The Diabetic Retinopathy Clinical Research Network

1. The Diabetic Retinopathy Clinical Research Network Randomized Trial Evaluating Short-Term Effects of Intravitreal Ranibizumab or Triamcinolone Acetonide on Diabetic Macular Edema Following Panretinal Photocoagulation Supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services EY14231, EY14229, EY018817 

2. BackgroundPRP in Eyes with Central DME • Scatter or panretinal photocoagulation (PRP) is standard treatment for PDR • DRS: 2-year risk of severe visual acuity loss without treatment was reduced by ~60% • ETDRS: 5-year risk of severe visual acuity loss among patients (both eyes) with PDR could be reduced to 1% with prompt PRP

3. BackgroundPRP in Eyes with Central DME • Reported side effects of PRP include: • Worsening macular edema and loss of visual acuity (prior to OCT) • DRCR.net reported PRP in 1 or 4 sittings, respectively, results in median +14 or +15 µm increase in OCT CSF (25th, 75th percentile = +5 or +6, +20 or +34 µm) with little decreased acuity 17 weeks after initiating PRP in eyes without central DME • Is change in OCT CSF and change in visual acuity similar in eyes receiving PRP with central DME which around the same time also receive focal/grid laser for the DME?

4. BackgroundPRP in Eyes with Central DME • Focal/grid laser of central DME in absence of prompt PRP usually associated with short term improvement (at 16 weeks) of macular edema with little change in visual acuity

5. BackgroundPRP in Eyes with Central DME • If some eyes with central DME receiving PRP at the time of focal/grid laser have at least short term substantial worsening of macular edema and visual acuity loss, . . . • . . . then reducing the proportion of eyes with worsening of macular edema and visual acuity loss following PRP could improve quality of life for individuals undergoing this therapy in the short term

6. BackgroundAnti-VEGF and Triamcinolone for DME • Inflammation and increased levels of vascular endothelial growth factor (VEGF) contribute to the development or exacerbation of DME • DRCR.net and RESTORE reported benefits for ≥1 year of intravitreal ranibizumab treatment of DME in the absence of DR requiring prompt PRP (Protocol I) • DRCR.net and others have suggested a benefit of intravitreal corticosteroids for DME (though not superior to ranibizumab or focal/grid laser) • Anti-VEGF drugs or corticosteroids might have a role in reducing PRP-induced exacerbation of macular edema in eyes with DME and severe NPDR or PDR for which PRP also is given

7. Laser-Ranibizumab-Triamcinolone+PRP Randomized Clinical Trial for DME Study Objective Evaluate short term effects of intravitreal ranibizumab or intravitreal triamcinolone on exacerbation of macular edema and associated visual acuity loss in eyes requiring PRP for severe NPDR or PDR and receiving focal/grid laser for center-invovled DME.

8. Study Design Randomized, multi-center clinical trial At least 1 eye meeting all of the following criteria: • Severe NPDR or PDR requiring prompt PRP • Presence of central DME on clinical exam and CST on OCT ≥250 microns • Best corrected E-ETDRS visual acuity letter score ≥24 (~20/320 or better) Sham+ Focal/Grid/PRP Laser Ranibizumab+ Focal/Grid/PRP Laser Triamcinolone+ Focal/Grid/PRP Laser Primary outcome: Change in visual acuity from baseline to 14 weeks (intent to treat analysis)

9. Follow-up Schedule • 1st injection at baseline • Safety visit 3-10 days • Focal/grid laser 3-10 days • Initial PRP (following focal/grid ) 3-14 days Baseline to 2 Weeks • 2nd injection (ranibizumab for ranibizumab group and sham for sham and triamcinolone groups) • Follow-up visit 4 Weeks 14 Weeks • Primary outcome visit 34 Weeks & 56 Weeks • Safety follow-up visits

10. Study Enrollment Eyes Randomized: N = 364 (333 Study Participants) Sham+ Focal/Grid Laser & PRP N = 133 Ranibizumab+ Focal/Grid Laser & PRP N = 116 Triamcinolone+ Focal/GridLaser & PRP N = 115 14 Week Visit Completion* (Primary Outcome): 95% 56 Week Visit Completion*: 87% *Includes deaths

11. Baseline Characteristics (N=345)

12. Baseline Characteristics

13. Panretinal Photocoagulation Treatment

14. Panretinal Photocoagulation Treatment • Number of sittings planned prior to randomization was similar to the number of sittings performed. • † Only 1 study participant had 4 PRP sittings performed

15. Panretinal Photocoagulation Treatment

16. Additional Treatment for DME *Number of eyes, each combination of treatment only counted once

17. Visual Acuity

18. Primary Outcome Change in Visual Acuity at 14 Weeks *Adjusted for baseline visual acuity, number of planned PRP sittings, and correlation between 2 study eyes.

