DRCR

1. Protocol S DRCR.net Prompt PRP vs. Ranibizumab + Deferred PRP for PDR Study

2. Background • DRCR.net Protocol S (PRP vs. Ranibizumab for PDR) • Primary outcome: mean change in VA from baseline to 2-years with ranibizumab no worse than (non-inferior to) PRP • Secondary outcomes: • Ranibizumab: • superior mean VA over course of 2 years (AUC) • superior mean visual field outcomes at 2 years (although not necessarily perceived by study participant per NEI VFQ-25 questionnaire) • 3-fold decrease in occurrence of vitrectomies • decreased development of central-involved DME with vision impairment over 2 years among eyes without this at baseline • PRP rarely given for failure or futility of ranibizumab to control PDR • more visits and injections • only cost effective (within range frequently cited as cost-effective in the United States) when DME present and causing vision impairment

3. Study Design Randomized, multi-center clinical trial (55 Sites) • Participants meeting all of the following criteria: • Age ≥18 years with Type 1 or type 2 diabetes • Study eye(s) meeting all of the following criteria (a participant can have 2 study eyes): • PDR • No history of PRP • Best corrected visual acuity letter score ≥24 • (~Snellen equivalent 20/320 or better) • Eyes with or without central-involved DME were eligible Primary Objective: Compare the efficacy and safety of PRP with that of intravitreous ranibizumab (0.5-mg in 0.05 mL) for proliferative diabetic retinopathy (PDR)

4. Follow-up Schedule • PRP group: Visits every 16 weeks* • Ranibizumab group: Visits every 4 weeks to assess for PDR treatment • Both groups simultaneously evaluated for DME treatment Baseline to 1 Year • PRP group: Visits every 16 weeks* • Ranibizumab group: Visits every 4wk to 16wk to assess for PDR treatment • Interval is extended if injections for PDR and DME deferred (“Defer and Extend”) 1 Year to 5 Years *Eyes with DME could be seen more frequently for DME treatment as needed.

5. Visit Completion 394 Eyes Randomized (305 Participants) Ranibizumab Group N = 191 PRP Group N = 203 Baseline 2-Years Excluding Deaths 88% 86% 5-Years Excluding Deaths 69% 65% 5-Years Overall 61% 61%

6. Ocular Baseline Characteristics at Enrollment Required ranibizumab at baseline *Stratus equivalent; 2 eyes in each group were excluded because OCT CST measurements were missing. **Eyes with visual acuity letter score ≤ 78 (20/32 or worse) AND OCT CST ≥ machine and gender specific thresholds

7. Ocular Baseline Characteristics at Enrollment *Diabetic retinopathy level data were missing for 2 in the ranibizumab group and 4 in the PRP group.

8. Ocular Baseline Characteristicsby 5-Year Completion Status *Stratus equivalent; 1 eye in each group was excluded because OCT CST measurements were missing.

9. Ocular Baseline Characteristicsby 5-Year Completion Status * Diabetic retinopathy level data were missing for 2 non-completers in the Ranibizumab group, and 4 completers in the PRP group.

10. Results

11. Treatment

12. Mean Number of Injections 5-Year Completers Only

13. Number of Intravitreous Injections by Year Ranibizumab Group, 5-Year Completers Only

14. Panretinal Photocoagulation at Follow-up

15. Visual Acuity

16. Visual Acuity at 5-Years

17. Mean Changes in VA From Baseline Over Time -OverallCohort 5-Year Adjusted Mean Difference: +0.6 letters 95% Confidence Interval: (-2.3, +3.5), P = .68 +3.1 +3.0 N = 191 N = 117 N = 203 N = 123

18. Mean Changes in VA From Baseline Over Time for 5-Year Completers Only 5-Year AUC Difference: +1.6 letters 95% Confidence Interval: (0, 3.2), P = .05 +3.3 +1.5 N = 117 of 191 N = 123 of 203 Outlying values were truncated to 3 SD from the mean

19. Change in VA Letter Score at 5-Years

20. VA at 5-Years Stratified by Baseline DME with Decreased VA

21. Mean Change in Cumulative Visual Field Total Point Score (30-2 + 60-4) - Overall Cohort -330 -527 5-Year Adjusted Mean Difference: 208 dB 95% Confidence Interval(-9, 408), P = .04 N = 81 N = 41 N = 86 N = 38 Outlying values were truncated to 3 SD from the mean

22. Median Change in Cumulative Visual Field Total Point Score (30-2 + 60-4) - Overall Cohort -244 -480 N = 81 N = 41 N = 86 N = 38 Outlying values were truncated to 3 SD from the mean

23. Mean Change in Cumulative Visual Field Point Score (30-2) - Overall Cohort -157 -190 5-Year Adjusted Mean Difference: 29 dB 95% Confidence Interval(-91, 148), P = .64 N = 84 N = 44 N = 88 N = 41 Outlying values were truncated to 3 SD from the mean

24. Mean Change in Cumulative Visual Field Point Score (60-4) - Overall Cohort -199 -348 5-Year Adjusted Mean Difference: 140 dB 95% Confidence Interval(16, 265), P = .03 N = 82 N = 43 N = 87 N = 41 Outlying values were truncated to 3 SD from the mean

