The Diabetic Retinopathy Clinical Research Network

1. The Diabetic Retinopathy Clinical Research Network A Randomized Trial Comparing Intravitreal Triamcinolone Acetonide 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

2. Background

3. Background – Diabetic Macular Edema • Common cause of vision loss • Focal/grid laser reduces chance of moderate vision loss • Search for better treatments includes intravitreal injection of triamcinolone (IVT)

4. IntravitrealTriamcinolone (IVT) for DME • 2001-2002: potential benefit first reported1,2 • 2002: 52% of retina specialists had used IVT for DME3 • Short term improvement in visual acuity • Rapid decrease in retinal thickening on OCT 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 2002

5. Rationale for a Randomized Study • Short term data suggests benefit • Known side-effects • Risk of non-infectious endophthalmitis • Post-injection ocular inflammation reported with off-label intravitreal Kenalog (Bristol-Myers Squibb, Princeton, NJ) • No long term safety or efficacy data • No randomized comparison with standard care (focal/grid photocoagulation)

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

7. Study Design Multicenter, randomized clinical trial • Major Eligibility Criteria Assessed: • >18 years old • Type 1 or type 2 diabetes • Center-involved DME (with OCT CSF >250 µm) • VA letter score 73 to 24 (20/40 to 20/320) Eligible eyes randomized Subjects with 2 study eyes assigned alternative treatment in 2nd eye Focal/Grid Laser 4 mg IVT 1 mg IVT

8. Follow-up and Treatment Schedule Randomized treatment at Month 0 Focal/Grid Laser 4 mg IVT 1 mg IVT • Re-treatment (within 4 wks) unlessany of the following: • Treatment successful • Substantial improvement in macular edema • Adverse eventsor maximal treatment • Further treatment appears futile Month 4 . . . Re-treatment assessed and protocol enforced at every 4-month interval visit Follow-up visits every 4 months* . . . Month 36 * Additional safety visits 4 days and 4 weeks after injections

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

10. Safety Outcomes • Injection-related events • Infectious or inflammatory endophthalmitis • Retinal detachment • Steroid-related toxicities • Cataract • IOP related effects

11. Focal/Grid Photocoagulation Treatment Modified-ETDRS technique: *Cover areas of retinal thickening not judged to be due to microaneurysms 2 burn widths apart. If a fluorescein angiogram is obtained, cover areas of retinal thickening 2 burn widths apart within areas on angiography of diffuse leakage from retinal telangiectasis and consider covering areas of non-perfusion.

12. IVT Treatment • Aseptic technique • Antibiotics on day of procedure (not required on days prior to injection) • 5% povidone iodine • Lid speculum • Injection of 0.05 cc volume with 27 or 30 gauge needle

13. 2 and 3 Year Results

14. Study Enrollment and Completion • 840 eyes (693 subjects) enrolled at 88 clinical sites • Treatment Groups • Laser: N = 330 • 1 mg: N = 256 • 4 mg: N = 254 • 2-year visit completion rate • 83% including deaths • 88% excluding deaths

15. Completion of 3 Year Visit • Trial was discontinued following completion of all 2 year visits • Excluding deaths, 44% had potential* to complete, and of those 82% completed • 7% deaths • 48% non-completer w/out potential* • 9% non-completer w/potential* • 36% completed • Similar rates among treatment groups *Subjects enrolled <34 months (open window for 3 year visit) from the closeout date of the trial did not have potential to complete. 15

16. Baseline Characteristics • Mean age: 63 years • Diabetes type: 5% type 1, 95% type 2 • Visual acuity (Snellen equivalent) • 20/40 to 20/63: 58% • Worse than 20/63 to better than 20/200: 38% • 20/200 to 20/320: 5% • OCT central subfield thickness • Mean: 424 microns • Range: 133 to 1164 microns

17. Baseline Characteristics • Pseudophakic: 21% • Prior macular laser: 61% • Retinopathy severity: • Microaneurysms only: <1% • Mild to moderately severe non-proliferative: 61% • Severe non-proliferative: 12% • Non-high risk proliferative: 24% • High risk proliferative: 3%

18. Treatment Prior to 2 Years * Includes only subjects with a 2 year visit † e.g., IVT in laser group, or laser in IVT groups

