A Long-Term Safety Study Evaluating the Safety and Systemic Exposure of AR-15512

Study Overview
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Brief Summary
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This will be a 12-month, multicenter, vehicle-controlled, double-masked, randomized Phase 3 study conducted at approximately 10 sites in the United States. All subjects enrolled will have dry eye disease (DED). The study will consist of a Baseline (Day 1) visit as well as visits at Day 14, Day 90, Day 180, Day 270, and Day 365 (Study Exit).

Official Title
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A Long-Term Safety Study Evaluating the Safety and Systemic Exposure of AR-15512, a Cold Thermoreceptor Modulator, for the Treatment of Dry Eye Disease (COMET-4)

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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Key Inclusion Criteria: Male or female, 18 years of age or older at baseline visit Have a previous history of DED, clinician diagnosed or patient reported, within the previous 12 months of the Baseline visit Have used or desired to use artificial tears for DED symptoms within 3 months prior to the Baseline visit Have a documented Schirmer test with or without topical anesthesia score ≥ 2 and < 10 mm/5 min in at least one eye within 1 year prior to the Baseline visit Total ocular surface staining score of ≥ 1 and ≤ 12 and no region = 5, based on the Oxford grading scheme at the Baseline visit Corrected visual acuity equal to or better than logMar +0.7 (Snellen equivalent equal to or better than 20/100), as assessed by Early Treatment of Diabetic Retinopathy Study (ETDRS) scale in both eyes at the Baseline visit Good general and ocular health, as determined by the investigator using medical history, ophthalmic examination and history, and vital signs (heart rate and blood pressure) at the Baseline visit Key Exclusion Criteria: 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 Current evidence of other significant ophthalmic disease requiring topical medication (e.g. glaucoma, ocular hypertension), which may interfere with vision (e.g., cataract, macular degeneration) or other disease which the investigator believes may interfere with study findings or interpretation Use of contact lenses in either eye within 7 days prior to the Baseline visit or planned use during the study Use of any topical ocular anti-inflammatory medication within 30 days prior to the Baseline visit or anticipated use during the study (e.g., ocular cyclosporine [Restasis®, Cequa™], lifitegrast [Xiidra®], or any other prescription ophthalmic product for DED, topical ocular corticosteroid- or non-steroidal anti-inflammatory agents Use of topical ocular autologous serum within 30 days prior to the Baseline visit or anticipated use during the study Use of any topical ocular glaucoma medication within 30 days prior to the Baseline visit or anticipated use during the study Use of Tyrvara™ (varenicline solution, nasal spray 0.03mg) within 30 days prior to the Baseline visit or anticipated use during the study Use of medications for the treatment of severe DED and/or Meibomian gland disease such as oral pilocarpine, oral cevimeline, oral macrolides, oral tetracyclines, oral tetracycline derivatives, and oral retinoids within 30 days prior to the Baseline visit or anticipated use during the study Use of lid heating therapy (i.e., LipiFlow®, iLUX®) or Meibomian gland probing/therapeutic expression within 6 months prior to the Baseline visit or anticipated during the study

Ages Eligible for Study
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Minimum Age: 18 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 2:1 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 365 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 365 days. Both eyes will be treated. | Drug: AR-15512 Ophthalmic Solution<br>* Topical ocular administration of one drop in both eyes BID for 365 days.<br>|
| Placebo Comparator: Vehicle<br>AR-15512 vehicle to be administered BID for 365 days. Both eyes will be treated. | Drug: Vehicle<br>* Topical ocular administration of one drop in both eyes BID for 365 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | Incidence of Adverse Events Subjects will be verbally asked by clinic staff to report any changes to any aspect of their health (systemic or ocular) at each study visit. A low incidence indicates a better outcome. | Day 1, 14, 90, 180, 270 & 365 | 
| Blood Pressure | Change from baseline Each subjects systolic and diastolic blood pressure will be measured using an appropriate sphygmomanometer and will be recorded in mmHg. Minimal change from the start of the study indicates a better outcome. | Day 1, 14, 90, 180, 270 & 365 | 
| Heart Rate | Change from Baseline Each subjects heart rate will be measured using manual or automated methods and recorded in bpm. Minimal change from the start of the study indicates a better outcome. | Time Frame: Day 1, 14, 90, 180, 270 & 365 | 
| Endothelial cell counts | Change from baseline Specular microscopy will be used to measure cells in the central cornea to determine cell density which will be recorded. Minimal change from the start of the study indicates a better outcome. | Day 1 and 365 | 
| Hematology, chemistry, and urinalysis | Change from baseline A small volume of blood and urine will be collected from each subject and these samples will be sent to a laboratory to evaluate each subjects overall health. Values for each assessment will be recorded in their respective clinical units. Minimal change from the start of the study indicates a better outcome. | Day 1, 180 & 365 | 
| LogMAR Visual Acuity | Change from baseline Each subject's vision will be assessed using an eye chart and the score will be recorded as the number of letters read. If a subject wears glasses, these will be worn during the test. Minimal change from the start of the study indicates a better outcome. | Day 1, 14, 90, 180, 270 & 365 | 
| Early Treatment of Diabetic Retinopathy Study (ETDRS) Visual Acuity | Change from baseline Change from baseline Each subject's vision will be assessed using a standardized eye chart and ETDRS testing procedure. The score will be recorded as the number of letters read. Minimal change from the start of the study indicates a better outcome. | Day 1 & 365 | 
| Biomicroscopy | Change from baseline With the aid of a microscope, the front part of the eyes and eyelids and the surface of the cornea will be examined and graded based on standard clinical scales and recorded as normal or abnormal. Minimal change from the start of the study indicates a better outcome. | Day 1, 14, 90, 180, 270 & 365 | 
| Total ocular staining | Change from baseline Dye is applied to the surface of the eye and the amount of dye that remains after several minutes will viewed through a microscope and graded using a standardized scale (0-5). Lower scores indicate a better outcome. | Day 1, 14, 90, 180, 270 & 365 | 
| Intraocular pressure (IOP) | Change from baseline A small tonometer device will be pressed against the surface of the eye to determine the pressure inside the eye. The pressure will be recorded in mmHg. Lower scores indicate a better outcome. | Day 1, 14, 90, 180, 270 & 365 | 
| Dilated fundus exam | Change from baseline The back of the eyes will be dilated, examined and graded based on standard clinical scales and recorded as normal or abnormal. Minimal change from the start of the study indicates a better outcome | Day 1, 14, 90, 180, 270 & 365 |