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DRCR Retina Network

Explore treatment options for DME in eyes with good visual acuity (20/25 or better) through a randomized clinical trial evaluating aflibercept, laser, or observation. Results show efficacy in maintaining or improving vision over 2 years.

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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) Adam Glassman, MS and Carl Baker MD

  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. • Adam Glassman • Regeneron and Genentech (Grants to institution) • Carl Baker • Regeneron, Genentech, Allergan, Novartis (Research Support)

  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 = 28

  6. Study DesignRandomized Multi-center 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

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

  8. Study Follow-up Initiation With Outcome Visit Schedule Treatment Visit Schedule 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 • Visits at 8 and 16 weeks, followed by q 16-week visits thereafter. If VA/OCT are worsening or aflibercept is initiated, visits at q 4, 8, or 16 weeks depending on disease progression and treatment. • Observation 9

  9. 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 • Observation • 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 10

  10. Participant Baseline Characteristics

  11. Ocular Baseline Characteristics

  12. Visits

  13. Visual Acuity (VA)

  14. ≥5-Letter Loss At 2 YearsPrimary Outcome Treatment Group Comparisons

  15. ≥10-Letter Loss At 2 Years Treatment Group Comparisons

  16. ≥5-Letter Gain At 2 Years Treatment Group Comparisons

  17. VA at 2 Years ≥84 letters (20/20 or better) Treatment Group Comparisons

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

  19. 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 8-Week 1-Year 2-Year Error bars represent 95% confidence Intervals

  20. Mean Change in VA Letter Score 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 1-Year 2-Year Error bars represent 95% confidence Intervals

  21. Mean Change in VA Letter Score from Baseline +0.9 +0.1 -0.4 2 Year: 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 = 205 N = 212 N = 208 N = 226 N = 240 N = 236 8-Week 1-Year 2-Year Error bars represent 95% confidence Intervals

  22. Mean Change in VA Letter Score Over 2 Years (AUC)Exploratory Analysis Treatment Group Comparisons AUC Mean Change in Letter Score Over 2 Years Aflibercept Laser Observation

  23. Central Subfield Thickness (CST)

  24. 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 1-Year 8 Week N = 226 N = 240 N = 236 N = 205 N = 212 N = 208 Error bars represent 95% confidence Intervals

  25. 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 1-Year 8 Week N = 226 N = 240 N = 236 N = 205 N = 212 N = 208 Error bars represent 95% confidence Intervals

  26. DME Treatment

  27. 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

  28. Aflibercept Treatment for DME Note: Injection adherence was approximately 98%.

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

  30. Aflibercept Treatment for DME

  31. Safety

  32. Ocular Adverse Events

  33. APTCEvents Occurring At Least Once APTC = Antiplatelet Trialists’ Collaboration

  34. 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 result 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

  35. 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 • Likely clinical relevant in eyes with good vision • Unlikely due to chance variation

  36. 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.

  37. 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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