A Phase 3b Study to Evaluate 0.003% AR-15512 Safety and Drop Attributes
Phase: PHASE3
Conditions: Dry Eye Disease
Sponsor: Alcon Research

 
 
 
 
 
A Phase 3b Study to Evaluate 0.003% AR-15512 Safety 
and Drop Attributes 
 
STUDY ID 
DEF512-E005 
 
 
PROTOCOL v.2 
08 Jan 2025 
 
 
NCT06660290 

AR-15512 ophthalmic solution 0.003% 
Clinical Trial Protocol: DEF512-E005 
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Confidential 
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Clinical Trial Protocol: DEF512-E005 
 
Protocol Title: 
A Phase 3b Study to Evaluate 0.003% AR-15512 
Safety and Drop Attributes 
Protocol Number: 
DEF512-E005 
Study Phase: 
Phase 3b 
Investigational Product 
Name: 
AR-15512 ophthalmic solution 0.003% 
IND Number: 
147005 
Indication: 
Dry Eye Disease 
Investigators: 
Multi-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. 

AR-15512 ophthalmic solution 0.003% 
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AR-15512 ophthalmic solution 0.003% 
Clinical Trial Protocol: DEF512-E005 
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Version 2.0, 08Jan2025 
Confidential 
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1 
SYNOPSIS 
 
Protocol Title: 
A Phase 3b Study to Evaluate 0.003% AR-15512 Safety and 
Drop Attributes 
Protocol Number: 
DEF512-E005 
Investigational Product: 
AR-15512 ophthalmic solution 0.003% 
Study Phase: 
Phase 3b 
 
Primary Objective(s): 
To evaluate the proportion of ocular adverse events reported 
in subjects with dry eye disease (DED) between the 
intervention arm [0.003% AR-15512 (512)] vs. Refresh® 
Classic. 
Overall Study Design: 
Structure: 
Multi-center, subject-masked, randomized, single-visit, 
crossover study 
Duration: 
This study will consist of a 1 day single visit (acute), lasting 
approximately 7-8 hours. 
 
 
 
 
 
Dosage/Dose Regimen/ 
Instillation/Application/Use: 
Qualified subjects will be dosed once with an artificial tear 
(Refresh Classic), as 1 drop in the right eye only, by site 
staff prior to instillation of any variation of 512. 
After a wait period of 30 minutes ± 5 minutes, subjects will 
then receive 512, instilled in clinic by site staff. 
Note: Four 512 instillation variations will be utilized (in 
randomized sequence starting with the left eye). A wait 
period of 30 minutes ± 5 minutes will take place between 
left eye and right eye instillation. Each variation will be 
instilled in only 1 eye. Following the first two instillation 
variations, a wait period of 2 to 3 hours must elapse prior to 
instillation of the remaining two 512 variations. 
Summary of Visit Schedule: 
The study consists of 1 Visit (Screening, Enrollment and 
Assessments). 
Study Population Characteristics: 
Number of Subjects: 
Approximately 36 to 55 subjects will be enrolled. 
Condition/Disease: 
Dry Eye Disease 

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Inclusion Criteria: 
To be eligible to participate in this trial, an individual must 
meet all the following criteria: 
1. Male or female, 18 years of age or older. 
3. Corrected Visual Acuity (Snellen) 20/200 or better in 
both eyes. 
4. Good general and ocular health, as determined by the 
Investigator using medical history, ophthalmic 
examination and history. 
5. 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. 
6. Written informed consent from the subject has been 
obtained prior to any study-related procedures. 
7. 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 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). 
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 

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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 regular 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 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 
(e.g., antihistamines or tricyclic antidepressants) 
within 7 days of the Study Visit. 
18. Initiation, discontinuation, or change in dose of a 
systemic corticosteroid within 14 days of the Study 
Visit. 
Note: Non-ocular topically applied corticosteroids 
(including topical creams, nasal sprays and inhalers) 
are not applicable to this exclusion. 

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19. Initiation, discontinuation, or change in dose of a 
systemic immunomodulator (e.g., 
hydroxychloroquine, methotrexate, cyclosporine) 
within 30 days of the Study Visit. 
20. Vaccination 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: 
x 
AR-15512 ophthalmic solution 0.003% 
x 
Refresh Classic 
Evaluation Criteria: 
Primary Endpoint: 
x 
Proportion of ocular AEs reported by intervention arm 
(512 vs. Refresh Classic). 

