The Diabetic Retinopathy Clinical Research Network Intravitreal Ranibizumab for Diabetic Macular Edema with Prompt vs Deferred Laser Treatment: 3-year Randomized Trial Results

Background As previously reported, intravitreal ranibizumab with either prompt or deferred laser was more effective for DME through at least 2 years as compared with prompt laser alone The study was extended from the planned 3 years to 5 years to provide insight into the long- term course of DME treated with ranibizumab This report presents comparison data through 3 years for eyes randomized to the two ranibizumab groups 2

Completion of 3 Year Visit Completed: N = 291 (81%) Not Completed: N = 70 (19%) Death: N = 26 Withdrawals from the study: N = 27 Lost to follow-up: N = 14 Missed: N = 3 Completion rate (excluding deaths): 87% Baseline characteristics similar among completers and non-completers 3 3

Visits Prior to 3 Years* Ranibizumab + Prompt Laser N=144 + Deferred Laser N=147 Median number of visits in year one 13 Median number of visits in year two 8 10 Median number of visits in year three 7 Median number of visits prior to 3 year visit 28 30 * Only eyes that completed 3 year visit

Treatment

Injections Prior to 3 Year* Ranibizumab + Prompt Laser N=144 + Deferred Laser N=147 Maximal number of injections prior to 3- year visit 39 *Only eyes that completed 3 year visit

Injections Prior to 3 Year* Ranibizumab + Prompt Laser N=144 + Deferred Laser N=147 Maximal number of injections prior to 3- year visit 39 Median number of injections in year one (1st / 2nd 6 months) 8 (6/3) 9 (6/3) *Only eyes that completed 3 year visit

Injections Prior to 3 Year* Ranibizumab + Prompt Laser N=144 + Deferred Laser N=147 Maximal number of injections prior to 3- year visit 39 Median number of injections in year one (1st / 2nd 6 months) 8 (6/3) 9 (6/3) Median number of injections in year two 2 3 *Only eyes that completed 3 year visit

Injections Prior to 3 Year* Ranibizumab + Prompt Laser N=144 + Deferred Laser N=147 Maximal number of injections prior to 3- year visit 39 Median number of injections in year one (1st / 2nd 6 months) 8 (6/3) 9 (6/3) Median number of injections in year two 2 3 Median number of injections in year three 1 Median number of injections prior to 3 year visit 12 15 *Only eyes that completed 3 year visit

Focal/Grid Laser Prior to 3 Years* Ranibizumab + Prompt Laser N = 144 + Deferred Laser N = 147 Maximal possible number of focal/grid laser treatments prior to 3-year visit 12 10 Median number of focal/grid laser treatments from baseline to (prior to) 3-year visit 3 % of eyes that received focal/grid laser treatments from baseline to (prior to) 3-year visit 100% 46% * Only eyes that completed 3-year visit

Visual Acuity

Mean Change in Visual Acuity* at Follow-up Visits N = 338 (52 weeks) N = 317 (104 weeks) N = 291 (156 weeks) 52 104 156 *Truncated to ± 30 letters

Change in Visual Acuity* Change in Visual Acuity (letters)** Ranibizumab + Prompt Laser N = 144 Deferred N = 147 Estimated Difference (B vs. C) (95% CI) [P-Value] 2-years (Estimated Means) +7.2 +9.0 -1.8 (-3.6 to +0.1) [P = 0.06] 3- Years (Estimated Means) +6.8 +9.7 -2.9 (-5.4 to -0.4) [P = 0.02] *Visits occurring between 980 and 1204 days from randomization were included as 3 year visits **truncated to ± 30 letters, based on longitudinal analyses adjusting for baseline VA

Visual Acuity Gain at 3 Years Proportion of Visual Acuity Change Ranibizumab + Prompt Laser N = 144 Ranibizumab + Deferred Laser N = 147

Visual Acuity Subgroup Analyses

Change in Visual Acuity at 3 Year Stratified by Baseline Visual Acuity

Retinal Thickening

Mean Change in CSF Thickening at Follow-up Visits N = 334 (52 weeks) N = 305 (104 weeks) N = 259 (156 weeks) 52 104 156

Conclusions Results suggest that focal/grid laser treatment at the initiation of intravitreal ranibizumab is no better, and possibly worse, for vision outcomes than deferring laser treatment for 24 weeks or more in eyes with DME involving the fovea and with vision impairment. Some of the observed differences in visual acuity at 3 years may be related to the fewer number of ranibizumab injections during follow-up in the prompt laser treatment group. Despite the decreasing number of injections given in the 2nd and 3rd year of management, the ranibizumab + deferred laser treatment group showed no decline in visual acuity, and the ranibizumab + prompt laser treatment group showed only a slight decline from the 1-year to 3-year visit.