The Diabetic Retinopathy Clinical Research Network Expanded 2-year Follow-up of Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema Sponsored by the National Eye Institute, National Institutes of Health, U.S. Department of Health and Human Services 1

Changes to Protocol I To Initiate After Primary Results Published   Study extended to 5 years from randomization   All study participants given opportunity to receive ranibizumab injections if edema present or develops   Triamcinolone+prompt laser (Group D) participants can continue to receive triamcinolone injections instead of ranibizumab at investigator discretion 2

3 Availability of 2-Year Data  Completed prior to implementation of protocol change: N=642 (75%)  Unavailable: N=212 (25%) death (35) withdrawals from the study (47) lost to follow (28) unavailable for the 2-year visit (3) completed after the protocol change implemented (99)

Treatments 4

5 Injections Prior to 2 Year * Ranibizumab + Prompt Laser N=136 Ranibizumab + Deferred Laser N=139 Triamcinolone + Deferred Laser N=141 Maximal possible # of injections prior to 2- year visit 26 8 Median number of study drug injections from baseline to (prior to) 1-year visit 893 Median number of study drug injections from 1-year to (prior to) 2- year visit 231 * Restrict to eyes that completed 2 year visit

6 Injections Prior to 2 Year (continued)* Ranibizumab + Prompt Laser N=136 Ranibizumab + Deferred Laser N=139 Triamcinolone + Deferred Laser N=141 Number (%) of eyes that met success at 16 weeks and then received injection by 1-year visit 58 (87%) of 6746 (84%) of 5547 (85%) of 55 Number (%) of eyes that met success at 1-year visit and then received injection by 2-year visit 47 (56%) of 8441 (59%) of 6943 (56%) of 77 * Restrict to eyes that completed 2 year visit

7 Focal/Grid Laser Prior to 2 Years * Ranibizumab + Prompt Laser N=136 Ranibizumab + Deferred Laser N=139 Triamcinolone + Deferred Laser N=141 Maximal possible number of focal/grid laser treatments prior to 2-year visit 868 Median number of focal/grid laser treatments from baseline to (prior to) 1-year visit 202 % of eyes that received focal/grid laser treatments from 1-year to (prior to) 2-year visit 40%29%52% * Restrict to eyes that completed 2 year visit

Visual Acuity (includes all data up to and including the first visit when all investigators are unmasked to primary outcome results) 8

9 Change in Visual Acuity (LOCF) at 1 Year* Change in Visual Acuity (letters) Sham + Immediate Laser N=211 Ranibizumab + Immediate Laser N=136 Ranibizumab + Deferred Laser N=139 Triamcinolone + Immediate Laser N=142 Mean Difference in mean change from Sham + Laser [P -Value]** +5.2 [P <0.001] +6.1 [P <0.001] +0.6 [P=0.61] *Visits occurring between 308 and 420 days from randomization were included as 1 year visits. When more than 1 visit occurred in this window, data from the visit closest to the 1 year target date were used. For other eyes w/o any 1 year data (1 eye in the sham+immediate laser group and 1 eye in the triamcinolone+immediate laser group) the last observation carried forward method was used to impute data for the primary analysis. **Analysis of covariance adjusted for correlation between 2 study eyes and baseline visual acuity

10 Change in Visual Acuity at 2 Years* Change in Visual Acuity (letters) Sham + Immediate Laser N=211 Ranibizumab + Immediate Laser N=136 Ranibizumab + Deferred Laser N=139 Triamcinolone + Immediate Laser N=142 Mean Difference in mean change from Sham + Laser [P-Value]** +3.7 [P=0.03] +5.8 [P<0.001] -1.5 [P=0.35] *Visits occurring between 616 and 840 days from randomization were included as 2 year visits **Analysis of covariance adjusted for correlation between 2 study eyes and baseline visual acuity

Mean Change in Visual Acuity * at Follow-up Visits 11 *Truncated to ± 30 letters P-values for difference in mean change in VA from sham+prompt laser at the 104 week visit: ranibizumab+prompt laser =0.03; ranibizumab+deferred laser <0.001; and triamcinolone+prompt laser=0.35. N = 626 (52 weeks) N = 600 (68 weeks) N = 600 (84 weeks) N = 628 (104 weeks)