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Safety Measures: 
x 
Corrected Visual Acuity 
x 
Slit-Lamp Biomicroscopy 
x 
Adverse Events (AEs) 
General Statistical Methods and Types of Analyses 
Analysis Sets: 
x 
Safety Analysis Set (SAF): The SAF will include all subjects who have received at 
least one dose of Refresh Classic or one dose of 512. 
x 
Full Analysis Set (FAS): The FAS will include all subjects who have received at least 
one dose of Refresh Classic and one dose of 512 instillation variation, and who have at 
least one rating of the Rating Sensation Assessment. 
Safety Analysis: 
The AEs will be collected after subject signs the ICF and coded using the latest Medical 
Dictionary for Regulatory Activities (MedDRA) version. Treatment-emergent adverse events 
(TEAEs) will be summarized using the SAF by system organ class and preferred term. Other 
safety parameters collected will be summarized. 

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2 
TABLE OF CONTENTS 
1 
SYNOPSIS ................................................................................................................................. 3 
2 
TABLE OF CONTENTS ............................................................................................................. 9 
3 
LIST OF ABBREVIATIONS ...................................................................................................... 13 
4 
INTRODUCTION ...................................................................................................................... 15 
4.1 
Dry Eye Disease .................................................................................................. 15 
5 
STUDY OBJECTIVES .............................................................................................................. 16 
5.1 
Primary Objective(s) ........................................................................................... 16 
 
 
6 
CLINICAL HYPOTHESES ........................................................................................................ 16 
7 
OVERALL STUDY DESIGN ..................................................................................................... 17 
8 
STUDY POPULATION ............................................................................................................. 19 
8.1 
Number of Subjects ............................................................................................. 19 
8.2 
Study Population Characteristics ......................................................................... 20 
8.3 
Inclusion Criteria ................................................................................................. 20 
8.4 
Exclusion Criteria ................................................................................................ 20 
8.5 
Withdrawal Criteria (if applicable) ..................................................................... 23 
9 
STUDY PARAMETERS ............................................................................................................ 23 
9.1 
Measures and Endpoints ...................................................................................... 23 
9.1.1 
Primary Measure(s) ....................................................................................... 23 
 
 
9.1.3 
Safety Measures ............................................................................................ 24 
10 STUDY MATERIALS ................................................................................................................ 24 
10.1 
Study Treatment(s) .............................................................................................. 24 
10.1.1 
Study Intervention/Formulation ..................................................................... 24 
10.1.2 
Instructions for Use and Instillation .............................................................. 24 
10.2 
Other Study Supplies ........................................................................................... 25 
11 STUDY METHODS AND PROCEDURES................................................................................ 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 

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11.2 
Demographics ..................................................................................................... 26 
11.3 
Medical and Surgical History ............................................................................. 27 
11.4 
Prior and Concomitant Medications ................................................................... 27 
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 ........................................................................... 28 
11.7 
Collection of Study Intervention ........................................................................ 28 
11.8 
Safety Assessments ............................................................................................ 28 
11.8.1 
Corrected Visual Acuity ............................................................................... 28 
11.8.2 
Slit Lamp Biomicroscopy ............................................................................. 28 
11.10 Examination Procedures ..................................................................................... 30 
11.10.1 Procedures to be Performed at Study Visit with Regard to Study 
Objective(s) .................................................................................................. 30 
11.11 Schedule of Measurements and Dosing ............................................................. 30 
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 ............................................................................................. 31 
11.14 Study Termination .............................................................................................. 31 
11.15 Study Duration ................................................................................................... 31 
11.16 Monitoring and Quality Assurance .................................................................... 31 
11.17 Quality Tolerance Limits ................................................................................... 32 
12 ADVERSE EVENTS ................................................................................................................. 32 
12.1 
Performing Adverse Event Assessments ............................................................ 32 
13 ADVERSE EVENT DEFINITIONS ............................................................................................ 33 

