The Diabetic Retinopathy Clinical Research Network

1. The Diabetic Retinopathy Clinical Research Network Dedicated to multicenter clinical research of diabetic retinopathy, macular edema and associated conditions 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, EY018817 

2. DRCR.net Overview • Objective: • The development of a collaborative network to facilitate multicenter clinical research on diabetic retinopathy, DME and associated conditions. • Funding: • National Eye Institute (NEI) and The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-sponsored cooperative agreement initiated September 2002. • Current award 2014-2018

3. Priority Initiatives • Involvement of community-based practices, as well as “academic” or university-based centers. • Collaborate with industry to facilitate investigations and pursue opportunities otherwise not possible and to do so in a manner consistent with the Network’s dedication to academic integrity and optimal clinical trial performance.

4. DRCR.net Status(as of 1/6/14)

5. How to Join the Network • All retina specialists are welcome to apply • E-mail drcrnet@jaeb.org • Your request will be reviewed and if approved the necessary paperwork will be sent to you

6. How to Submit a Protocol Idea • Go to the public* website: drcr.net • Click on Information for Investigators. • Scroll down to Protocol Idea Form. • E-mail form to drcrnet@jaeb.org • It will be reviewed by the Operations Group at the next in-person meeting. * Forms also available on the study website

7. DRCR Network Completed Protocols (as of 2/12/14)

8. DRCR Network Ongoing Protocols (as of 2/12/14) * Enrollment done/in active follow-up; **Recruiting

9. What Has Been Learned?Diabetic Macular Edema Treatment • Protocol B: Over 2 years, focal/grid photocoagulation is more effective and has fewer side effects than 1 mg or 4 mg doses of preservative-free intravitreal triamcinolone. • Protocol E: In cases of DME with good visual acuity, peribulbar triamcinolone, with or without focal photocoagulation, is unlikely to be of substantial benefit. • Protocol H: The results demonstrated that intravitreal bevacizumab can reduce DME in some eyes, but the study was not designed to determine whether the treatment was beneficial.

10. What Has Been Learned?Diabetic Macular Edema Treatment • Protocol I: Intravitreal ranibizumab with prompt or deferred (≥24 weeks) focal/grid laser is more effective through 2 years in increasing visual acuity compared with focal/grid laser treatment alone for the treatment of DME involving the central macula. Ranibizumab should be considered for patients with DME and decreased visual acuity. • Protocol K: Sixteen weeks after focal/grid laser for DME in eyes with a definite reduction, but not resolution, of central edema, 23% to 63% likely will continue to improve without additional treatment.

11. What Has Been Learned?Diabetic Retinopathy Treatment • Protocol F: Results suggest that clinically meaningful differences are unlikely in OCT thickness or visual acuity following application of PRP in 1 sitting compared with 4 sittings. These results suggest PRP costs to some patients in terms of travel and lost productivity as well as to eye care providers could be reduced. • Protocol J: The addition of 1 intravitreal triamcinolone injection or 2 intravitreal ranibizumab injections in eyes receiving focal/grid laser for DME and PRP is associated with better visual acuity and decreased macular edema by 14 weeks. Whether continued long-term intravitreal treatment is beneficial cannot be determined from this study.

12. What Has Been Learned?OCT and Retinal Thickening • Protocol C: Although on average there are slight decreases in retinal thickening during the day, most eyes with diabetic macular edema have little meaningful change in OCT central subfield thickening or visual acuity between 8 AM and 4 PM. • Protocol C: Reproducibility of retinal thickness in DME was better for central subfield thickness measurements than for center point measurements. A change in central subfield thickness exceeding 11% is likely to be real. • Protocol G (Secondary Outcomes): While subclinical DME may be uncommon, this study suggests that between approximately one-quarter and one-half of eyes with subclinical DME will progress to more definite thickening or be judged to need treatment for DME within 2 years after its identification.

