Sponsored by the National Eye Institute, A Randomized Trial Comparing Intravitreal Triamcinolone to Focal/Grid Photocoagulation for Diabetic Macular Edema Sponsored by the National Eye Institute, National Institutes of Health, U.S. Department of Health and Human Services.

Intravitreal Triamcinolone for DME 2001-2002: potential benefit first reported1,2 Short term improvement in visual acuity Rapid decrease in retinal thickening on OCT 2005: 91% of retina specialists surveyed (N=371) would use IVT for persistent DME3 Community equipoise present: Randomized, controlled comparison with standard care (focal/grid photocoagulation) needed 1- Jonas JB, et al. Am J Ophthalmol 2001;132:425-7 2- Martidis A, et al. Ophthalmology 2002;109:920-7 3- American Society of Retina Specialists Preferences and Trends Survey 2005

DRCR.net Study Design Multicenter, randomized clinical trial Three treatment groups Focal/grid laser 1 mg IVT 4 mg IVT Duration of follow-up: 3 years Follow-up visits and re-treatment as often as every 4 months

Primary Study Objective To compare the efficacy and safety of preservative-free IVT (1 mg or 4 mg) with focal/grid laser

Efficacy Outcomes Primary outcome assessment at 2 years Primary outcome measure: visual acuity Scientific objective: mean change in VA Regulatory objective for FDA: proportion with decrease in VA letter score >15 Secondary measure: Retinal thickening on OCT

Major Eligibility Criteria At least 18 years old Type 1 or type 2 diabetes Center-involved DME confirmed on OCT (central subfield thickness >250 microns) Best-corrected VA letter score 73 to 24 (Snellen equivalent 20/40 to 20/320)

Results

Study Enrollment and Completion 840 eyes (693 subjects) enrolled at 88 clinical sites (2004-2006) Treatment Groups Laser: N = 330 1 mg: N = 256 4 mg: N = 254 2-year visit completion rate 88% excluding deaths

Primary Outcome: Mean Change in Visual Acuity at 2 Years Mean Change in VA (letter score) Laser N=330 1 mg N=256 4 mg N=254 +1 -2 -3 Pairwise Comparisons Mean Difference* P value* Laser vs. 1 mg +3.5 letters 0.02 Laser vs. 4 mg +4.6 letters 0.002 1 mg vs. 4 mg +1.1 letters 0.49 * Adjusted for baseline VA and prior focal/grid laser

Median Visual Acuity in Laser and IVT Treated Eyes 20/32 - 20/40 - # + * # * # Visual Acuity Score 20/50 - * 20/63 - 20/80 - P < 0.005 * Laser vs. 1mg # Laser vs. 4mg + 1mg vs. 4mg Months 10 10

% Increased >10 Letters in Laser and IVT Treated Eyes Months 11 11

Visual Acuity at 2 Years According to Lens Status Mean Change in VA (letter score) Laser 1 mg 4 mg Pseudophakic at 2 Yrs or Minimal or No Cataract at 2 Yrs N=178 N=136 N=159 +3 Pseudophakic at Baseline N=54 N=48 N=43 +2 -1 Includes only subjects with a 2 year visit

Mean Visual Acuity Over 3 Years in All Eyes 20/32 20/40 Visual Acuity Score 20/50 20/63 20/80 4 8 12 16 20 24 28 32 36 Months 13 13

OCT Central Subfield (CSF) Thickening at 2 Years Change in OCT CSF Laser N=220 1 mg N=178 4 mg N=162 Mean* -139 -86 -77 Thickening Decreased >50% 67% 46% 48% Thickness <250 microns 53% 34% 38% *Pairwise Comparisons P value Laser v 1 mg <0.001 Laser v 4 mg 1 mg v 4 mg 0.91

Median OCT Central Subfield Thickness in Laser and IVT Treated Eyes (microns) Months 15 15

Change in CSF from 2 Years to 3 Years* 2 year CSF >=250 Laser N=50 1mg N=59 4mg N=54 Mean change (microns) -79 -44 -84 <250 microns at 3 years 36% 31% 39% Decreased >=20% and >=50 microns 54% 34% 46% Increased >=20% and >=50 microns 10% 12% 13% * Among completers of both the 2 year and 3 year visit 16 16

Major Ocular Adverse Events During 2 Years of Follow-up Laser N=330 1 mg N=256 4 mg N=254 Endophthalmitis* Pseudoendophthalmitis Retinal detachment† 2 3 Retinal vein occlusion† 1 Retinal artery occlusion† Glaucoma procedure 4 Vitrectomy‡ 31 26 19 * 1 case of endophthalmitis occurred after vitrectomy, not related to study drug injection † Judged not necessarily related to treatment ‡ Includes vitrectomy for diabetic macular edema, vitreous hemorrhage or other cause

Intraocular Pressure During 3 Years of Follow-up* Laser N=115 1 mg N=93 4 mg N=98 Increase >10 mmHg any time 3% 17% 31% Mean IOP at 3 yr visit (mmHg) 16 17 IOP >21 mmHg at 3 yr visit 5% 15% 10% On IOP-lowering meds at 3 yr visit 8% 12% 30% * Among completers of the 3 year visit 18 18

Cataract Surgery Prior to 2 Years Laser 1 mg 4 mg Phakic at Baseline N=262 N=203 N=197 Cataract Surgery 13% 23% 51%

Cumulative Probability of Cataract Surgery* Over 3 Years 83% 46% 31% 4 8 12 16 20 24 28 32 36 Months * Among phakic eyes at baseline 20 20

Conclusion VA benefit in 4 mg IVT group at 4 months consistent with published case series However, no difference in VA between IVT groups and laser group by 1 year By 2 years, there was a greater VA benefit and fewer side effects (IOP and cataract) in laser group compared with the IVT groups 3 year results similar to the 2 year results OCT results mirrored VA results

Conclusion Results re-affirm importance of laser in management of DME Focal/grid currently most effective treatment for patients with DME (with characteristics similar to those enrolled in this trial) Focal/grid currently benchmark against which other new treatments for DME should be compared in clinical trials for DME