Study Evaluating the Safety and Efficacy of AR-15512

Study Overview
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Brief Summary
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This will be a Phase 3, multicenter, vehicle-controlled, double-masked, randomized study conducted at approximately 20 sites in the United States. All subjects enrolled will have dry eye disease (DED). The study will consist of Screening (Day -14) and Baseline (Day 1) visits as well as visits at Day 7, Day 14, Day 28, and Day 90 (Study Exit).

Official Title
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A Phase 3 Study Evaluating the Safety and Efficacy of AR-15512, a Cold Thermoreceptor Modulator, for the Treatment of Dry Eye Disease (COMET-2)

Conditions
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Dry Eye Disease

Intervention / Treatment
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* Drug: AR 15512 Ophthalmic Solution
* Drug: Vehicle


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 30 years of age or older at the Screening visit Signs of DED at the Screening and Baseline visits assessed by corneal staining and Schirmer test Symptoms of DED at both Screening and Baseline visits assessed by SANDE questionnaire and ODS-VAS Corrected visual acuity (+0.70 LogMAR) or better in both eyes at both the Screening and Baseline visits Exclusion Criteria: History or presence of any ocular disorder or condition (other than DED) in either eye that would, in the opinion of the investigator, likely interfere with the interpretation of the study results or subject safety Regular use of lid hygiene within 14 days prior to the Screening visit or any planned use during the study Use of artificial tears within 2 hours prior to the Screening visit or anticipated use during the study Use of any topical ocular anti-inflammatory medication within 30 days prior to the Screening visit or anticipated use during the study (e.g., ocular cyclosporine [Restasis®, Cequa™], lifitegrast [Xiidra®], or any other prescription ophthalmic solution for DED, topical ocular corticosteroid- or non-steroidal-anti-inflammatory agents Use of Tyrvaya™ (varenicline solution, nasal spray 0.03mg) within 30 days prior to the Screening visit or anticipated use during the study Use of medications for the treatment of severe DED and/or Meibomian gland disease such as oral tetracyclines, oral tetracycline derivatives and oral retinoids within 30 days prior to the Screening visit or anticipated use during the study Initiation, discontinuation, or change in dose of a systemic medication known to cause ocular drying (e.g. antihistamines or tricyclic antidepressants) less than 14 days prior to the Screening visit or a change in dosage is anticipated during the study. Initiation, discontinuation, or change in dose of a systemic corticosteroid less than 60 days prior to the Screening visit or a change in dosage is anticipated during the study. Initiation, discontinuation, or change in dose of a systemic immunomodulator (e.g., hydroxychloroquine, methotrexate, cyclosporine) less than 60 days prior to the Screening visit or a change in dosage is anticipated during the study History or presence of significant systemic disease (i.e.: cardiovascular, pulmonary, hepatic, renal, hematologic, immunologic)

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Qualified subjects will be enrolled in the study and randomized in a 1:1 ratio within each site to receive 0.003% AR 15512 or AR-15512 vehicle to be administered twice daily (BID) as 1 drop in each eye for 90 days.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AR 15512 Ophthalmic Solution (0.003%)<br>0.003% AR 15512 to be administered BID for 90 days. Both eyes will be treated. | Drug: AR 15512 Ophthalmic Solution<br>* Topical ocular administration of one drop in both eyes BID for 90 days.<br>|
| Placebo Comparator: Vehicle<br>AR-15512 vehicle to be administered BID for 90 days. Both eyes will be treated. | Drug: Vehicle<br>* Topical ocular administration of one drop in both eyes BID for 90 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Unanesthetized Schirmer test | Proportion of subjects ≥ 10 mm increase in unanesthetized Schirmer score. Schirmer strips placed, without anesthesia, in both eyes measure the amount of tear wetting over a 5-minute period, in whole millimeters to a maximum score of 35 mm. An ≥ 10 mm score over time indicates a better outcome. | Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SANDE (Symptom Assessment iN Dry Eye) Questionnaire Score | Change from Baseline in SANDE score. The SANDE questionnaire consists of two visual analogue scales (VAS), each ranging from 0mm to 100mm to indicate the frequency (from Rarely to All the Time) and severity (from Very Mild to Very Severe) of dry eye symptoms. A higher score indicates greater frequency or severity. Each subject marks both VAS to indicate their level of frequency and severity. The SANDE score is calculated by multiplying the frequency score by the severity score and obtaining the square root. A reduced SANDE score over time indicates a better outcome. | Day 28 | 
| SANDE (Symptom Assessment iN Dry Eye) Questionnaire Score | Change from Baseline in SANDE score. The SANDE questionnaire consists of two visual analogue scales (VAS), each ranging from 0mm to 100mm to indicate the frequency (from Rarely to All the Time) and severity (from Very Mild to Very Severe) of dry eye symptoms. A higher score indicates greater frequency or severity. Each subject marks both VAS to indicate their level of frequency and severity. The SANDE score is calculated by multiplying the frequency score by the severity score and obtaining the square root. A reduced SANDE score over time indicates a better outcome. | Day 7, 14 & 90 | 
| Unanesthetized Schirmer score | Change from Baseline Schirmer strips placed, without anesthesia, in both eyes measure the amount of tear wetting over a 5-minute period, in whole millimeters to a maximum score of 35 mm. An increased score over time indicates a better outcome. | Day 7, 14, 28 & 90 | 
| Ocular Discomfort Score (ODS) - VAS | Change from Baseline Subjects mark a visual analogue scale (VAS) between 0mm to 100mm to indicate (from no symptom to maximal symptom) their ocular discomfort. A reduced score over time indicates a better outcome. | Day 28 & 90 | 
| Eye Dryness Score (EDS) - VAS | Change from Baseline Subjects mark a visual analogue scale (VAS) between 0mm to 100mm to indicate (from no symptom to maximal symptom) their eye dryness. A reduced score over time indicates a better outcome. | Day 28 & 90 | 
| Unanesthetized Schirmer score | Proportion of subjects with ≥ 10 mm increase in score Schirmer strips placed, without anesthesia, in both eyes measure the amount of tear wetting over a 5-minute period, in whole millimeters to a maximum score of 35 mm. An ≥ 10 mm score over time indicates a better outcome. | Day 7, 28 & 90 | 
| Quality of Life VAS | Change from Baseline Subjects mark a visual analogue scale (VAS) between 0mm to 100mm to indicate (from strongly disagree to strongly agree) their agreement with the statement Over the past 3 days my dry eye has interfered with my daily activities and reduced my quality of life. A reduced score over time indicates a better outcome. | Day 7, 14, 28 & 90 | 
| Ocular Pain - VAS | Change from Baseline Subjects mark a visual analogue scale (VAS) between 0mm to 100mm to indicate (from no symptom to maximal symptom) their ocular discomfort. A reduced score over time indicates a better outcome. | Day 90 | 
| Conjunctival Redness | Change from Baseline Investigators or designated sub-Investigators grade redness of the eye on a scale from 0 to 4 (from 0 normal to 4 severe). A reduced score over time indicates a better outcome. | Day 90 |