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13.1 
Reporting Adverse Events .................................................................................. 34 
13.1.1 
AEs and Prior Medical History .................................................................... 34 
13.1.2 
Severity ........................................................................................................ 35 
13.1.3 
Relationship to Investigational Product ....................................................... 35 
13.1.4 
Expectedness ................................................................................................ 36 
13.2 
Serious Adverse Events, Serious Adverse Reactions or Suspected Unexpected 
Serious Adverse Reactions ................................................................................. 37 
13.2.1 
Serious Adverse Events ................................................................................ 37 
13.3 
Procedure for Reporting Adverse Events ........................................................... 38 
13.3.1 
Reporting SAEs or SARs ............................................................................. 38 
13.3.2 
Reporting Suspected Unexpected Serious Adverse Reactions (SUSARs) ... 38 
13.3.3 
SAE Report Contact Information ................................................................. 38 
13.4 
Procedures for Unmasking ................................................................................. 39 
13.5 
Type and Duration of the Follow-up of Subjects after Adverse Events ............ 39 
13.6 
Drug Technical Events and Device Deficiencies for Drug/Device Combination 
Products .............................................................................................................. 39 
14 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES ............................................ 40 
14.1 
Analysis Set ........................................................................................................ 40 
14.2 
Analyses Supporting Primary and Secondary Objectives(s) .............................. 40 
14.4 
Statistical Model, Hypotheses and Methods of Analysis ................................... 44 
14.5 
Safety Analysis ................................................................................................... 44 
14.6 
Sample Size Determination ................................................................................ 44 
14.7 
Interim Analyses ................................................................................................ 44 
15 COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL CONSIDERATIONS, AND 
ADMINISTRATIVE ISSUES ..................................................................................................... 44 
15.1 
Protection of Human Subjects ............................................................................ 44 
15.1.1 
Subject Informed Consent ............................................................................ 44 
15.1.2 
Institutional Review Board Approval........................................................... 45 
15.2 
Ethical Conduct of the Study ............................................................................. 45 

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15.3 
Subject Confidentiality ....................................................................................... 45 
15.4 
Documentation ................................................................................................... 46 
15.4.1 
Retention of Documentation ........................................................................ 46 
15.5 
Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Investigational Product ....................................................................................... 46 
15.5.1 
Labeling/Packaging ...................................................................................... 46 
15.5.2 
Storage of Investigational Product ............................................................... 47 
15.5.3 
Accountability of Investigational Product .................................................... 47 
15.5.4 
Return or Disposal of Investigational Product ............................................. 47 
15.6 
Recording of Data on Source Documents and Case Reports Forms .................. 47 
15.7 
Handling of Biological Specimens ..................................................................... 48 
15.8 
Publications ........................................................................................................ 48 
16 REFERENCES ......................................................................................................................... 49 
17 APPENDICES .......................................................................................................................... 50 
Appendix 1: Schedule of PROCEDURES .................................................................................................... 50 

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3 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
AR 
Adverse Reaction 
AUC 
Area Under the Curve 
BID 
Twice Daily 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
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 
HR 
Hazard Ratios 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IEC 
Independent Ethics Committee 
IP 
Investigational Product 
IRB 
Institutional Review Board 
LogMAR 
Logarithmic Minimum Angle of Resolution 
LS Means 
Least Squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
OTC 
Over-the-Counter 
 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 

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SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TEAE 
Treatment-Emergent Adverse Event 
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 (Craig 2017). 
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 To evaluate the proportion of ocular adverse events reported in subjects with DED 
between the intervention arm (512) vs. Refresh Classic. 
 
6 
CLINICAL HYPOTHESES 
 
The clinical hypothesis for this study is that adjustments in 512 instillation procedure will 
reduce either the intensity or duration of subject reported instillation site sensation. 

