1. The Diabetic Retinopathy Clinical Research Network Protocol I: Clinical Applications 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 1

2. Diabetic Macular Edema Treatment  Focal/Grid Photocoagulation ~25 years following ETDRS  Intravitreal Steroids ~10 years  Anti-VEGF Agents Late stage studies ~15 months

3. Mean Change in Visual Acuity * 3 * Values that were ±30 letters were assigned a value of 30 P-values for difference in mean change in visual acuity from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser <0.001; ranibizumab+deferred laser <0.001; and triamcinolone+prompt laser=0.31. Ranibizumab + prompt laser Ranibizumab + deferred laser Primary Outcome Time Point (1 Year) Letter Improvement Weeks Sham + prompt laser P<0.001 DRCR Protocol I Overall Study: 854 eyes, 691 participants

4. Background  Protocol I demonstrated that ranibizumab (with prompt or deferred focal/grid laser) resulted in superior visual acuity outcomes compared with laser alone through 2 years  The treatment regimen for ranibizumab (with prompt or deferred laser ) was very detailed and facilitated by a real-time web-based system 4

5. Purpose of this Presentation To discuss clinical applications that might provide clinicians with: a simplified approach to retreatment in accord with the general opinion of the DRCR.net investigators, and is based on the Protocol I retreatment algorithm 5

6. Visit/Treatment Schedule: Year 1 – the “4:2:7” Guide 6 Sham+Prompt Laser Ranibizumab +Prompt Laser Ranibizumab +Deferred Laser **Triamcinolone +Prompt Laser 048 12 ‘4’ required injections 1620 ‘2’ required injections if not a success* 2428323640444852 ‘7’ additional follow-up visits every 4 weeks; required injection if improvement † but not success* since last injection; otherwise optional Primary Endpoint  Visits were every 4 weeks regardless of whether the eye status was successful, improved, or failed. *Success: Visual acuity letter score ≥84 (~20/20) or OCT CSF <250 µm; retreatment at investigator discretion. † Improvement: OCT central subfield thickness decreased by >10% or visual acuity letter score improved by >5. Sham+prompt laser Ranibizumab+prompt laser Ranibizumab+deferred laser Triamcinolone+prompt laser **Triamcinolone q 16 wks w/ sham q 4 wks in between.

7. Follow-up Visits at and After 52 Week Visit if Ranibizumab Injection Given 7 Ranibizumab +Deferred or Prompt Laser Drug 5256  Four wks after any ranibizumab injection, the study eye is evaluated for possible additional ranibizumab injection using retreatment criteria as in year 1: If not a success*, but improvement † since last injection, retreatment required; otherwise, retreatment is up to investigator. 606468…………104 *Success: Visual acuity letter score ≥84 (~20/20) or OCT CSF <250 µm; retreatment at investigator discretion. † Improvement: OCT central subfield thickness decreased by >10% or visual acuity letter score improved by >5. Drug Visit Visit*

8. Follow-up Visits at and After 52 Week Visit if Ranibizumab Not Given (4 to 8 to 16 Weeks) 8 Ranibizumab +deferred or Prompt Laser No Drug 52 56  If a ranibizumab injection is not given at the current and previous 2 visits (e.g. week 60 above), the next follow-up visit is in 8 weeks.  If at the next 8 week interval visit the injection is deferred again, the next follow-up visit is in 16 weeks; visits continue every 16 weeks unless a ranibizumab injection is given, at which point the visit schedule goes back to 4 week intervals. No Drug 606468……………….……84 No Drug Visit Skip VisitVisit Skip 16 wks Visit

9. SIMPLIFIED Retreatment and Follow-up of Center-Involved DME with Anti-VEGF DME Improving? DME Worsens or Recurs? No Injection and return in 1 month YES NO YES Assessment 1 month after initial serial series of injection(s) Double Follow-Up Interval Up to 4 Months Re-inject and Return in 1 Month

10. Anti-VEGF Treatment Concepts Clinical Practice Considerations DRCR.net Study Patients could be enrolled if they had edema involving the center of the macula defined as central subfield thickness ≥250µm and vision impairment defined as Snellan equivalent of 20/32 to 20/320.  For which eyes with DME should anti-VEGF therapy be considered? 10

11. Anti-VEGF Treatment Concepts Clinical Practice Considerations DRCR.net Study Patients could be enrolled if they had edema involving the center of the macula defined as central subfield thickness ≥250µm and vision impairment defined as Snellan equivalent of 20/32 to 20/320.  For which eyes with DME should anti-VEGF therapy be considered? 11 Patients with edema involving the center of the macula

12. Anti-VEGF Treatment Concepts Clinical Practice Considerations DRCR.net Study 4 required injections at 4- weekly intervals, followed by 2 injections at next 4-weekly intervals unless edema resolved or vision improved to 20/20 or better  What follow-up interval could be considered after initiating therapy? 12 † “Improvement” in the DRCR.net study was defined as “increase of at least 5 letters (approximately 1 line) in visual acuity or at least a 10% reduction in the central subfield thickness on OCT since the last injection.

