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

 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 these drops reduce the risk of progression to central-involved DME?  Do these drops reduce the risk of progression of current non-central DME?  Do these drops increase the chance of resolution of non-central DME? 2 Study Question

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 <250 µm in spectral domain OCT machines within the central subfield  Typical Management – observation until center becomes thickened or until imminent involvement of center is perceived 3

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 4

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 5

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 6

Nepafenac 0.1%(Nevanac ® )  Nepafenac in ocular tissue is converted to active metabolite, amfenac  Nepafenac and amfenac inhibit both cyclooxygenase (COX) I and II enzymes 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) 7

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

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

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% 10

Subject Eligibility Criteria (cont.)  Exclusion Use of systemic corticosteroids or anti-VEGF therapy. Current use of prescription systemic NSAIDs. History of auto-immune diseases such as rheumatoid arthritis. 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. 11

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 12

Ocular Eligibility Criteria (cont.)  CSF <250 μm in spectral domain OCT machines  Thickened non-central macular subfields on OCT macular map must meet either one of the following criteria: * Threshold= average normal + 2 standard deviations (SD) 13 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 14

How can investigators know if an eye meets the protocol definition of non-central DME?  The Coordinating Center will provide site an OCT grid with the threshold values for reference  Site personnel will enter the thickness value of each subfield directly into the study website for eligibility confirmation  Computer algorithm will determine if eyes meet protocol criteria for non-central DME 15

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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 17

Permitted OCT Machines  Only the following spectral domain OCT machines should be used in this study  Zeiss Cirrus  Heidelberg Spectralis  Optovue RTVue 18

Run-in Phase  Purpose  Filtering participants with poor compliance at the start of the study  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 is assessed at end of run-in phase before randomization 19

Randomization  All eligibility criteria must be reconfirmed again after run-in phase  Data collected at randomization will be the baseline data  Study participants must show good compliance with drops during the run-in period in order to be eligible for randomization 20

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 21

Compliance Assessment  Digital scales will be provided to sites by the Coordinating Center  Each bottle will be weighed prior to dispending to study participant  Each bottle will be re-weighed when participant comes for next visit  At enrollment, each participant will be provided with 1 artificial tears bottle  At randomization and follow up visits each participant will be provided 6 bottles of drug/placebo 22

Study Testing Procedures 23 EnrollmentRandomization4M8M12M Run-in (30-60 days) Baseline±1M E-ETDRS BCVA/ Eye Exam/ OCT XXXXX Fundus Photo XX Blood Pressure XX Hb A1c X Weighing Bottles XXXXX

Guidelines for DME Treatment Primary outcome analysis at 1 year Randomized eye drops  Central subfield thickness increases to 310 μm or more  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 No treatment for DME is given unless

Secondary Outcomes  Mean change in macular retinal volume (mm 3 ) between baseline and 12 months 25 Outcome Measures Primary Outcome  Progression of non-central involved DME  Correlation of progression of DME in OCT and fundus photographs  Visual Acuity  Safety Outcomes

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

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

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