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DRCR Retina Network

DRCR Retina Network. Treatment for Center-Involved DME in Eyes with Good Visual Acuity (Protocol V). Financial Disclosures. Funding/Support: Cooperative Agreement with NEI and NIDDK of NIH , U.S. Department of Health and Human Services.

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DRCR Retina Network

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  1. DRCR Retina Network Treatment for Center-Involved DME in Eyes with Good Visual Acuity (Protocol V)

  2. Financial Disclosures • Funding/Support: Cooperative Agreement with NEI and NIDDK of NIH, U.S. Department of Health and Human Services. • Additional Contributions: Regeneron provided the aflibercept for the study. In addition, Regeneron provided funds to the DRCR Retina Network to defray the study’s clinical-site costs.

  3. Anti-VEGF Has Not Been Evaluated In Eyes That Have Center-Involved DME with Good VA (20/25 Or Better) How should we treat eyes with center-involved DME and visual acuity 20/25 or better?

  4. Treatment of DME in ETDRS • ~40% of eyes in ETDRS with CI-DME had good VA.

  5. Eyes in Protocol I and ETDRS with ≥5 Letter VA Loss N = 110 N = 113 N = 118 N = 231 N = 237 % of Eyes N = 246 N = 28 N = 26 N = 28 Months

  6. Anti-VEGF Has Not Been Evaluated In Eyes That Have Center-Involved DME with Good VA (20/25 Or Better) Anti-VEGF? How should we treat eyes with center-involved DME and visual acuity 20/25 or better? Focal/Grid Laser (Add Anti-VEGF if VA drops)? Observation (Add anti-VEGF if VA drops)?

  7. Study DesignRandomized Multicenter Clinical Trial (N = 91 Sites) • Aflibercept • ≥18 years old with type 1 or type 2 diabetes • Center-involved DME on OCT* • VA letter score 20/25 or better* • No or minimal** prior treatment for DME Outcomes Primary Proportion of eyes that lost ≥5 letters of VA at 2 years Secondary Mean change in VA and CST from baseline at 1 and 2 years • Laser+ • (Aflibercept prn) • Observation+ • (Aflibercept prn) *Confirmed at 2 visits 1-28 days apart (screening and randomization) **No more than 1 laser and/or 4 injections, at least 12 months ago

  8. Randomization702 eyes of 702 participants total Initiation With Included in the Primary Analyses 104 Weeks • Aflibercept • N = 226 • N = 205 • (94%)* • N = 226 • Laser+ • (Aflibercept prn) • N = 240 • N = 212 • (91%)* • N = 240 • Observation+ • (Aflibercept prn) • N = 236 • N = 208 • (90%)* • N = 236 *Excluding deaths

  9. Study Follow-up Outcome Visit Schedule Treatment Visit Schedule Initiation With Visits q 4 weeks during the first 24 weeks, q 4-16 weeks thereafter. All participants had visits at 1 and 2 years for outcome assessment. • Aflibercept • Laser+ • (Aflibercept prn) • Visits at 8 and 16 weeks followed by q 16-week visits thereafter. If VA/OCT worsen or aflibercept is initiated, visits at q 4, 8, or 16 weeks depending on disease progression and treatment. • Observation+ • (Aflibercept prn)

  10. Study Treatment Initiation With • Aflibercept • Injection at baseline • Evaluation at each visit for re-injection based on protocol criteria • Focal/grid laser at baseline • Evaluation at each visit for initiating aflibercept based on VA loss* • Retreatment with laser if protocol criteria are met • Laser+ • (Aflibercept prn) • Observation+ • (Aflibercept prn) • No treatment at baseline • Evaluation at each visit for initiating aflibercept based on VA loss* * VA decrease ≥10 letters at 1 visit or 5-9 letters at two consecutive visits

  11. Participant Baseline Characteristics

  12. Ocular Baseline Characteristics * Randomization stratification factor

  13. Ocular Baseline Characteristics

  14. Visits

  15. Visual Acuity (VA)

  16. ≥5-Letter Loss At 2 YearsPrimary Outcome Treatment Group Comparisons

  17. ≥10-Letter Loss At 2 Years Treatment Group Comparisons

  18. ≥5-Letter Gain at 2 Years Treatment Group Comparisons

  19. ≥84 Letters (20/20 or Better) at 2 Years Treatment Group Comparisons

  20. VA Letter Score at 2 Years 20/25 or Better 86% 86% 84% N = 205 N = 212 N = 208

  21. Mean VA Letter Score At 2 Years 86.0 (20/20) 85.3 (20/20) 84.2 (20/20) N = 226 N = 240 N = 236 N = 205 N = 212 N = 208 2-Year 8-Week 1-Year Error bars represent 95% confidence Intervals

