 
12.2 
Adverse Event Definitions 
The following definitions of terms apply to this section:  
x 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.  
x 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 
1HZ'UXJ,1'VDIHW\UHSRUWLQJ³UHDVRQDEOHSRVVLELOLW\´PHDQVWKHUHLV
evidence to suggest a causal relationship between the administration of the drug 
and the AE.  
a) 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.  
b) 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. 
1HLWKHUWKHFRQGLWLRQKRVSLWDOL]DWLRQSURORQJHGKRVSLWDOL]DWLRQQRU
surgery are reported as a serious adverse event when the hospitalization 

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or prolonged hospitalization was for an elective surgical procedure or for 
a preexisting condition (with no increase in severity).  
x Unexpected AE or unexpected AR: an AE or AR is considered “unexpected” if it 
is not listed in the Investigator’s Brochure (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. 
12.3 
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 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 TEAEs.  
Surgery should not be reported as an outcome of an adverse event if the purpose of the 
surgery was diagnostic and the outcome was uneventful. 
12.3.1 
AEs and Prior Medical History 
Any medical condition present prior to informed consent which remains unchanged or 
improved should not be recorded as an AE at subsequent visits. However, an AE should 
be recorded if the frequency, intensity, or the character of a pre-existing condition 
worsens during the study period beyond what would be expected from the natural 
progression of that condition.  
Symptoms and signs that are consistent with the natural history of DED are not 
considered reportable adverse events. Such developments are recorded but are not 
reportable adverse events. Worsening of symptoms and signs of DED should be recorded 
as an AE or SAE only if judged by the investigator to have unexpectedly worsened in 
severity and/or frequency or changed in nature at any time during the study. When 
recording an unanticipated worsening of DED, it is important to convey why the 
development was unexpected.  
If there is a question as to whether a medical development should be reported as an 
adverse event, the Investigator is recommended to contact the Sponsor for guidance. 

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12.3.2 
Severity 
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an 
AE as determined by the investigator or reported to him/her by the subject. The 
assessment of severity is made irrespective of relationship to IP or seriousness of the 
event and should be evaluated according to the following scale: 
x Mild: Event is noticeable to the subject but is easily tolerated and does not 
interfere with the subject’s daily activities. 
x Moderate: Event is bothersome, possibly requiring additional therapy, and may 
interfere with the subject’s daily activities. 
x Severe: Event is intolerable, necessitates additional therapy or alteration of 
therapy, and interferes with the subject’s daily activities. 
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.  
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serves as a guide for defining regulatory reporting obligations. 
12.3.3 
Relationship to Investigational Product 
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.  

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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. 
12.3.4 
Expectedness 
x 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. 
x 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 ARs 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. 
x An Investigator must immediately (i.e., within 24 hours from time of awareness) 
report any SAE or SAR (see Section 12.2 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. 

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12.4 
Serious Adverse Events, Serious Adverse Reactions or Suspected Unexpected 
Serious Adverse Reactions 
12.4.1 
Serious Adverse Events 
An adverse event is considered serious if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
c) Death; 
d) A life-threatening adverse event; 
1RWH$QDGYHUVHHYHQWLVFRQVLGHUHG³OLIH-threatening” if, in the view of 
either the investigator or sponsor, its occurrence places the subject at 
immediate risk of death. It does not include an adverse event that, had it 
occurred in a more severe form, might have caused death. 
e) Inpatient hospitalization or prolongation of existing hospitalization; 
1RWH7KHWHUP³LQSDWLHQWKRVSLWDOL]DWLRQ´UHIHUVWRDQ\LQSDWLHQWDGPLVVLRQ
(even if less than 24 hours). For chronic or long-term inpatients, inpatient 
admission includes transfer within the hospital to an acute/intensive care 
inpatient unit. Inpatient hospitalization does not include: emergency room 
visits; outpatient/same-day/ambulatory procedures; observation/short stay 
units; rehabilitation facilities; hospice facilities; nursing homes; or clinical 
research/phase 1 units. 
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extension of an inpatient hospitalization beyond the stay anticipated or 
required for the reason for the initial admission as determined by the 
investigator or treating physician. 
f) A persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions; 
1RWH$VHULRXVDGYHUVHHYHQWVSHFLILFDOO\UHODWHGWRYLVXDOWKUHDWZRXOGEH
interpreted as any potential impairment or damage to the subject’s eyes (e.g., 
hemorrhage, retinal detachment, central corneal ulcer or damage to the optic 
nerve). 
g) A congenital anomaly/birth defect. 

