The Diabetic Retinopathy Clinical Research Network

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

2. 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 3

4. Visits Prior to 3 Years* * Only eyes that completed 3 year visit

5. Treatment

6. Injections Prior to 3 Year* *Only eyes that completed 3 year visit

7. Injections Prior to 3 Year* *Only eyes that completed 3 year visit

8. Injections Prior to 3 Year* *Only eyes that completed 3 year visit

9. Injections Prior to 3 Year* *Only eyes that completed 3 year visit

10. Injections Prior to 3 Year (continued)* *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* * Only eyes that completed 3 year visit

12. Focal/Grid Laser Prior to 3 Years* * Only eyes that completed 3-year visit

13. Focal/Grid Laser Prior to 3 Years (Continued)* * Only eyes that completed 3 year visit

14. Visual Acuity

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

16. 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

17. Change in Visual Acuity* *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 Ranibizumab + Prompt Laser N = 144 N = 147

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

20. Visual AcuitySubgroup Analyses

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

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

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

24. Retinal Thickening

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

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

27. Change in Retinal Thickening at 2 Years* *Visits occurring between 616 and 840 days from randomization were included as 2 year visits

28. Change in Retinal Thickening at 3 Years* *Visits occurring between 980 and 1204 days from randomization were included as 3 year visits

29. 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.

30. 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: • median 3 injections, average decline of ~1 letter • ranibziumab + deferred laser group: • median 6 injections, average increase of ~1 letter

31. 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