13. What Has Been Learned?Optical Coherence Tomography • Protocol G (Primary Outcomes): CSF thickness on Stratus OCT™ in people with diabetes and minimal or no retinopathy are similar to thicknesses reported from a normative database of people without diabetes. CSF thickness is greater in men than in women. Studies involving comparisons of retinal thickness to expected norms should consider different mean values for women and men. • Protocol O: Mean CSF thickness is ~70 µm thicker when measured with Heidelberg Spectralis OCT as compared with Stratus OCT among individuals with diabetes in the absence of retinopathy or with minimal non-proliferative retinopathy and a normal macular architecture.  CSF thickness values ≥320 µm for men and 305 µm for women are proposed as gender-specific thickness levels.

14. What Has Been Learned?Optical Coherence Tomography • Protocol O: Conversion equations may be used to transform CSF values obtained on a SD-OCT to a TD scale for group comparisons. However, the CSF conversion equations do not appear to predict TD values for an individual accurately enough to warrant use of these conversion equations confidently in clinical decision-making at the patient level.

15. Recently Completed Protocols

16. Protocol I: Intravitreal Ranibizumab or Triamcinolone Acetonide in Combination with Laser Photocoagulation for Diabetic Macular Edema

17. Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010 June;117(6):1064-1077.e35.  

18. Mean Change in Visual Acuity*at Follow-up Visits N = 626 (52 weeks) N = 600 (68 weeks) N = 600 (84 weeks) N = 628 (104 weeks) *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.

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

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

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

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

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

24. 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

25. 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

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

27. Conclusions • Intravitreal ranibizumab with prompt or deferred (≥24 weeks) focal/grid laser is more effective through 2 years in increasing visual acuity compared with focal/grid laser treatment alone for the treatment of DME involving the central macula.  Ranibizumab should be considered for patients with DME and decreased visual acuity.

28. Conclusions: Ranibizumab + prompt laser vs. deferred laser • 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.

29. Protocol M: Effect of Diabetes Education During Retinal Ophthalmology Visits on Diabetes Control

31. Protocol R: A Phase II Evaluation of Topical NSAIDs in Eyes with Non Central Involved DME

33. Active Studies Image: National Eye Institute, National Institutes of Health

34. Protocols in Follow-up

35. Protocol S: Prompt PRP versus Intravitreal Ranibizumab with Deferred PRP for PDR • Objective • To determine if visual acuity outcomes at 2 years in eyes with PDR that receive anti-VEGF therapy with deferred PRP are non-inferior to those in eyes that receive standard prompt PRP therapy. Image: National Eye Institute, National Institutes of Health

36. Protocol S: Prompt PRP versus Intravitreal Ranibizumab with Deferred PRP for PDR • Major Eligibility Criteria • Study eye with • PDR for which PRP can be safely deferred for at least 4 weeks in the investigator’s judgment. • No prior PRP • Visual acuity letter score in the study eye > 24 (~ Snellen equivalent of 20/320 or better) • Enrollment (Completed) • Total enrolled: 305 participants and 394 study eyes at 56 sites

37. Protocol T: A Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab and Ranibizumab for DME Image: National Eye Institute, National Institutes of Health

38. Study Objective and Treatment Arms (N = 660) To compare the efficacy and safety of (1) intravitreal aflibercept, (2) intravitreal bevacizumab, and (3) intravitreal ranibizumab when given to treat central-involved DME in eyes with visual acuity of 20/32 to 20/320. • 2.0 mg • intravitreal aflibercept • 1.25 mg intravitreal bevacizumab • 0.3 mg intravitreal ranibizumab

39. Major Inclusion Criteria • Age ≥18 years • Type 1 or 2 diabetes • Study eye: • Visual acuity (~Snellen equivalent) 20/32 or worse and 20/320 or better • Definite retinal thickening due to central-involved DME on clinical exam • OCT CSF ≥ OCT-machine gender specific cut-off for definite central involved DME