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Important medical events that may not result in death, are 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. 
12.5 
Procedure for Reporting Adverse Events 
All adverse events and their outcomes must be reported to Ora, the study sponsor, and the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) as required by the 
IRB/IEC, federal, state, or local regulations and governing health authorities and recorded 
on the appropriate eCRF. 
12.5.1 
Reporting SAEs or SARs 
An Investigator must immediately (i.e., within 24 hours) report any SAE or SAR (see 
Section 12.2 for definitions) to the Sponsor or its CRO representative, whether or not 
considered study intervention-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.  
SAE reports will be evaluated by the Medical Monitor. Regulatory authorities, 
Institutional Review Board (IRB), and Investigators at each of the study sites will be 
informed as required. 
12.5.2 
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 for the study and submit an SAE report 
form and record the event within the Electronic Data Capture (EDC) system within 24 
hours of notification, 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. 
12.5.3 
SAE Report Contact Information 
 

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12.6 
Procedures for Unmasking 
This is an open-label study; masking procedures are not applicable. 
12.7 
Type and Duration of the Follow-up of Subjects after Adverse Events 
The investigator will follow AE outcomes until study completion, the subject is 
considered lost to follow-up, or the AE is otherwise classified. The outcome of the AE at 
the time of study completion/lost to follow-up should be recorded in the AE eCRF. If the 
subject is lost to follow-up, the Investigator should make 3 reasonable attempts to contact 
the subject via telephone, post, or certified mail. All follow-up will be documented in the 
VXEMHFW¶VVRXUFHGRFXPHQW1RQ-serious AEs identified on the last scheduled contact must 
be recorded on the AE eCRF with the status noted. 
If the Investigator becomes aware of any new information regarding an existing SAE 
(i.e., resolution, change in condition, or new treatment), a new SAE/Unanticipated Report 
Form must be completed and faxed to Ora within 24 hours of the site’s awareness of the 
new information. The original SAE form is not to be altered. The report should describe 
whether the event has resolved or continues and how the event was treated. 
12.8 
Drug Technical Events and Device Deficiencies for Drug/Device Combination 
Products 
Any technical events concerning the test article formulations or device deficiencies 
concerning the ophthalmic delivery device (i.e., blow-fill-seal) must be reported to the 
sponsor. The pharmacy manual provides instructions on how to report to the sponsor. 
A drug technical event is a deficiency of any non-device constituents of the study 
LQWHUYHQWLRQ1RQ-device constituents include the drug and drug excipients, packaging, 
information supplied by the manufacturer, and labelling related to the study intervention. 
Events may include inadequacies in quality, identity, safety, strength, purity, 
performance, and/or physical characteristics.  
A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, usability, safety, or performance. 

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Do not use any study intervention suspected to have a drug technical event and/or device 
deficiency. Isolate the study intervention from other products in the same storage 
condition until follow-up communication and instructions are received from the sponsor.  
A drug technical event or device deficiency may or may not be associated with subject 
harm. Adverse events, whether related or not related to technical events or device 
deficiencies, must be recorded in the adverse event eCRF. 
13 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
13.1 
Analysis Set 
The following analysis population will be considered: 
x Safety Analysis Set: The safety analysis set will include all subjects who have 
received at least one dose of 0.003% AR-15512. 
x Full Analysis Set (FAS): The FAS will include all subjects who have received at 
least one dose of 0.003% AR-15512 and have pre-drop and 3-minute post-drop 
TMH measurements. 
x Per Protocol Set (PPS): The PPS will include all subjects who are part of the FAS 
and have no major protocol deviations that could potentially influence the primary 
efficacy endpoint. 
13.2 
Statistical Hypotheses and Analyses Supporting Key Study Objectives 
13.2.1 Stage 1 
The primary hypothesis, for Stage 1, will focus on the change from baseline in TMH 
(measured at 3-minute post-drop minus pre-drop measurement) on the FAS. The primary 
efficacy hypotheses are as follows: 
H0: Mean change from baseline in TMH = 0 
HA: Mean change from baseline in TMH > 0 
The study will be considered successful if the null hypothesis (H0) is rejected in favor of 
the alternative hypothesis (HA) at the 5% (one-sided) significance level. 
The primary analysis will assess the change from baseline (pre-drop compared to 
3 minutes post-drop) in TMH using OCT. A paired t-test using the FAS will be 

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performed to test the pre-drop and post-drop difference in TMH. Descriptive statistics 
such as the mean, standard deviation, minimum, and maximum, as well as 90% 
confidence intervals, will be reported for the observed and change from baseline results. 