  22. Mean VA Letter Score Change from Baseline +2.1 +0.1 0 1 Year: Adjusted Treatment Group Comparisons Aflibercept vs. Laser:2.1 (0.9 to 3.2); P <.001 Aflibercept vs. Observation: 2.2 (1.0 to 3.5); P <.001 Laser vs. Observation:0.1 (-0.9 to 1.2); P = .82 N = 226 N = 240 N = 236 N = 205 N = 212 N = 208 8-Week 2-Year 1-Year Error bars represent 95% confidence Intervals

  23. Mean VA Letter Score Change from Baseline +0.9 +0.1 -0.4 2 Years: Adjusted Treatment Group Comparisons Aflibercept vs. Laser:1.0 (-0.4 to 2.5); P = .21 Aflibercept vs. Observation: 1.3 (-0.3 to 2.8); P = .14 Laser vs. Observation:0.2 (-1.0 to 1.5); P = .70 N = 226 N = 240 N = 236 N = 205 N = 212 N = 208 8-Week 2-Year 1-Year Error bars represent 95% confidence Intervals

  24. Mean Change in VA Letter Score Over 2 Years (Area Under the Curve)Exploratory Analysis AUC Mean Change in Letter Score Over 2 Years Treatment Group Comparisons Aflibercept Laser Observation

  25. Central Subfield Thickness (CST)

  26. Mean Change in OCT CST from Baseline 1 Year: Adjusted Treatment Group Comparisons Aflibercept vs. Laser: -22 (-34 to -11); P <.001 Aflibercept vs. Observation: -28 (-41 to -15); P <.001 Laser vs. Observation: -6 (-17 to 6); P = .34 -25 -30 -50 8-Week 1-Year 2-Year N = 226 N = 240 N = 236 N = 205 N = 212 N = 208 Visit Error bars represent 95% confidence Intervals

  27. Mean Change in OCT CST from Baseline 2 Year: Adjusted Treatment Group Comparisons Aflibercept vs. Laser: -12 (-24 to 1); P = .07 Aflibercept vs. Observation: -13 (-27 to 1); P = .07 Laser vs. Observation: -1 (-13 to 11); P = .82 -42 -41 -48 8-Week 1-Year 2-Year N = 226 N = 240 N = 236 N = 205 N = 212 N = 208 Visit Error bars represent 95% confidence Intervals

  28. DME Treatment

  29. Time to First Aflibercept Injection(Laser and Observation Groups) Laser vs. Observation Hazard Ratio: 0.66 (95% CI, 0.47-0.92)P = .01 Cumulative Probability, % 36% 28% 26% 13% Weeks

  30. Aflibercept Treatment for DME Note: Injection adherence was 98% in each group.

  31. Aflibercept Treatment for DME(Eyes receiving at least one injection) * 2-year completers only

  32. Number of Injections Over 2 Years Aflibercept (N=205) Laser (N=212) Observation (N=208) * 2-year completers only

  33. Aflibercept Treatment for DME

  34. Safety

  35. Ocular Adverse Events

  36. APTC* Systemic Adverse Events *APTC = Antiplatelet Trialists’ Collaboration

  37. Summary In this cohort of individuals with center-involved DME and good visual acuity (> 20/25): • No difference in rates of 1 or more lines of VA loss at 2 years among eyes initiating management with aflibercept, laser or observation • All three management strategies resulted in mean VA at 2 years of 20/20 • Proportion of eyes 20/20 or better was significantly greater with aflibercept (77%) than observation (66%) • Proportion of eyes 20/25 or better was similar in each group (~85%) • Majority of eyes in laser group (~3/4) and observation group (~2/3) did not receive aflibercept during study

  38. Discussion • Study did not compare monotherapies; study did compare 3 different management strategies • Eyes were followed carefully; aflibercept was initiated in the laser and observation groups if vision decreased by 1 line at 2 consecutive visits or 2 or more lines at 1 visit. • Changes on OCT did not trigger aflibercept initiation • Primary outcome was loss of 5 or more letters (≥1 line) • Likely clinical relevant in eyes with good vision • Unlikely due to chance variation

  39. Conclusion Among eyes with CI-DME and good VA, no significant difference in VA loss at 2 years whether eyes were initially managed with aflibercept, or with laser photocoagulation or observation and given aflibercept only if VA worsened. Given the costs and risk associated with interventions, observation without treatment unless VA worsens may be a reasonable strategy for these eyes.

  40. CW Baker and coauthors Effect of Initial Management With Aflibercept vs Laser Photocoagulation vs Observation on Vision Loss Among Patients With Diabetic Macular Edema Involving the Center of the Macula and Good Visual Acuity: A Randomized Clinical Trial

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