The Diabetic Retinopathy Clinical Research Network

1. The Diabetic Retinopathy Clinical Research Network Prompt PRP vsRanibizumab+Deferred PRP for PDR Study Jennifer K. Sun, MD for the Diabetic Retinopathy Clinical Research Network 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 EY14231, EY14229, EY018817 

2. Disclosures Dr. Sun has served as a consultant for Abbott Labs, EISAI, Genentech, and Novartis She receives research support from Boston Micromachines, Genentech, and Optovue This presentation will discuss off-label use of ranibizumab for proliferative diabetic retinopathy

3. Anti-VEGF Treatment and DR Severity • Clinical trials of anti-VEGF treatment for DME have clearly demonstrated a beneficial effect of anti-VEGF on overall DR severity level *Photos were missing or ungradeable for 61 eyes in the sham+prompt laser group, 72 eyes in the ranibizumab groups, and 33 eyes in the triamcinolone+prompt laser group 3

4. Protocol I: PDR-related Outcomes During 1 Year of Follow-up

5. Cumulative Probability of Worsening of Retinopathy for Eyes with Non-PDR at Baseline 1-Year 2-Years 3-Years

6. Cumulative Probability of Worsening of Retinopathy for Eyes with PDR at Baseline 1-Year 2-Years 3-Years

7. Median (Quartile) # of InjectionsEyes with Non-PDR at Baseline *Only included eyes that completed 1-year visit †Only included eyes that completed 2-year visit prior to protocol change §Only included eyes that completed 3-year visit prior to protocol change

8. Median (Quartile) # of InjectionsEyes with PDR at Baseline *Only included eyes that completed 1-year visit †Only included eyes that completed 2-year visit prior to protocol change §Only included eyes that completed 3-year visit prior to protocol change

9. RISE/RIDE: Risk of PDR Outcomes in Sham vs Ranibizumab Groups Time to First Progression to PDR Outcome 3 fold higher risk in sham group Months Cumulative probabilities calculated using the Kaplan-Meier method. Progression was defined by (1) progression from NPDR (DR severity level < 60) at baseline to PDR (DR severity level  60) at a later time point, (2) need for PRP laser, (3) vitreous hemorrhage (AE or slit lamp grade 0 at baseline to > 0 at a later time point, (4) cases identified by ophthalmoscopy, (5) vitrectomy, (6) iris neovascularization AE, or (7) retinal neovascularization AE. 1 month = 30 days. AE, adverse event; PRP, panretinal photocoagulation.

10. How Often & How Long to Continue Anti-VEGF for PDR? 8 Days after Anti-VEGF Baseline 8 mo after Last Anti-VEGF

11. Safety of Anti-VEGF in Eyes with PDR • Endophthalmitis 11 From Goldberg RA, Am J Ophthalmol. 2012;153(2):204-208. Bhavsar AR, et al. Arch Ophthalmol. 2012 Jun;130(6):809-10.

12. Safety of Anti-VEGF in Eyes with PDR • Traction detachment In most eyes with PDR without traction threatening the macula, anti-VEGF appears safe and well-tolerated From Arevalo JF, et al. Br J Ophthalmol. 2008;92(2):213-6. 12

13. Background • Current standard treatment for PDR is panretinal photocoagulation (PRP) • 96% reduction in severe vision loss with timely therapy! • BUT, PRP is • Inherently destructive • Adverse effects on visual function Would initial treatment of PDR with intravitreal anti-VEGF delay or prevent need for PRP? 13

14. Protocol S: 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 non-inferior to those in eyes that receive prompt PRP. • Prompt PRP 0.5mg ranibizumab with deferred PRP 14

15. Important Secondary Objectives(assuming visual acuity outcomes are non-inferior) • Compare visual function outcomes (including Humphrey visual field testing and study participant self-reports of visual function) • Determine percent of eyes not requiring PRP when intravitreal anti-VEGF is given in the absence of prompt PRP • Compare safety outcomes • Perform cost effectiveness analysis 15

16. Major Inclusion Criteria • Age ≥ 18 years • Type 1 or 2 diabetes • 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 • Visual acuity (Snellen equivalent) 20/320 or better • Note: eyes with or without DME may be enrolled 16

17. Major Exclusion Criteria • Systemic • Significant renal disease • BP > 180/110 • Cardiac event or stroke within 4 months • 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

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

19. Treatment for DME • If DME present at baseline causing VA loss, ranibizumab must be given • 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 • Additional follow-up visits for DME retreatment are at the discretion of the investigator (not part of visit schedule) 19

20. Study Timeline First 2-Year (Primary Outcome) Visit Review of Primary Outcome Data Last 1-Year Visit Last 2-Year Visit Last 5-Year Visit Dec 2013 Feb 2014 Dec 2014 Feb 2015 Dec 2017

21. Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net) 21