The Diabetic Retinopathy Clinical Research Network Intravitreal Ranibizumab for Diabetic Macular Edema with Prompt vs Deferred Laser Treatment: 3-year Randomized Trial Results 1

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

3 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

4 Visits Prior to 3 Years * Ranibizumab + Prompt Laser N=144 Ranibizumab + Deferred Laser N=147 Median number of visits in year one 13 Median number of visits in year two 810 Median number of visits in year three 78 Median number of visits prior to 3 year visit 2830 * Only eyes that completed 3 year visit

Treatment 5

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

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

8 Injections Prior to 3 Year * Ranibizumab + Prompt Laser N=144 Ranibizumab + Deferred Laser N=147 Maximal number of injections prior to 3- year visit 39 Median number of injections in year one (1 st / 2 nd 6 months) 8 (6/3)9 (6/3) Median number of injections in year two 23 *Only eyes that completed 3 year visit

9 Injections Prior to 3 Year * Ranibizumab + Prompt Laser N=144 Ranibizumab + Deferred Laser N=147 Maximal number of injections prior to 3- year visit 39 Median number of injections in year one (1 st / 2 nd 6 months) 8 (6/3)9 (6/3) Median number of injections in year two 23 Median number of injections in year three 12 Median number of injections prior to 3 year visit 1215 *Only eyes that completed 3 year visit

10 Injections Prior to 3 Year (continued) * Ranibizumab + Prompt Laser N=144 Ranibizumab + Deferred Laser N=147 Number (%) of eyes that met success** at 16 weeks and then received injection by 1-year visit 58 (88%) of 6647 (82%) of 57 Number (%) of eyes that met success at 1-year visit and then received injection by 2-year visit 52 (60%) of 8646 (67%) of 69 Number (%) of eyes that met success at 2-year visit and then received injection by 3-year visit 43 (47%) of 9246 (53%) of 87 *Only eyes that completed 3 year visit **VA letter score ≥84 (~20/20) or OCT CSF < 250 µm

11 Focal/Grid Laser Prior to 3 Years * Ranibizumab + Prompt Laser N = 144 Ranibizumab + Deferred Laser N = 147 Maximal possible number of focal/grid laser treatments prior to 3-year visit 1210 Median number of focal/grid laser treatments prior to 3-year visit (from baseline) 30 % of eyes that did not receive focal/grid laser treatments prior to 3-year visit (from baseline) 054% * Only eyes that completed 3 year visit

12 Focal/Grid Laser Prior to 3 Years * Ranibizumab + Prompt Laser N = 144 Ranibizumab + Deferred Laser N = 147 Maximal possible number of focal/grid laser treatments prior to 3-year visit 1210 Median number of focal/grid laser treatments from baseline to (prior to) 3-year visit 30 % 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

13 Focal/Grid Laser Prior to 3 Years (Continued) * Ranibizumab + Prompt Laser N = 144 Ranibizumab + Deferred Laser N = 147 % of eyes that did not receive focal/grid laser treatments from 1-year to (prior to) 2-year visit 58%73% % of eyes that did not receive focal/grid laser treatments from 2-year to (prior to) 3-year visit 75%86% * Only eyes that completed 3 year visit

Visual Acuity 14

Mean Change in Visual Acuity * at Follow-up Visits 15 *Truncated to ± 30 letters N = 338 (52 weeks) N = 317 (104 weeks) N = 291 (156 weeks)

Mean Change in Visual Acuity * at Follow-up Visits 16 *Truncated to ± 30 letters N = 338 (52 weeks) N = 317 (104 weeks) N = 291 (156 weeks)

17 Change in Visual Acuity* Change in Visual Acuity (letters)** Ranibizumab + Prompt Laser N = 144 Ranibizumab + Deferred Laser N = 147 Estimated Difference (B vs. C) (95% CI) [P-Value] 2-years (Estimated Means) (-3.6 to +0.1) [P = 0.06] 3- Years (Estimated Means) (-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

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

19 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 20

Change in Visual Acuity at 3 Years Stratified by Prior Laser Treatment 21

Change in Visual Acuity at 3 Year Stratified by Baseline Visual Acuity 22

23 N=41 N=63 N=67 N=35 N=36 N=49 Change in Visual Acuity at 3 Year Stratified by Eyes with Diffuse vs. Focal Edema at Baseline as Graded by Study Ophthalmologist

Retinal Thickening 24

Mean Change in CSF Thickening at Follow-up Visits 25 N = 334 (52 weeks) N = 305 (104 weeks) N = 259 (156 weeks)

Mean Change in CSF Thickening at Follow-up Visits 26 N = 334 (52 weeks) N = 305 (104 weeks) N = 259 (156 weeks)

27 Change in Retinal Thickening at 2 Years* Change in OCT CSF Ranibizumab + Immediate Laser N = 152 Ranibizumab + Deferred Laser N = 153 Median change from baseline (µm) Mean change from baseline (µm) Thickness <250 µm with at least a 25 µm decrease from baseline 61%60% *Visits occurring between 616 and 840 days from randomization were included as 2 year visits

28 Change in Retinal Thickening at 3 Years* Change in OCT CSF Ranibizumab + Prompt Laser N = 136 Ranibizumab + Deferred Laser N = 132 Median change from baseline (µm) Mean change from baseline (µm) Thickness <250 µm with at least a 25 µm decrease from baseline 61%63% *Visits occurring between 980 and 1204 days from randomization were included as 3 year visits

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 2 nd and 3 rd 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. 29

Conclusions   Focal/grid laser performed at the initiation of intravitreal ranibizumab is no better, and possibly worse, than deferring laser for at least 24 weeks in eyes with DME involving the fovea and vision impairment.   Fewer injections were needed in years 2 and 3 to sustain VA gains observed in year 1. However, more were needed in the ranibizumab+deferred laser group. 26 possible injections between week 52 and week 156 ranibizumab + prompt laser group: o omedian 3 injections, average decline of ~1 letter ranibziumab + deferred laser group: o omedian 6 injections, average increase of ~1 letter 30

Conclusions   Focal/grid laser at the initiation of intravitreal ranibizumab is no better, and possibly worse, than deferring laser for at least 24 weeks in eyes with DME involving the fovea with vision impairment   Few injections in years 2 and 3 to sustain VA gains in year 1   More (3 more) injections, on average, in ranibizumab + deferred laser group compared with ranibizumab + prompt laser Of 26 possible injections from week 52 to week 156, 3 given in ranibizumab + prompt laser group with an average decline of ~1 letter from week 52 compared with 6 given in ranibziumab + deferred laser group with an average increase of ~1 letter from week 52 31