12 Visual Acuity Gain at 2 Years Proportion of Visual Acuity Improvement N=187 N=122 N=126N=129

13 Visual Acuity Loss at 2 Years Proportion of Visual Acuity Worsening N=187 N=122 N=126 N=129

14 Mean Change in Visual Acuity* at Follow-up Visits: Pseudophakic Eyes at Baseline *Truncated ± 30 letters N = 205 (52 weeks) N = 199 (68 weeks) N = 196 (84 weeks) N = 206 (104 weeks)

Retinal Thickening (includes all data up to and including the first visit when all investigators are unmasked to primary outcome results) 15

16 Change in Retinal Thickening at 2 Years* Change in OCT CSF a Sham + Immediate Laser N=211 Ranibizumab + Immediate Laser N=136 Ranibizumab + Deferred Laser N=139 Triamcinolone + Immediate Laser N=142 Mean change from baseline (µm) Difference in mean change from Sham + Laser [P Value]** -31 [P=0.003] -28 [P=0.01] -10 [P=0.37] Thickness <250 microns with at least a 25 µm decrease from baseline 39%54%56%45% *Visits occurring between 616 and 840 days from randomization were included as 2-year visits. When more than 1 visit occurred in this window,data from the visit closest to the 2-year target date were used. ** Analysis of covariance adjusted for baseline OCT retinal thickness and visual acuity and correlation between 2 study eyes ª Excluding missing or ungradable data for 3 eyes in the Sham +Immediate Laser group, 5 eyes in the Ranibizumab +Immediate Laser group, 4 in the Ranibizumab +deferred Laser, and 10 eyes in the Triamcinolone +Immediate Laser group

Mean Change in CSF Thickening at Follow-up Visits 17 *P values are for the difference in mean change in OCT CSF retinal thickness from Sham + Immediate Laser at the 52 week visit: ranibizumab+prompt laser =0.003, ranibizumab+deferred laser =0.01, and triamcinolone+prompt laser =0.37. N = 617 (52 weeks) N = 581 (68 weeks) N = 568 (84 weeks) N = 606 (104 weeks)

18 Mean Change in CSF Thickening at Follow-up Visits among eyes that were Pseudophakic at baseline *Truncated ± 30 letters N = 202 (52 weeks) N = 192 (68 weeks) N = 188 (84 weeks) N = 200 (104 weeks)

Safety ( all available data ) 19

20 Cardiovascular Events According to Antiplatelet Trialists’ Collaboration 20 Sham a N * =130 Ranibizumab N * =375 Triamcinolone b N * =186 Non-fatal myocardial infarction 3%1%3% Non-fatal cerebrovascular accident-ischemic or hemorrhagic (or unknown) 6%2% Vascular death (from any potential vascular or unknown cause) 6%3%4% Any ATC cardiovascular event 13%7%8% * N=Number of Study Participants. Study participants with 2 study eyes are assigned to the non- sham group. Multiple events within a study participant are only counted once per event. a one participant began receiving ranibizumab prior to nonfatal stroke b one participant began receiving ranibizumab prior to nonfatal stroke

21 Major Ocular Adverse Events During Follow-up 21 Sham + Prompt Laser † N=293 Ranibizumab + Prompt Laser N=187 Ranibizumab + Deferred Laser N=188 Triamcinolone + Prompt Laser † N=186 Number of injections* (91) (53) Endophthalmitis 1 (<1%)2 (1%) 0 Pseudoendophthalmitis 1 (<1%)001 (1%) Ocular vascular event ‡ 2 (1%) 1 (%)3 (2%) Retinal detachment 1 (<1%)01 (1%)0 *Numbers in parenthesis indicate # ranibizumab injections †No major ocular adverse events for eyes with ranibizumab injections

Cumulative Probability of Cataract Surgery Over 2-Years 22 74% 18% 16%

Summary   Expanded 2-year results are similar to results published previously and reinforce conclusions with respect to: Visual acuity outcomes OCT outcomes Pseudophakic subgroup analyses Injections given Lasers given Safety results 23