The Diabetic Retinopathy Clinical Research Network DRCR net

The Diabetic Retinopathy Clinical Research Network DRCR. net Prompt PRP vs Ranibizumab+Deferred PRP for PDR Study Jeffrey G. Gross, M. D. – Protocol Chair Supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services EY 14231, EY 14229, EY 018817 1

Background Ø Current treatment for PDR is panretinal photocoagulation (PRP) • Inherently destructive • Adverse effects on visual function Ø Some eyes with PDR+DME now receive anti-VEGF as standard care for DME Ø Would initial treatment of PDR with intravitreal anti-VEGF delay or prevent need for PRP? 2

Study Objective and Treatment Groups To determine if visual acuity outcomes at 2 years in eyes with PDR (with or without concurrent DME) that receive anti-VEGF therapy with deferred PRP are noninferior to those in eyes that receive prompt PRP therapy. Prompt PRP 0. 5 mg ranibizumab with deferred PRP 3

Important Secondary Objectives (assuming visual acuity outcomes are non-inferior) Ø Compare visual function outcomes (including Humphrey visual field testing and study participant self-reports of visual function) Ø Determine percent of eyes not requiring PRP when intravitreal anti-VEGF is given in the absence of prompt PRP Ø Compare safety outcomes Ø Perform cost effectiveness analysis 4

Sample Size Ø Minimum of 380 eyes Ø Subjects may have one or two study eyes Ø 316 participants assuming 20% have two study eyes 5

Major Inclusion Criteria Ø Age ≥ 18 years Ø Type 1 or 2 diabetes Ø PDR for which PRP is planned but in the investigator’s opinion can be deferred for at least 4 weeks if an intravitreal anti. VEGF injection is given Ø Visual acuity (Snellen equivalent) 20/320 or better Ø Note: eyes with or without DME may be 6 enrolled

Major Exclusion Criteria Ø Systemic • Significant renal disease • BP > 180/110 • Cardiac event or stroke within 4 months Ø Study eye • • • Prior PRP Tractional retinal detachment involving the macula NV of the angle History of intravitreal anti-VEGF within past 2 months History of corticosteriod in the past 4 months 7

Rationale for Combining Eyes With and Without DME Ø Eyes without DME at baseline may develop DME during follow-up, requiring concurrent anti-VEGF treatment anyway Ø Treatment effect of Prompt vs Deferred PRP in both cohorts is expected to be similar Ø Logistically easier for sites compared with two separate protocols 8

Follow-up Schedule Baseline to 1 Year to 3 Years 4 to 5 Years • Both groups: Visits every 16 weeks • IVR+Deferred PRP group: Visits every 4 weeks to evaluate for ranibizumab…interval may only be extended if PRP is given • Both groups: Visits every 16 weeks • IVR+Deferred PRP group: Visit every 4 -16 w to evaluate for ranibizumab…interval is extended if injections for PDR continually deferred • Primary outcome visit at 2 years • Annual visits for data collection only • Treatment as part of usual care 9

Study Procedures PROCEDURE Medical history TIMING Baseline only E- ETDRS Visual Acuity All visits Binocular E-ETDRS VA Annually only Questionnaires (4) HVF Testing (30 -2 and 60 -4)* 7 MF or 4 W Digital Photos (+additional fields as needed) OCT Ocular Exam w/IOP 3 Annually; 1 q 16 w Annually only + Prior to PRP in Deferred Group Annually + As Needed for DME Evaluations All visits Blood Pressure Baseline only Hb. A 1 c Baseline only *Only at sites with HVF capabilities 10

PRP Treatment Ø Prompt PRP group receives 1200 to 1600 burns initiated on day of randomization (or within 14 days of baseline if injection for DME given) and completed within 8 weeks. Ø Anti-VEGF+Deferred PRP may receive PRP only if failure/futility criteria are met 11

Anti-VEGF Injections for PDR (IVR+Deferred PRP Group) Ø Injections every 4 weeks through 12 - week visit • NV status does not matter • Injection can only be skipped if an adverse event occurs Ø If at anytime the investigator thinks PRP is needed within 1 week to avoid substantial vision loss, PRP may be given once protocol chair approval obtained 12

Injection Retreatment Criteria for PDR (IVR+Deferred PRP Group) Ø Starting at the 16 -week visit, each eye will be categorized into one of the following 5 groups: Category Injection PRP Resolved At investigator discretion No Improved Required 1 st 2 times stable; then at investigator discretion No Required No At investigator discretion Yes Stable Not fully treated (worsening) Failure/Futility No 13

Treatment for DME Ø If DME present at baseline causing VA loss, ranibizumab must be given Ø If DME develops during follow-up, treatment is at investigator discretion using study ranibizumab and/or focal/grid laser with Protocol I retreatment criteria as guidelines Ø Additional follow-up visits for DME retreatment are at the discretion of the investigator (not part of visit schedule) 14

Referrals Ø Please consider any eyes with proliferative diabetic retinopathy that might normally be treated with PRP Ø Study participants must be willing to be randomized to either group and continue followup for 5 years Ø Consenting/Enrollment/Randomization may be split into several visits 15

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. 16