19. Mean Change in Visual Acuity* from Baseline Randomized Phase (DME treatment according to protocol) Safety Phase (DME treatment at investigator discretion) Safety Phase (DME treatment at investigator discretion) * Values that were ±30 letters were assigned a value of 30

20. Change in Visual Acuity at 56 Weeks *Adjusted for baseline visual acuity, number of planned PRP sittings, and correlation between 2 study eyes.

21. Visual AcuitySubgroup Analysis

22. Subgroup Analyses No obvious clinically important difference in results at 14-week primary outcome visit for any of the following subgroups: Prior treatment for DME Baseline visual acuity Baseline OCT-measured central subfield thickening Baseline level of diabetic retinopathy on photos Baseline HbA1c level Description of edema by ophthalmologist as predominantly focal or predominantly diffuse PRP in a single sitting vs. multiple sittings 22

23. Retinal Thickening

24. Change in Retinal Thickening at 14 Weeks* *Missing (or ungradeable) data as follows for the sham+focal/grid/PRP laser group, ranibizumab+focal/grid/PRP laser group, and triamcinolone+focal/grid/PRP laser groups, respectively: 3, 3, 2 † Adjusted for baseline OCT retinal thickness and visual acuity, number of planned PRP sittings, and correlation between 2 study eyes.

25. Correlation between Visual Acuity and Central Subfield Thickness at 14 Weeks

26. Change in Retinal Thickening at 56 Weeks* *Missing (or ungradeable) data as follows for the sham+focal/grid/PRP laser group, ranibizumab+focal/grid/PRP laser group, and triamcinolone+focal/grid/PRP laser group, and respectively: 10, 3, 4 † Adjusted for baseline OCT retinal thickness and visual acuity, number of planned PRP sittings, and correlation between 2 study eyes.

27. Mean Change in Retinal Thicknessfrom Baseline Randomized Phase (DME treatment according to protocol) Safety Phase (DME treatment at investigator discretion) Safety Phase (DME discretion)

28. ≥ 2 Step Improvement in LogOCT Central Subfield Thickness from Baseline Randomized Phase (DME treatment according to protocol) Safety Phase (DME treatment at investigator discretion) Safety Phase (DME discretion)

29. Safety

30. Major Ocular Adverse Events Prior to the 14-Week Visit * One case related to study drug injection in the ranibizumab+focal/grid/PRP laser group. 30

31. Major Ocular Adverse Events from 14 Weeks to 56 Weeks 31

32. Elevated Intraocular Pressure/Glaucoma Prior to the 14-Week Visit 32 *Excludes eyes with IOP lowering medications at baseline

33. Elevated Intraocular Pressure/Glaucoma from 14 Weeks to 56 Weeks *Excludes eyes with IOP lowering medications at baseline † Includes 2 Ahmed valve (neovascular glaucoma) 33

34. Cataract Surgery During Follow-up

35. Number of Deaths

36. Cardiovascular or Cerebrovascular Events According to Antiplatelet Trialists’ Collaboration through 56 Weeks • *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. • † 1event occurred between baseline and 4 week injections, 1 event occurred about 3 weeks after the 4 week injection, and the other events from the remaining 6 study participants occurred over 4 weeks after the 4 week injection

37. Cardiovascular Events According to AntiplateletTrialists’ Collaboration* through 56 Weeks Vascular or unknown death Sham Ranibizumab Triamcinolone 4 14 34 56 Randomized Phase (DME treatment according to protocol) Safety Phase (DME treatment at investigator discretion) *Antiplatelet Trialists’ Collaboration. BMJ. 1994 Jan 8;308(6921):81-106. Non-fatal cerebrovascular accidents include ischemic, hemorrhagic or unknown. Vascular death includes any potential vascular or unknown cause.