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7 
OVERALL STUDY DESIGN 
 
This is a Phase 3b, subject-masked, randomized, single-visit, crossover design conducted 
in the United States at approximately 6 sites. 
Approximately 36 to 55 DED subjects will be enrolled. The study will consist of 1 Visit 
(Screening, Enrollment, Assessments). All subjects will be exited from the study at the 
end of the Study Visit. 
At the end of the Screening phase, all qualified subjects will be enrolled and instilled a 
drop of artificial tear (Refresh Classic) in the right eye only. All subjects will then be 
dosed with 512 under four different instillation variations as described in Table 1. 
Subjects will be randomized to one of the four sequences of 512 instillation variations 
based on a Williams design randomization sequence (Table 2). 
Each 512 instillation variation will be dosed in one (1) eye only as described in the 
randomization sequence (Table 2), starting with the left eye. After the first two 512 
instillation variations are complete, subjects will start a wait period of a minimum of 
2 hours and a maximum of 3 hours prior to completion of dosing of the remaining two 
512 instillation variations. A wait period of 30 minutes ± 5 minutes will take place 
between left eye and right eye instillation. 
 
  
 
 
Details of assessments performed can be found in Appendix 1 (Schedule of Procedures) 
as well as in the Manual of Procedures. 

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8.2 
Study Population Characteristics 
 
All subjects must be at least 18 years of age, of either sex at birth, 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 this trial, an individual must meet all the following criteria: 
 
1. Male or female, 18 years of age or older. 
 
3. Corrected Visual Acuity (Snellen) 20/200 or better in both eyes. 
 
4. Good general and ocular health, as determined by the Investigator using medical 
history, ophthalmic examination and history. 
5. 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. 
6. Written informed consent from the subject has been obtained prior to any study-
related procedures. 
7. 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 the study: 
Ophthalmic: 
1. Current evidence of clinically significant ophthalmic disease other than DED 
(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. 

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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 either 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 regular 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 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. 

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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 (e.g., antihistamines or tricyclic antidepressants) within 7 
days of the Study Visit. 
18. Initiation, discontinuation, or change in dose of a systemic corticosteroid within 
14 days of the Study Visit. 
Note: Non-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 30 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.). 

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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. 
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 
Measures and Endpoints 
 
9.1.1 
Primary Measure(s) 
 
x Proportion of ocular AEs reported by intervention arm (512 vs. Refresh Classic). 
 
 
 
 
 

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9.1.3 Safety Measures 
 
x Corrected Visual Acuity 
 
x Slit-Lamp Biomicroscopy 
 
x 
Adverse Events (AEs) 
 
10 
STUDY MATERIALS 
 
10.1 
Study Treatment(s) 
 
10.1.1 
Study Intervention/Formulation 
 
x AR-15512 ophthalmic solution 0.003% 
 
x Refresh Classic 
 
10.1.2 
Instructions for Use and Instillation 
 
This is an acute dosing study, and study interventions are summarized in Table 3. Post 
enrollment, all subjects will first have 1 drop of Refresh Classic, instilled to the right eye 
only. Subjects will then receive a total of four drops of 512, instilled sequentially to only 
1 eye, starting with the left eye. After the first 2 drops of 512 are instilled, a wait period 
of 2 to 3 hours must elapse prior to instilling the remaining 2 drops. Each instillation will 

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differ based on the variations described in Table 1. The order of the four 512 instillation 
variations will be randomized (Table 2). 
Table 3 
Study Intervention 
 
Intervention 
Name 
Refresh Classic 
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Intervention 
Description 
Artificial tear (Refresh Classic) to 
be instilled in clinic by site staff as 
1 drop in right eye only, prior to 
instillation of 512. 
512 administered twice per eye in clinic 
by site staff. 
Note: Four 512 instillation variations 
will be utilized (in randomized 
sequence, starting with the left eye). 
Each variation will be instilled in only 
1 eye. Following the first two 
instillation variations, a wait period of 
between 2 to 3 hours must elapse prior 
to instillation of the remaining two 
variations. 
Use 
Experimental 
Experimental 
Dose 
Formulation 
Ophthalmic solution 
Ophthalmic solution 
Route of 
Instillation 
Topical 
Topical 
Duration 
Acute (1 day) 
Acute (1 day) 
10.2 
Other Study Supplies 
 
Details of other study supplies can be found in the Manual of Procedures. 
 