40. Follow-up Schedule Baseline to 1 Year • Visits every 4 weeks • Primary outcome at 1 year • Urine sample • Blood pressure (another BP measurement will be taken at the first 4 week visit after the optional visit) Optional Visit 2-3 Days after 1st 2nd or 3rd visit • Visits every 4 to 16 weeks • Depends on disease status and treatment 1 Year to 2 Years

41. Protocols Currently Enrolling

42. Protocol V Very Good Visual Acuity

43. Protocol V - Treatment for Central-involved DME in Eyes with Very Good Visual Acuity • Objective: compare the safety and efficacy of 1) prompt laser with deferred anti-VEGF, 2) observation with deferred anti-VEGF, and 3) prompt anti-VEGF in eyes with center involved DME and good vision (defined as visual acuity  20/25). • Primary Outcome: proportion of eyes with a visual loss of at least 5 letters at 1 year, confirmed at 2 consecutive 4-week visits

44. Study Design Randomized, multi-center clinical trial At least one eye meeting all of the following criteria: • Central-involved DME on OCT (Cirrus/Spectralis only)* • VA letter score 20/25 or better* • No prior treatment for DME • Prompt • anti-VEGF • Prompt laser + deferred anti-VEGF • Observation + deferred anti-VEGF Primary outcome: Proportion of eyes that have lost ≥5 letters of VA at 2 years *Confirmed at 2 visits (screening and randomization 1-28 days apart)

45. Outcome Measures • Primary Outcome • % with VA loss of ≥ 5 letters at 2 years • Secondary Outcomes • Mean change in VA letter score • % with at least 10 and 15 letter VA gain/loss • Visual acuity area under the curve • Mean change in OCT CSF thickness • % with 1 or 2 log step gain or loss on OCT • Number of injections/lasers performed • Worsening/improvement of DR severity level • Low contrast visual acuity • Safety outcomes 45

46. Major Eligibility Criteria • Type 1 or 2 diabetes • Study Eye: • Central-involved DME on clinical exam, confirmed on OCT at two consecutive visits (1-28 days apart) • VA letter score >79 (~20/25 or better) at two consecutive visits (1-28 days apart) • The investigator is comfortable with the eye being randomized to any of the three treatment groups • No history of prior DME treatment • Non-study eye: • Investigator must be willing to use (or switch to using) study aflibercept on the non-study eye if needed 46

47. Major Exclusion Criteria • Systemic • History of chronic renal failure requiring dialysis or kidney transplant • Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months prior to randomization or plans to do so in the next 4 months • BP > 180/110 • Study eye • Macular edema not due to DME (eyes with thickening due to ERM, prior cataract surgery or other non-DME reason should not be enrolled) • PRP in last 4 months or anticipated in next 6 months • History of or anticipated need for intravitreal anti-VEGF for an ocular condition other than DME

48. Follow-Up Schedule • Total follow-up through 2 years • Visit schedule will vary by treatment group and disease progression • Prompt anti-VEGF group: visits every 4 weeks through 24 weeks, then every 4 to 16 weeks depending on whether injections are being given • Deferred groups (observation and laser groups): visits at 8 and 16 weeks, then every 16 weeks unless vision and/or OCT are worsening or anti-VEGF is initiated (visits every 4, 8 or 16 weeks depending on disease progression and treatment) • All participants will have visits at 1 and 2 years

49. Protocol U Short-term Evaluation of Combination Corticosteroid+Anti-VEGF Treatment for Persistent CI-DME Following Anti-VEGF Therapy in Pseudophakic Eyes

50. Objectives • To assess short-term effects of combination steroid+anti-VEGF therapy on OCT retinal thickness and visual acuity in comparison with that of continued anti-VEGF therapy alone in pseudophakic eyes with persistent DME and visual acuity impairment despite previous anti-VEGF treatment. • To provide more information needed for future conduct of a definitive phase III clinical trial.