38. Discussion

39. Summary Randomized Phase • 14 week primary outcome visit: • On average, both ranibizumab and triamcinolone statistically significantly improve visual acuity and retinal thickness compared to sham injection in eyes with central DME receiving focal/grid laser and requiring prompt PRP Safety Phase • 14 week to 56 week visits: • Differences in visual acuity and retinal thickness outcomes above no longer significant

40. SummaryMacular Edema after Prompt PRP in Eyes with Central DME Also Receiving Focal/Grid Laser – Sham Injection Group • Focal/grid laser of central DME in absence of prompt PRP usually associated decreased macular edema by 16 weeks

41. Macular Edema after Prompt PRP in Eyes with Central DME Receiving Focal/ Grid Laser – Sham Injection Group Compared to Eyes without Central DME and No Focal/Grid Laser • 14 week primary outcome visit: • The magnitude and frequency of short term OCT central subfield thickening and visual acuity loss following prompt PRP appears similar in eyes with central DME receiving focal/grid laser than eyes without central DME

42. Macular Edema after Prompt PRP in Eyes with Central DME Receiving Focal/ Grid Laser – Sham Injection Group Compared to Eyes without Central DME and No Focal/Grid Laser • 34 week visit: • The magnitude and frequency of OCT central subfield thickening and visual acuity loss following prompt PRP appears similar in eyes with central DME receiving focal/grid laser than eyes without central DME

43. SummarySafety • Ranibizumab: • Endophthalmitis: one eye receiving ranibizumab • Long term safety of ranibizumab injections in persons with characteristics similar to those enrolled in this protocol remains largely unknown • Triamcinolone: • Associated with increased risk of elevated IOP between 14 and 56 weeks; even with only one treatment at baseline • Unlike prior studies, not associated with higher incidence of cataract surgery • Why? Only 1 injection? Younger cohort? Lower enthusiasm to operate on cataracts in this advance DR cohort? Other factors?

44. SummarySafety • This study did not identify an increased risk of traction retinal detachments beyond that which could be attributed to chance alone. • Cerebrovascular or cardiovascular events did not occur with a difference in frequency among the 3 groups that could not be attributed to chance alone.

45. Conclusions • Eyes with central DME receiving prompt PRP at time of focal/grid laser for DME appear more likely to have increased macular edema and visual acuity loss in short term than: • Eyes without central DME receiving prompt PRP but no focal/grid laser • Eyes with central DME receiving foca/grid laser but no prompt PRP

46. Conclusions • The risk of short-term exacerbation of macular edema and associated visual acuity loss following prompt PRP in eyes also receiving focal/grid laser for DME can be reduced by intravitreal triamcinolone or ranibizumab. • Benefits were not maintained at 1 year, but study injections were discontinued after 1 (triamcinolone) or 2 (ranibizumab) injections

47. Conclusions – Other Considerations • Eyes with central DME requiring prompt PRP which receive ranibizumab or triamcinolone at the time of PRP and focal/grid laser may be less likely to need additional PRP, develop vitreous hemorrhage, develop traction retinal detachment, or undergo vitrectomy

48. Conclusions – Other Considerations • Effects of ranibizumab or triamcinolone on diabetic retinopathy appear consistent with similar findings in eyes with the following: • Central DME not requiring prompt PRP treated with triamcinolone alone (Protocol B) or triamcinolone + prompt focal/grid laser (Protocol I) • Central DME not requiring prompt PRP treated with intravitreal ranibizumab with deferred (>24 weeks) or prompt focal/grid laser (Protocol I

49. Conclusions – Other Considerations • Single study injection of intravitreal triamcinolone appears associated with increased risk of elevated IOP, even between 14 and 56 weeks • Further study seems necessary to assess long-term risks and benefits of intravitreal injections of ranibizumab or corticosteroids in persons with central DME also receiving prompt PRP

50. Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net) • 48 clinical study sites • Study participants who volunteered to participate in this trial • DRCR.net Data and Safety Monitoring Committee • Genentech (provided the ranibizumab) and Allergan, Inc. (provided the triamcinolone) for the study and collaborated in a manner consistent with the Network’s DRCR.net Industry Collaboration Guidelines, the DRCR.net had complete control over the design of the protocol, ownership of the data, and all editorial content of presentations and publications related to the protocol. • DRCR.net investigators and staff 50