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 

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informed consent document must be maintained in the study files at the Investigator’s 
site. Signed informed consent must be attained prior to conducting any study procedures. 
The Investigator is responsible for ensuring that no subject completes any study-related 
procedures or activity before that subject has given informed consent. The subject 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 subject. 
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, but this will not impact their subsequent care. 
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 s/he does not understand and if 
necessary, ask for more information. At the end of the interview, the subject may be 
given time to reflect if this is required, or if the subject requests more time. Subjects 
and/or legal guardian will be required to sign and date the ICF. 
11.1.3 
Washout Intervals 
 
Prohibited medications and treatments 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 exclusion 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 5001 and will follow the 
four-digit site number (e.g., subject 5001 at Site 9999 will have Screening Number 
9999-5001). 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 in the study. 
11.2 
Demographics 
 
Demographic data including age, sex at birth, race, and ethnicity will be collected and 
recorded. 

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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 per the Manual of Procedures. 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 subject 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. 
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 
 
No escape medications are required for this study. 
 
11.4.3 
Special Diet or Activities 
 
No special diets or activities are required for this study. 
 
11.5 
Clinical Laboratory Tests 
 
11.5.1 
Pregnancy Testing 
 
Urine pregnancy tests for women of childbearing (WOCBP) 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. 

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11.6 
Dispensing Study Intervention 
 
Study intervention will be instilled at the Study Visit only by site staff. Details of dosing 
are displayed in Figure 1 and further details will be provided in the Manual of 
Procedures. 
11.7 
Collection of Study Intervention 
 
Used vials should be destroyed per site standard procedures after each instillation. 
 
The number of unused vials will be recorded at site inventory level, and returned to depot 
at end of study. 
11.8 
Safety Assessments 
 
11.8.1 
Corrected Visual Acuity 
 
Monocular logarithmic minimum angle of resolution (LogMAR) corrected visual acuity 
in both eyes must be assessed using an Early Treatment of Diabetic Retinopathy Study 
(ETDRS) Series 2000 chart. Corrected visual acuity should be evaluated prior to all other 
ocular examinations as specified in the Schedule of Procedures (Appendix 1). Additional 
procedural details can be found in the Manual of Procedures. 
11.8.2 
Slit Lamp Biomicroscopy 
 
Slit lamp biomicroscopic observations will be graded as Normal or Abnormal. Abnormal 
findings will be categorized as clinically significant (findings that may interfere with 
study parameters or otherwise confound the data as determined by the Investigator) or not 
clinically significant. The following will be examined in both eyes: 
x Eyelid 
 
x Conjunctiva 
 
x Cornea 
 
x Anterior Chamber 
 
x Iris 
 
x Lens 

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Additional procedural details can be found in the Manual of Procedures. 
 
 
 
 
 
 
 
 
 

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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 Measurements and Dosing 
 
Refer to Appendix 1 for the Schedule of Procedures. 
 
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 Withdrawal by subject 
 
x Withdrawal by Investigator 
 
x AEs 
 
x Protocol deviations 
 
x Administrative reasons (e.g., inability to continue) 
 
x Study termination by sponsor 

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x Other 
 
Note: In addition, any subject may be discontinued for any sound medical reason. 
 
Notification of a subject discontinuation and the reason for discontinuation will be made 
to Ora and/or the sponsor and will be clearly documented on the eCRF. 
11.13.3 Screen Failures 
 
Subjects 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 subject might meet the eligibility criteria. It is encouraged 
for the Investigator to discuss potential rescreening with the sponsor. Rescreened subjects 
should be assigned a new subject 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, lasting approximately 7-8 
hours. 
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 study intervention (i.e., 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. 

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11.17 Quality Tolerance Limits 
 
Quality tolerance limits (QTLs) will be predefined through a risk management process 
and monitored on an ongoing basis, with documentation of QTLs that are met 
summarized in the final clinical study report. 
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 None 
 
x Study Intervention Discontinued 
 
x Study Intervention Interrupted 
 
2. AE Outcome: 
 
x Fatal 
 
x Not Recovered/Not Resolved 

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x Recovered/Resolved 
 
x Recovered/Resolved with Sequelae 
 
x Recovering/Resolving 
 
x Unknown 
 
13 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 
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. 
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 