25. Mean Change in Cumulative Visual Field Point Score for 5-Year Completers in Ranibizumab Group without PRP Treatment -96 -119 Outlying values were truncated to 3 SD from the mean

26. Median Change in Cumulative Visual Field Point Score for 5-Year Completers in Ranibizumab Group without PRP Treatment -87 -87 Outlying values were truncated to 3 SD from the mean

27. Development of Vision- Impairing DME:Central Subfield Thickening with Visual Acuity ~20/32 or Worse

28. Development of Vision-Impairing DME Among Eyes Without Vision-Impairing DME at Baseline Hazard Ratio = 0.4 95% CI: 0.3 to 0.7 P < .001 38% 22%

29. Diabetic Retinopathy

30. DR on Fundus Photographs at 5 Years* *Observed data only, only include eyes with active NV at baseline as graded by reading center. **Not applicable or cannot determine for PRP group.

31. DR Adverse Events: Over 5 Years

32. Development of Retinal Detachment Hazard Ratio = 0.4 95% CI: 0.2 to 0.8 P = .004 18% 7%

33. Development of First Vitreous Hemorrhage after Baseline Difference = 4% 95% CI: -7% to 16% P = .47 58% 54%

34. Safety

35. Ocular Adverse Events Event defined as occurring at least once through 5 years.

36. Systemic Adverse Events Event defined as occurring at least once through 5 years. *Anti-platelet Trialists’ Collaboration Arterial Thromboembolic Events.

37. Time to First APTC Event* *Anti-platelet Trialists’ Collaboration Arterial Thromboembolic Events.

38. Systemic Adverse Events Event defined as occurring at least once through 5 years.

39. Summary: 5-Year ResultsVisits, Injections, PRP Sessions • 66% of participants (excluding death) completing 5-year visit (117 eyes in ranibizumab and 123 eyes in PRP group) • Median number of visits* • Ranibizumab = 43 • PRP = 21 • Mean number of injections • Ranibizumab = 19 • PRP = 5 • Mean number of PRP sessions • Ranibizumab = 0 • PRP = 2 * Counting participants with one study eye only

40. Summary: 5-Year ResultsCentral and Peripheral Vision • Mean change in VA letter score • Ranibizumab = 3.1±14.3 letters • PRP = 3.0±10.5 letters • Difference = 0.6 (95% CI: -2.3 to 3.5) • Mean change in cumulative visual field total point score (HFA 30-2 + 60-4) • Ranibizumab = -330±645 dB (N = 41) • PRP = -527±635 dB (N = 38) • Difference = 208 (95% CI: 9 to 408)

41. Summary: 5-Year ResultsComplications • Development of Vision-Impairing DME (~Snellen equivalent 20/32 or worse) • Ranibizumab = 22% • PRP = 38% • Hazard Ratio = 0.4 (95% CI: 0.3 to 0.7) • Underwent Vitrectomy • Ranibizumab = 15% • PRP = 22% • Hazard Ratio = 0.5 (95% CI: 0.3 to 0.8) • No statistically significant differences between groups in major SAE rates were identified.

42. Discussion • VA in both treatment groups was good (mean ~20/25) and patient reported vision-related quality of life scores were similar between the groups over 5 years, even though more eyes in the PRP group developed vision-impairing DME. • Overall, for participants completing the 5-year visit, few eyes in either group developed neovascular glaucoma or iris neovascularization and the rates were similar between groups. • The overall rate of retinal detachment in the PRP group was higher (15% vs 6%). • Most of these did not progress to involve the center of the macula and did not undergo vitrectomy, suggesting the detachments were not vision-threatening.

43. Discussion • Few eyes in either group (6%) had substantial visual loss(≥15 letters from baseline). • On average the PRP group on average had more peripheral visual field loss through 2 years than ranibizumab group; however, visual field loss, on average, progressed in both the PRP and ranibizumab groups from years 2 through 5 and the difference between groups diminished in this small sub-study. • Further analysis of this finding seems warranted. • Almost half of all eyes developed vitreous hemorrhage with 22% vs 41% needing vitrectomy in the ranibizumab and PRP groups respectively. • The decision to perform vitrectomy was made by an unmasked investigator.

44. Discussion • Despite the reduction in the mean number of injections for participants in the ranibizumab group, mean VA change from baseline remained fairly constant between 2 and 5 years. • While there have been inconsistent reports of increased APTC events for patients receiving anti-VEGF, this full 5-year dataset does not show any definitive differences. • No ocular safety concerns were identified.

45. Discussion • Major Study Limitations • Retention for this study was less than 65% for each group. • No differences were identified between baseline factors and treatment groups for the completers vs non-completers. • Eyes in the ranibizumab group that did not complete follow-up had more improvement in VA and OCT CST at their last measured follow-up visit. • The outcomes for participants who did not complete the study are unknown.

46. Conclusion • Loss to follow-up was relatively high. • Visual acuity in most study eyes that completed follow-up was very good. • Severe vision loss or serious PDR complications were uncommon in either group. • Ranibizumab group had lower rates of developing vision-impairing DME and less visual field loss. • There were no meaningful treatment group differences in patient-centered outcomes. • These findings support either ranibizumab or PRP as viable treatments for PDR. • Patient-specific factors, including anticipated visit compliance, number of visits, cost, and systemic health should be considered when choosing a treatment for PDR.