The Diabetic Retinopathy Clinical Research Network A Phase II Evaluation of Topical NSAIDs in Eyes with Non-Central Involved DME (Protocol R) Scott Friedman MD Protocol Chair Sponsored by the National Eye Institute, National Institutes of Health, U.S. Department of Health and Human Services.

Study Question Do topical non-steroidal anti-inflammatory drugs (NSAIDs) have biological effects on non-central involved DME? Is macular volume influenced by using NSAID drops in these eyes? Do NSAIDs reduce the risk of progression to central-involved DME? Do NSAIDs reduce the risk of progression of current non-central DME? Do NSAIDs increase the chance of resolution of non-central DME? 2

Non-central DME Clinical Definition - Retinal thickening due to DME within 3000µm of, but not involving, the center of macula OCT definition - Retinal thickening due to DME >2 SD beyond the normal value outside the central subfield BUT <mean+2 SD in spectral domain OCT machines within the central subfield Typical Management – observation until center becomes thickened or until imminent involvement of center is perceived

Progression of Non-center Involved DME ETDRS 22% of study participants with non-center involved (DME) by color fundus photographs assigned to deferral of laser progressed to the center of the macula by 1 year Protein Kinase C-β DME Study Group 1/3 of eyes with non-central DME in the control group progressed to the central subfield within 1 year

Rationale for Use of NSAIDs on Non-central DME Possible role of inflammatory markers in DME Some topical NSAID medicines reach posterior segment of the eye Observational studies showed some beneficial effects of topical NSAID eye drops on DME

Study Objectives Primary Objective: Assess effect of topical NSAIDs on retinal volume compared with placebo in eyes with non-central DME Secondary Objective: Assess effect of topical NSAIDs on central subfield thickness, and to compare the progression of non-central to central DME as determined by spectral domain OCT, and as determined by color fundus photographs

Nepafenac 0.1%(Nevanac®) Converted to active metabolite, amfenac, in ocular tissues Nepafenac and amfenac inhibit both cyclooxygenase (COX) I and II which catalyze the formation of pro-inflammatory prostaglandins that contribute to edema FDA approved to treat pain and inflammation associated with cataract surgery Dosage: 1 drop, 3 times per day (TID)

Study Design Phase II Multi-center Randomized Double-masked Clinical Trial

Study Design Primary outcome analysis at 1 year Eligibility Criteria Met/Informed Consent Run-In Phase/Enrollment Visit 30-60 days Randomization Visit/Baseline Nepafenac (TID) Placebo (TID) 4 Months 4 Months 8 Months 8 Months Primary outcome analysis at 1 year

Subject Eligibility Criteria Inclusion Age ≥ 18 years Diabetes mellitus (type 1 or type 2) Successful completion of the run-in phase during which level of compliance is more than 80%

Subject Eligibility Criteria (cont.) Exclusion Use of systemic corticosteroids or anti-VEGF therapy Current use of prescription systemic NSAIDs. Auto-immune diseases judged to result in a higher risk for corneal complications Known allergy to any component of the study drug Blood pressure > 180/110 mmHg For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 12 months

Ocular Eligibility Criteria Inclusion BCVA letter score ≥ 74 E-ETDRS (20/32 or better) By Clinical exam: Retinal thickening due to DME within 3000 µm of but not involving the macular center By OCT: Thickened non-central macular subfields Media clarity If patient on other drop(s), willingness to comply with a multi-drop regimen

Ocular Eligibility Criteria (cont.) CSF less than the gender-specific mean thickness from a normal cohort + 2 SD, from one of the following SD OCT machines: Machine Women Men Zeiss Cirrus <290 <305 Optovue RTVue Heidelberg Spectralis <320

Ocular Eligibility Criteria (cont.) Thickened non-central macular subfields on OCT map must meet either one of the following criteria: * Threshold= average normal + 2 standard deviations (SD) At least two subfields with thickness above threshold* in spectral domain OCT machines At least one subfield with thickness of at least 15μm above threshold in spectral domain OCT machines

Ocular Eligibility Criteria (cont.) Exclusion Focal/grid laser within the last 6 months or other treatment for DME within the last 4 months Anticipated need to treat DME during the study NSAID eye drops use within the last 30 days or anticipated need for such drops during the study History of PRP within 4 months prior to randomization Need for PRP in the 6 months following randomization Need for cataract surgery of study eye during the study  Lipid in the fovea  History of major ocular surgery within prior 4 months or anticipated within the next 6 months An ocular condition, other than DME, that may affect VA YAG capsulotomy within 2 months of randomization Severe external ocular infection   Aphakia Vitrectomy for any reason Cataract surgery within the prior 1 year Uncontrolled glaucoma

How can investigators know if an eye meets the protocol definition of non-central DME? OCT threshold grids provided by the coordinating center for reference Site personnel enter each subfield thickness value directly into the study website Computer algorithm determines if an eye meets protocol criteria for non-central DME

Study Eye Both eyes may be evaluated for eligibility, but only ONE eye will be enrolled If both eyes are eligible at the time of enrollment, study eye will be selected by investigator and study participant

Run-in Phase Purpose Protocol Filtering participants with poor compliance Protocol All eligibility criteria must be met before enrollment Artificial tears (Tears Naturale Forte®)-1 drop, 3 times per day At least 30 days (30-60 days) Compliance assessed at end of run-in phase before randomization

Randomization All eligibility criteria, except VA and OCT, will be reconfirmed again after run-in phase OCT and VA will not be reconfirmed at randomization, provided investigator is not planning on DME treatment Randomization data will be the baseline Study participants must show good compliance with drops during the run-in period

Compliance Assessment and Randomization Eligibility Compliance will be assessed by weighing bottles and comparing to an expected weight Study participants will be eligible for randomization if compliance was 80% or more of expected

Compliance Assessment Digital scales are provided by the Coordinating Center Each bottle will be weighed prior to dispending to study participant Each bottle will be re-weighed at the next visit One artificial tears bottle for run-in phase Six drug/placebo bottles at randomization and each follow-up visit

Study Testing Procedures Enrollment Randomization 4M 8M 12M Run-in (30-60 days) Baseline ±1M E-ETDRS BCVA/ Eye Exam/ OCT X Fundus Photo Blood Pressure HbA1c Weighing Bottles

Guidelines for DME Treatment Randomized eye drops OCT CSF increases to more than gender and machine specific mean+2 SD value, provided at least 10% increase from baseline. Computer algorithm will calculate and give appropriate alert. Extenuating circumstances after protocol chair discussion e.g. rapidly-developing cataract prior to cataract surgery No treatment for DME is given unless Study participants will continue their study treatment through 12 months regardless of whether treatment for DME is received Primary outcome analysis at 1 year

Outcome Measures Primary Outcome Secondary Outcomes Mean change in macular retinal volume (mm3) between baseline and 12 months Secondary Outcomes Progression of non-central involved DME Correlation of progression of DME in OCT and fundus photographs Visual Acuity Safety Outcomes

Safety Outcome Cornea Cataract/cataract surgery Irritation/burning sensation Corneal edema Superficial keratitis Ulceration Melting Note: Corneal complications will be expeditiously sent for review by the DSMC Cataract/cataract surgery Ocular infection/inflammation

Sample Size 60 study participants per group convenience sample size will be recruited Total number of eyes is 120 in 120 study participants

Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net) Dedicated to multicenter clinical research of diabetic retinopathy, macular edema and associated disorders. 28