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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 an SAE when the hospitalization 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. 
13.1 
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 intervention, it should be recorded as an AE. Any change in the 
health status after commencement of study intervention should be recorded as TEAEs. 
Surgery should not be reported as an outcome of an AE if the purpose of the surgery was 
diagnostic and the outcome was uneventful. 
13.1.1 
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 but such developments are recorded in the medical history per 
Section 11.3. Worsening 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 Visit. When recording an 
unanticipated worsening of DED as an AE, it is important to convey why the 
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As this study is specifically asking subjects to describe the ocular sensation they may 
experience upon instillation of study intervention, generally mild sensations are not to be 
considered as AEs and should not be documented as such. An ocular AE should only be 
recorded if the subject reports severe painful or unexpected ocular sensations. 
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. 
13.1.2 
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 during the Study Visit will be recorded. 
Note: A severe AE is not the same as a serious AE (SAE). Seriousness of an AE (NOT 
severity) serves as a guide for defining regulatory reporting obligations. 
13.1.3 
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: 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: 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 

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relationship. Therefore, there is not a reasonable possibility that the AE was caused by 
the product, device, or procedure. 
Possibly Related: Event follows a reasonable, temporal sequence from the time of study 
intervention instillation 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: Event follows a reasonable, temporal sequence from the time of study 
intervention instillation 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 intervention 
administration or procedure, or improves on stopping the study intervention, or reappears 
on repeat exposure, or there is a positive reaction at the instillation site. 
13.1.4 
Expectedness 
 
x AEs or ARs are considered “unexpected” if they are not listed in the Reference 
Safety Information section of the IB for 512 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 512 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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13.2 
Serious Adverse Events, Serious Adverse Reactions or Suspected Unexpected 
Serious Adverse Reactions 
13.2.1 
Serious Adverse Events 
 
An AE is considered serious if, in the view of either the Investigator or sponsor, it results 
in any of the following outcomes: 
a) Death; 
 
b) A life-threatening AE; 
 
Note: An AE 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 that, had it occurred in a more severe form, 
might have caused death. 
c) Inpatient hospitalization or prolongation of existing hospitalization; 
 
Note: The term “inpatient hospitalization” refers to any inpatient admission 
(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. 
Note: The term “prolongation of existing hospitalization” refers to any 
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. 
d) A persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions; 
Note: A SAE specifically related to visual threat would be 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). 
e) 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. 
13.3 
Procedure for Reporting Adverse Events 
 
All AEs 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. 
13.3.1 
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, IRB, and 
Investigators at each of the study sites will be informed as required. 
13.3.2 
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, 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. 
13.3.3 
SAE Report Contact Information 
 
 
 
 

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13.4 
Procedures for Unmasking 
 
This is a subject-masked study; masking procedures to be employed will be described in 
the Pharmacy Manual as well as the Manual of Procedures. 
13.5 
Type and Duration of the Follow-up of Subjects after Adverse Events 
 
The Investigator will follow AE outcomes until study completion or the AE is otherwise 
classified. The outcome of the AE at the time of study completion should be recorded in 
the AE eCRF. All follow-up will be documented in the subject’s source document. Non-
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 been resolved or continues and how the event was treated. 
13.6 
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 
intervention. Non-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. 
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 
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A drug technical event or device deficiency may or may not be associated with subject 
harm. AEs, whether related or not related to technical events or device deficiencies, must 
be recorded in the AE eCRF. 
14 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
 
In case of any discrepancies or differences between the protocol and the Statistical 
Analysis Plan (SAP) concerning descriptions or explanations, including but not limited to 
the definitions of endpoints or the statistical approach/model for primary, secondary, or 
exploratory objectives, the SAP shall take precedence and supersede the protocol. 
14.1 
Analysis Set 
 
The following analysis sets will be considered: 
 
x Safety Analysis Set (SAF): The SAF will include all subjects who received at 
least one dose of Refresh Classic or one dose of 512. 
x Full Analysis Set (FAS): The FAS will include all subjects who have received at 
least one dose of Refresh Classic and one dose of 512 instillation variation and 
who have at least one rating of the Rating Sensation Assessment. 
14.2 
Analyses Supporting Primary and Secondary Objectives(s) 
 
This Phase 3b does not have any efficacy objectives. For the safety primary objective, 
descriptive summaries, including counts and frequencies will be reported by intervention 
arm. Additional details will be presented in the SAP. 
 

