The Diabetic Retinopathy Clinical Research Network A Phase

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. 1

Study Question Ø Do topical non-steroidal anti-inflammatory drugs (NSAIDs) have biological effects on noncentral 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 Ø Clinical Definition - Retinal thickening due to DME within 3000µm of, but not involving, the center of macula Ø 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 Ø Typical Management – observation until center becomes thickened or until imminent involvement of center is perceived 3

Progression of Non-center Involved DME Ø 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 Ø 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 4

Rationale for Use of NSAIDs on Non-central DME Ø Possible role of inflammatory markers in DME Ø Some topical NSAID medicines reach posterior segment of the eye Ø Observational studies showed some beneficial effects of topical NSAID eye drops on DME 5

Study Objectives Ø Primary Objective: Assess effect of topical NSAIDs on retinal volume compared with placebo in eyes with non-central DME Ø 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 6

Nepafenac 0. 1%(Nevanac®) Ø Converted to active metabolite, amfenac, in ocular tissues Ø Nepafenac and amfenac inhibit both cyclooxygenase (COX) I and II which catalyze the formation of pro-inflammatory prostaglandins that contribute to edema Ø FDA approved to treat pain and inflammation associated with cataract surgery Ø Dosage: 1 drop, 3 times per day (TID) 7

Study Design Ø Phase II Ø Multi-center Ø Randomized Ø Double-masked Ø Clinical Trial 8

Study Design Eligibility Criteria Met/Informed Consent Run-In Phase/Enrollment Visit 30 -60 days Randomization Visit/Baseline Nepafenac (TID) Placebo (TID) 4 Months 8 Months Primary outcome analysis at 1 year 9

Subject Eligibility Criteria Ø 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% 10

Subject Eligibility Criteria (cont. ) Ø 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 mm. Hg • For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 12 months 11

Ocular Eligibility Criteria Ø 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 12

Ocular Eligibility Criteria (cont. ) Ø CSF less than the gender-specific mean thickness from a normal cohort + 2 SD, from one of the following SD OCT machines: Machine Zeiss Cirrus Optovue RTVue Heidelberg Spectralis Women <290 <305 Men <305 <320 13

Ocular Eligibility Criteria (cont. ) Ø Thickened non-central macular subfields on OCT map must meet either one of the following criteria: • 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 * Threshold= average normal + 2 standard deviations (SD) 14

Ocular Eligibility Criteria (cont. ) Ø 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 15

How can investigators know if an eye meets the protocol definition of non-central DME? Ø OCT threshold grids provided by the coordinating center for reference Ø Site personnel enter each subfield thickness value directly into the study website Ø Computer algorithm determines if an eye meets protocol criteria for non-central DME 16

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Study Eye Ø Both eyes may be evaluated for eligibility, but only ONE eye will be enrolled Ø If both eyes are eligible at the time of enrollment, study eye will be selected by investigator and study participant 18

Run-in Phase Ø Purpose § Filtering participants with poor compliance Ø 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 19

Randomization Ø All eligibility criteria, except VA and OCT, will be reconfirmed again after run-in phase Ø OCT and VA will not be reconfirmed at randomization, provided investigator is not planning on DME treatment Ø Randomization data will be the baseline Ø Study participants must show good compliance with drops during the run-in period 20

Compliance Assessment and Randomization Eligibility Ø Compliance will be assessed by weighing bottles and comparing to an expected weight Ø Study participants will be eligible for randomization if compliance was 80% or more of expected 21

Compliance Assessment Ø Digital scales are provided by the Coordinating Center Ø Each bottle will be weighed prior to dispending to study participant Ø Each bottle will be re-weighed at the next visit Ø One artificial tears bottle for run-in phase Ø Six drug/placebo bottles at randomization and each follow-up visit 22

Study Testing Procedures E-ETDRS BCVA/ Eye Exam/ OCT Enrollment Randomization 4 M 8 M 12 M Run-in (30 -60 days) Baseline ± 1 M X X X Fundus Photo Blood Pressure X X X Hb. A 1 c Weighing Bottles X X X 23

Guidelines for DME Treatment Randomized eye drops No treatment for DME is given unless Ø 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. Ø Extenuating circumstances after protocol chair discussion e. g. rapidly-developing cataract prior to cataract surgery 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 Ø Mean change in macular retinal volume (mm 3) between baseline and 12 months Secondary Outcomes Ø Progression of non-central involved DME Ø Correlation of progression of DME in OCT and fundus photographs Ø Visual Acuity Ø Safety Outcomes 25

Safety Outcome Ø Cornea • • • Irritation/burning sensation Corneal edema Superficial keratitis Ulceration Melting Note: Corneal complications will be expeditiously sent for review by the DSMC Ø Cataract/cataract surgery Ø Ocular infection/inflammation 26

Sample Size Ø 60 study participants per group convenience sample size will be recruited Ø Total number of eyes is 120 in 120 study participants 27

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