19. Non-Randomized Treatments for DME Prior to 2 Years * Alternative = IVT in laser group, or focal/grid laser in IVT groups

20. Number of Retreatmentsin 3rd Year* * Among completers of the 3 year visit 20

21. Non-Randomized Treatments for DME During 3 Years* * Among completers of the 3 year visit †laser in IVT groups, IVT in laser group ‡ primarily vitrectomy, Kenalog, bevacizumab 21

22. Primary Outcome:Mean Change in Visual Acuity at 2 Years * Adjusted for baseline VA and prior focal/grid laser

23. Change in VA from Baseline to 3 Years* 23 * Among completers of the 3 year visit

24. Median Visual Acuity in Laser Treated Eyes 20/32 20/40 Visual Acuity 20/50 Score 20/63 20/80 0 4 8 12 16 20 24 Months 24

25. Median Visual Acuity in Laser and 4 mg IVT Treated Eyes 20/32 20/40 Visual Acuity 20/50 Score 20/63 20/80 0 4 8 12 16 20 24 Months 25

26. Median Visual Acuity in Laser and IVT Treated Eyes 20/32 20/40 Visual # + * # * # Acuity 20/50 # Score 20/63 20/80 P < 0.005 0 4 8 12 16 20 24 * Laser vs. 1mg # Laser vs. 4mg + 1mg vs. 4mg Months 26

27. Mean Visual Acuity Over 3 Years in All Eyes 20/32 20/40 Visual Acuity 20/50 Score 20/63 20/80 20 36 8 24 28 0 16 12 32 4 Months 27

28. Mean Visual Acuity Limited to Completers of 3 Year Follow Up 20/32 20/40 Visual Acuity 20/50 Score 20/63 20/80 20 36 8 24 28 0 16 12 32 4 Months 28

29. Mean Visual Acuity In All Eyes and in Completers 20/32 20/40 Visual Acuity 20/50 Score 20/63 20/80 20 36 8 24 28 0 16 12 32 4 Months 29

30. 34% % Increased >10 Letters in Laser and 4mg Treated Eyes Months 30

31. % Increased >10 Letters in Laser and IVT Treated Eyes Months 31

32. % Decreased >10 Letters in Laser and 4mg Treated Eyes 19% Months

33. % Decreased >10 Letters in Laser and IVT Treated Eyes Months

34. Change in VA from 2 Years to 3 Years* * Among completers of both the 2 year and 3 year visit 34

35. Change in VA from 2 Years to 3 Years* * Among completers of both the 2 year and 3 year visit 35

36. % Increased >10 Letters at 2 YearsStratified by Baseline VA 13 13 129 12 92 94 N=189 149 149

37. % Decreased >10 Letters at 2 Years Stratified by Baseline VA 149 149 N=189 92 94 12 13 129 13

38. % Increased >10 Letters at 2 YearsStratified by Baseline CSF N=166 80 60 63 83 121 130 66 67

39. % Decreased >10 Letters at 2 Years Stratified by Baseline CSF 66 60 130 67 N=166 80 83 63 121

40. % Increased >10 Letters at 2 Years Stratified by Prior Laser N=132 158 198 102 96 154

41. % Decreased >10 Letters at 2 Years Stratified by Prior Laser 96 N=132 102 154 158 198

42. Visual Acuity at 2 YearsAccording to Lens Status Includes only subjects with a 2 year visit

43. OCT Central Subfield (CSF) Thickening at 2 Years

44. Change in CSFfrom Baseline to 3 Years* * Among completers of the 3 year visit 44

45. Median Central Subfield Thickness in Laser Treated Eyes Central Subfield Thickness (microns) Months

46. Median Central Subfield Thickness in Laser and 4mg Treated Eyes Central Subfield Thickness (microns) Months

47. Median Central Subfield Thickness in Laser and IVT Treated Eyes Central Subfield Thickness (microns) Months

48. % CSF <250 microns inLaser and 4mg Treated Eyes Months

49. % CSF <250 microns inLaser and IVT Treated Eyes Months

50. Change in CSFfrom 2 Years to 3 Years* * Among completers of both the 2 year and 3 year visit 50