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14.4 
Statistical Model, Hypotheses and Methods of Analysis 
 
No formal pre-planned Type I error rate will be controlled, meaning no specific threshold 
for false positives will be set beforehand. While p-values will be reported, results should 
be interpreted with caution. 
14.5 
Safety Analysis 
 
AEs will be collected after the subject signs the ICF and coded using the latest MedDRA 
version. TEAEs will be summarized using the SAF by system organ class and preferred 
term. Other safety parameters collected will be summarized. 
14.6 
Sample Size Determination 
 
No power calculation will be used to determine the sample size. 
 
 
 The 
study aims to recruit approximately 36 to 55 subjects. 
14.7 
Interim Analyses 
 
No interim analysis will be performed in this study. 
 
15 
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. 
15.1 
Protection of Human Subjects 
 
15.1.1 
Subject Informed 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 parent or legal guardian prior to enrollment into the study. 

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All informed consent forms must be approved for use by the sponsor and receive 
approval/favorable opinion from an IRB/IEC prior to their use. If the ICF 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. 
15.1.2 
Institutional Review Board 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. 
 
15.2 
Ethical Conduct of the Study 
 
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 
15.3 
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. 
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. 

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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. 
15.4 
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. 
15.4.1 
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. 
15.5 
Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Investigational Product 
15.5.1 
Labeling/Packaging 
 
The IP will be packaged into pouches. All pouches will be labeled according to 
applicable regulatory requirements. 
Refresh Classic will remain in the commercial packaging. A label with the protocol 
number will be applied to the outer carton. 

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15.5.2 
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 at 
refrigerated conditions (2 to 8°C / 36 to 46°F) upon receipt. See more details in the 
Pharmacy Manual. 
Note: Refresh Classic will be stored in accordance with the manufacturer's instructions. 
 
15.5.3 
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 administered 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, and the amount returned to the 
supplier upon the completion of the study. A detailed inventory must be completed for 
the IP. 
15.5.4 
Return or Disposal of Investigational Product 
 
When the study is completed or is terminated by the sponsor, all study materials 
including unused IP pouches/vials will be returned to the sponsor or their designee. All IP 
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 IPs. 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 unused IP pouches/vials to the sponsor 
or their designee. 
15.6 
Recording of Data on Source Documents and Case Reports Forms 
 
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 
data 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 

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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. 
15.7 
Handling of Biological Specimens 
 
Not applicable. 
 
15.8 
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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16 REFERENCES 
 
Craig, J. P., K. K. Nichols, E. K. Akpek, B. Caffery, H. S. Dua, C. K. Joo, Z. Liu, J. D. 
Nelson, J. J. Nichols, K. Tsubota and F. Stapleton (2017). "TFOS DEWS II Definition 
and Classification Report." Ocul Surf 15(3): 276-283. 

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17 APPENDICES 
 
APPENDIX 1: SCHEDULE OF PROCEDURES 
 
Assessment 
 
Informed consent 
X 
Demographics 
X 
Medical, ophthalmic, and surgical history 
X 
Prior or concomitant medication review 
X 
Urine pregnancy test (WOCBP only) 
X 
Corrected visual acuity (pre-drop) 
X 
Slit lamp biomicroscopy (pre-drop) 
X 
Inclusion and exclusion criteria review 
X 
Study Enrollment 
X 
Instillation of 1 drop of Refresh Classic to right eye 
X 
30 min ± 5 min wait 
X 
Randomization to order the sequence of 512 instillation variation (may occur during 
the 30 min ± 5 min wait period) 
X 
Instill first randomized 512 instillation variation to left eye 
X 
30 min ± 5 min wait 
X 
Instill second randomized 512 instillation variation to right eye 
X 
Minimum 2 hour and Maximum 3 hour wait 
X 
Instill third randomized 512 instillation variation to left eye 
X 
30 min ± 5 min wait 
X 
Instill fourth randomized 512 instillation variation to right eye 
X 

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Assessment 
 
Corrected visual acuity (post-last drop) 
X 
Slit lamp biomicroscopy (post-last drop) 
X 
Adverse events 
X 
Study Exit 
X 
Abbreviations: min = minutes; WOCBP = women of childbearing potential 

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Electronic Record and Signature Disclosure created on: 17-Nov-2021 | 11:28 
Parties agreed to: Abby Jimoh, Agustin Calatroni, Cecilia Chao, George Ousler, Michelle Senchyna