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13.2.2 Stage 2 
Following the final analysis of Stage 1, early trends in the data were identified to support 
subsequent planning. Results from this final analysis have guided the transition from 
Stage 1 to Stage 2. 
The primary hypothesis, for Stage 2, as in Stage 1 but analyzed independently, will focus 
on the change from baseline in TMH (measured at 3-minute post-drop minus pre-drop 
measurement) on the FAS. The primary efficacy hypotheses are as follows: 
H0: Mean change from baseline in TMH = 0 
HA: Mean change from baseline in TMH > 0 
The study will be considered successful if the null hypothesis (H0) is rejected in favor of 
the alternative hypothesis (HA) at the 5% (one-sided) significance level. 

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13.4 
Safety Analysis 
Adverse events will be collected and coded using the latest MedDRA version. Treatment-
emergent adverse events will be summarized using system organ class (SOC) and 
preferred terms (PT) based on the safety analysis set. Other safety parameters collected 
will also be summarized. Data on AEs and other safety parameters from Stage 1 and 
Stage 2 will be pooled for analysis, as the study design remains consistent across both 
stages. 1RIRUPDOLQIHUHQWLDOWHVWLQJZLOOEHSHUIRUPHGIRUVDIHW\RXWFRPHV 
13.5 
Sample Size Determination 
Stage 1: A sample size of 40 subjects provides at least 99% statistical power to detect a 
significant difference in mean change from baseline in TMH, at the 5% (one-sided) 
significance level. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 

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Stage 2: The primary objective of Stage 2 is to assess the change in TMH, assuming a 5% 
(one-sided significance). A sample size of 40 subjects will provide at least 99% power to 
detect the observed mean difference of 520 μm (SD 515 μm) for the difference between 
post-drop vs pre-drop measurements as identified in Stage 1. 
  
 
 
 
 
 
 
 
 
 
 
13.6 
Interim Analyses 
An interim analysis, in Stage 1, for futility (now called final analysis for Stage 1) will be 
performed on OCT-TMH 
 data after approximately 40 subjects have 
completed and exited from the study. During the interim analysis period, study 
enrollment will be temporarily paused. The primary purpose of the interim analysis is to 
identify early trends in the data for administrative planning purposes. Results from the 
planned futility analysis will guide the decision to either continue or terminate the study. 
Stage 1 data will also serve as pilot data for Stage 2, helping to inform its design. 
Detailed procedures for assessing futility will be outlined SAP, which will supersede the 
protocol in case of any discrepancies between the two documents regarding data analysis 
plans. There will be no interim analysis in Stage 2.  
14 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES 
This study will be conducted in compliance with the protocol, current Good Clinical 
Practices (GCPs), including the International Conference on Harmonization (ICH) 
Guidelines, and in general, consistent with the Declaration of Helsinki. In addition, all 
applicable local, state, and federal requirements relevant to the use of IP in the countries 
involved will be adhered to. 

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14.1 
Protection of Human Subjects 
14.1.1 
Subject Informed Consent 
Informed consent/assent 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 parent or legal guardian prior to enrollment into the study. If the 
subject is under the legal age of consent, the consent form must be signed by a legal 
guardian or as required by state and/or local laws and regulations. 
All informed consent/assent forms must be approved for use by the sponsor and receive 
approval/favorable opinion from an IRB/Independent Ethics Committee (IEC) 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 Ora prior to submission to 
the governing IRB/IEC 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 informed consent is taken under special circumstances (oral informed consent), then 
the procedures to be followed must be determined by Ora and/or sponsor and provided in 
writing by Ora and/or sponsor prior to the consent process. 
14.1.2 
Institutional Review Board (IRB) Approval 
This study is to be conducted in accordance with IRB regulations (U.S. 21 Code of 
Federal Regulations [CFR] Part 56.103). The investigator must obtain appropriate IRB 
approval before initiating the study and re-approval at least annually. 
Only an IRB/IEC-approved version of the informed consent form will be used. 
14.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 
14.3 
Subject Confidentiality 
All personal study subject data collected and processed for the purposes of this study 
should be maintained by the investigator and his/her staff with adequate precautions as to 
ensure that the confidentiality of the data is in accordance with local, state, and federal 
laws and regulations. 

