Protocol I Timeline - Jaeb

Protocol I Timeline - Jaeb

The Diabetic Retinopathy Clinical Research Network 5-Year Follow-up of a Randomized Trial Evaluating Ranibizumab Plus Prompt versus Deferred Laser for Diabetic Macular Edema Background: Protocol I Previously reported intravitreous ranibizumab with prompt or deferred laser more effective through at least 2 years compared with laser 3-year comparison of ranibizumab groups concluded prompt laser was no better and possibly worse than deferred laser Study extended to 5 years to assess longerterm course of DME treated with ranibizumab To report the comparison of ranibizumab groups through 5 years 2 Completion of 5 Year Visit Eyes originally randomized Completed 5 Year (excl deaths)

Death prior to 5 Year Ranibizumab Ranibizumab + Prompt Laser + Deferred Laser N = 180 N = 181 69% (76%) 9% 61% (74%) 17% 21% 22% Eyes in the extension study N = 132 N = 136

Completed 5 Year (excl deaths) Death prior to 5 Year Dropped prior to 5 Year 94% (97%) 3% 3% 82% (92%) 11% 7% Discontinued/Dropped prior to 5 Year Includes pts who did not consent to extension 3 Baseline Characteristics of Completers vs Non-Completers Ranibizumab + prompt laser

Ranibizumab + deferred laser NonNonCompleters completers Completers completers N = 124 N = 56 N = 111 N = 70 63 65 63 65

Prior PRP 33% 11% 21% 20% Lens Status Phakic 73% 61% 75% 63% Median VA (letter score)

65 65 67 62 Median CST (m) 375 372 394 378 Mild/Moderate/HR PDR 34%

27% 24% 37% Median Age 4 Visits Prior to 5 Year* Ranibizumab + Prompt Laser N=124 Ranibizumab + Deferred Laser N=111 Median # of visits in year 1

13 13 Median # of visits in year 2 8 10 Median # of visits in year 3 7 8 Median # of visits in year 4 5 6

Median # of visits in year 5 4 5 38 40 Median # of visits prior to 5 year visit * Only eyes that completed 5 year visit 5 Treatments 6 Injections Prior to 5 Year* + Prompt

Laser N=124 Ranibizumab + Deferred Laser N=111 Median # of injections in year 1 8 9 Median # of injections in year 2 2 3 Median # of injections in year 3

1 2 Median # of injections in year 4 0 1 Median # of injections in year 5 0 0 13 17 % of eyes that received >1 injection in year 4

46% 55% % of eyes that received >1 injection in year 5 38% 48% Ranibizumab Median # of injections prior to 5 year visit *Only eyes that completed 5 year visit 7 Focal/Grid Laser Prior to 5 Years* Ranibizumab Ranibizumab + Prompt + Deferred

Laser Laser N = 124 N = 111 % of eyes that did NOT receive laser treatments prior to the 5 year visit Median # laser treatments prior to the 5 year visit 0 56% 3 0 * Only eyes that completed 5 year visit 8 Visual Acuity

9 Mean Change in Visual Acuity* at Follow-up Visits +9.8 +7.2 10 Change in Visual Acuity at 5 Years Change in Visual Acuity (letters) Estimated Means* Estimated Diff* (95% CI)* [P-Value]* [adjusted P-Value] Ranibizumab Ranibizumab

+ Prompt + Deferred Laser Laser N = 124 N = 111 +7.2 +9.8 -2.6 (-5.5 to +0.4) [P = 0.09] [P = 0.15] *truncated to 30 letters, based on longitudinal analyses adjusting for baseline VA Additional adjustment for potential confounders (baseline lens status, CSF, DR severity, prior PRP, 11 age) Distribution of VA Change at 5 Years Change in Visual Acuity (letters) >15 letter gain RR (95%CI)

P value >10 letter gain RR (95%CI) P value >15 letter loss RR (95%CI) P value >10 letter loss RR (95%CI) P value Ranibizumab + Prompt N = 124 Ranibizumab + Deferred N = 111 27% 38%

1.47 (1.04, 2.09) 0.03 46% 58% 1.27 (1.01, 1.60) 0.04 6% 5% 0.96 (0.34, 2.72) 0.94 9% 8% 0.91 (0.40, 2.10) 0.83 12

Change in VA Over 5 Years Stratified by Baseline VA Test for interaction at 5 Year time point: P = 0.001 Test for interaction from longitudinal model: P = 0.004 13 Percent of Eyes with VA 20/40 (Letter Score 69) or Better 14 Percent of Eyes with VA 20/200 (Letter score 38) or Worse 15 Retinal Thickening 16

Mean Change in CSF Thickening at Follow-up Visits 17 Change in Retinal Thickness at 5 Years* Ranibizumab + Prompt Laser N = 124 Estimated Mean change* -167 Estimated Difference* (95% CI) [P-Value] [adjusted P-Value] Ranibizumab + Deferred Laser

N = 111 -165 -8 (-30 to +15) [P = 0.48] [P = 0.53] *Based on a longitudinal model adjusting for baseline CSF and VA Additional adjustment for potential confounders (baseline lens status, DR severity, prior PRP, age) 18 Reduced VA and Thickened at 5 Years Ranibizumab Ranibizumab + Prompt + Deferred Laser Laser N = 124

N = 111 VA 20/32 or worse and CSF >250 m 23% 24% 19 Endophthalmitis Number (%) cases Rate per injection Ns include ALL randomized eyes Ranibizumab + Prompt Laser treatment N = 187 eyes

1 (1%) N=2557 injections 0.04% Ranibizumab + Deferred Laser treatment N = 188 eyes 2 (1%) N=3176 injections 0.06% 20 Summary VA gain at 1 year was maintained to 5 years concomitant with diminishing need for treatment over time Adding laser at initiation of ranibizumab was no better than deferring laser at least 24 weeks Deferring laser may be associated with more VA gain through 5 years, especially in eyes with

worse VA at baseline 21 Summary Over half assigned to deferral never received laser through 5 years Eyes assigned to prompt laser needed fewer injections over 5 years Few eyes in either group had substantial VA loss About 1/3 still thickened more work to be done 22 Conclusions Differences in VA may be real, in particular for eyes with worse baseline VA, but deferral may require more injections over 5 years to achieve results seen in this report, and thus may entail greater costs (cost effectiveness analysis is beyond scope of study) Results apply to patients similar to those

enrolled in this trial and following same retreatment criteria. Eyes initiating ranibizumab (with prompt or deferred laser) can maintain vision gains obtained by first year through 5 years with minimal treatment after 3 years 25 The Diabetic Retinopathy Clinical Research Network Thank You

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