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Monitors, auditors, and other authorized representatives of Ora, the sponsor, the IRB/IEC 
approving this study, the Food and Drug Administration, the Department of Health and 
Human Services, other domestic government agencies, and other foreign regulatory 
agencies will be granted direct access to the subject’s original medical and study records 
for verification of the data and/or clinical trial procedures. Access to this information will 
be permitted to the aforementioned individuals to the extent permitted by law. 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the IP may ultimately be marketed, but the subject’s 
identity will not be disclosed in these documents. 
14.4 
Documentation 
Source documents may include a subject’s medical records, hospital charts, clinic charts, 
the investigator’s study subject files, as well as the results of diagnostic tests such as 
X-rays, laboratory tests, and EKGs. The investigator’s copy of the CRFs serves as the 
investigator’s record of a subject’s study-related data. 
14.4.1 
Retention of Documentation 
All study-related correspondence, subject records, consent forms, records of the 
distribution and use of all IP, and copies of CRFs should be maintained on file for at least 
two years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region; or until at 
least two years have elapsed since the formal discontinuation of clinical development of 
the IP. These documents will be retained for a longer period if required by the applicable 
regulatory requirements or by an agreement with the sponsor. It is the responsibility of 
the sponsor to inform the investigator/institution as to when these documents no longer 
need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address 
of the new custodian. 

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14.5 
Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Investigational Product 
14.5.1 
Labeling/Packaging 
Investigational product will be packaged and labeled into clinical kits. All clinical kits 
will be labeled according to applicable regulatory requirements. 
14.5.2 
Storage of Investigational Product 
The IP must be stored in a secure area accessible only to the investigator and his/her 
designees. The IP will be administered only to subjects entered into the clinical study, in 
accordance with the conditions specified in this protocol. The IP should be stored as 
directed on the investigational label and should be refrigerated at a controlled temperature 
(2 to 8°C / 36 to 46°F) until dispensed to subject. See more details in the Pharmacy 
Manual. 
14.5.3 
Accountability of Investigational Product 
The IP is to only be prescribed by the principal investigator or his/her named sub-
investigator(s) and is to only be used in accordance with this protocol. The IP must only 
be distributed to subjects properly qualified under this protocol to receive IP. 
The investigator must keep an accurate accounting of the IP received from the supplier. 
This includes the amount of IP dispensed to subjects, the amount of IP returned to the 
investigator by the subjects, and the amount returned or disposed of upon the completion 
of the study. A detailed inventory must be completed for the IP. 

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14.5.4 
Return or Disposal of Investigational Product 
When the study is completed or is terminated by the Sponsor, all study materials 
including used and unused study intervention kits / vials will be returned to the Sponsor 
or their designee. All study intervention accounting procedures must be completed before 
the study is considered to be concluded. The responsible person(s) at the Investigator’s 
site has the sole responsibility to account for all used, partially used, and unused study 
intervention. This site staff member at the Investigator’s site will complete a study 
intervention returns form or equivalent that will be signed by the Investigator or designee 
prior to returning the used and unused study intervention vials to the Sponsor or their 
designee. 
14.6 
Recording of Data on Source Documents and Case Reports Forms (CRFs) 
The investigator is responsible for ensuring that study data is completely and accurately 
recorded on each subject’s CRF, source document, and all study-related material. All 
study data should also be attributable, legible, contemporaneous, and original. Recorded 
datum should only be corrected in a manner that does not obliterate, destroy, or render 
illegible the previous entry (e.g., by drawing a single line through the incorrect entry and 
writing the revision next to the corrected data). An individual who has corrected a data 
entry should make clear who made the correction and when by adding to the correction 
his/her initials as well as the date of the correction. 
14.7 
Handling of Biological Specimens 
Please refer to Appendix 2 Handling of Biological Specimens 
14.8 
Publications 
Authorship and manuscript composition will reflect cooperation among all parties 
involved in the study. Authorship will be established before writing the manuscript. Ora 
and the sponsor will have the final decision regarding the manuscript and publication. 
 
 

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15 REFERENCES 
&UDLJ-3..1LFKROV(.$NSHN%&DIIHU\+6'XD&.-RR=/LX-'
1HOVRQ--1LFKROV.7VXERWDDQG)6WDSOHWRQ7)26'(:6,,'HILQLWLRQ
DQG&ODVVLILFDWLRQ5HSRUWOcul Surf 15(3): 276-283. 
Schiffman, R. M., M. D. Christianson, G. Jacobsen, J. D. Hirsch and B. L. Reis (2000). 
5HOLDELOLW\DQGYDOLGLW\RIWKH2FXODU6XUIDFH'LVHDVH,QGH[Arch Ophthalmol 118(5): 
615-621. 
6FKXLUPDQQ'-$FRPSDULVRQRIWKHWZRRQH-sided tests procedure and the 
SRZHUDSSURDFKIRUDVVHVVLQJWKHHTXLYDOHQFHRIDYHUDJHELRDYDLODELOLW\J 
Pharmacokinet Biopharm 15(6): 657-680. 
 
 
 

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APPENDIX 2: HANDLING OF BIOLOGICAL SPECIMENS 
Instructions for the handling of biological specimen will be provided in a separate 
laboratory manual. 

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