13. Anti-VEGF Treatment Concepts Clinical Practice Considerations DRCR.net Study 4 required injections at 4- weekly intervals, followed by 2 injections at next 4-weekly intervals unless edema resolved or vision improved to 20/20 or better  What follow-up interval could be considered after initiating therapy? 13 † “Improvement” in the DRCR.net study was defined as “increase of at least 5 letters (approximately 1 line) in visual acuity or at least a 10% reduction in the central subfield thickness on OCT since the last injection. Several serial monthly injec- tions until vision and edema are no longer improving † or can no longer improve (e.g. vision 20/20 or better, or edema resolved)

14. Anti-VEGF Treatment Concepts Clinical Practice Considerations DRCR.net Study If no improvement from prior injection, decision to re-inject was at investiga- tor discretion. Injections were recommended if there still was edema to treat.  What treatment is employed when the DME no longer is improving? 14

15. Anti-VEGF Treatment Concepts Clinical Practice Considerations DRCR.net Study If no improvement from prior injection, decision to re-inject was at investiga- tor discretion. Injections were recommended if there still was edema to treat.  What treatment is employed when the DME no longer is improving? 15 Focal/grid laser can be added if it not previously used and injections would continue. Injections may be withheld, but resumed if the edema worsens.

16. Anti-VEGF Treatment Concepts Clinical Practice Considerations DRCR.net Study Re-injection was at the investigator’s discretion if edema recurred or worsened, but was recommended if there was edema to treat; follow-up then returned to 4- week intervals once injections resumed  When should treatment be resumed after it has not been given? 16

17. Anti-VEGF Treatment Concepts Clinical Practice Considerations DRCR.net Study Re-injection was at the investigator’s discretion if edema recurred or worsened, but was recommended if there was edema to treat; follow-up then returned to 4- week intervals once injections resumed  When should treatment be resumed after it has not been given? 17 Injections may be re- sumed if edema recurs or worsens; follow-up then returns to monthly intervals until injection is not given

18. Anti-VEGF Treatment Concepts Clinical Practice Considerations DRCR.net Study Starting with the second year of treatment, if an injection was withheld at 3 consecutive 4- weekly visits, follow-up interval was extended to 8 weeks, and then again to 16 weeks if treatment still not warranted  What follow-up is employed when the DME does not recur or worsen after an injection is not given? 18

19. Anti-VEGF Treatment Concepts Clinical Practice Considerations DRCR.net Study Starting with the second year of treatment, if an injection was withheld at 3 consecutive 4- weekly visits, follow-up interval was extended to 8 weeks, and then again to 16 weeks if treatment still not warranted  What follow-up is employed when the DME does not recur or worsen after an injection is not given? 19 If injection was not given and edema does not recur, follow-up may be doubled (up to 4 months or longer).

20. Anti-VEGF Treatment Concepts Clinical Practice Considerations DRCR.net Study Randomized treatment groups included either prompt (within 3- 10 days) or deferred (at least 24 weeks) focal/grid laser. If deferred, laser only could be added if edema was still present after 24 weeks and there was no improvement from two prior consecutive injections  When should focal/grid laser treatment be added? 20

21. Anti-VEGF Treatment Concepts Clinical Practice Considerations DRCR.net Study Randomized treatment groups included either prompt (within 3- 10 days) or deferred (at least 24 weeks) focal/grid laser. If deferred, laser only could be added if edema was still present after 24 weeks and there was no improvement from two prior consecutive injections  When should focal/grid laser treatment be added? 21 Focal/grid laser may be given initially or deferred. If deferred, laser may be added at any time if edema is no longer improv- ing after an injection.

22. Anti-VEGF Treatment Concepts Clinical Practice Considerations DRCR.net Study Once initiated, focal/grid was re-applied if 1) edema was present, 2) eye did not have “complete” laser, and 3) it had been at least 13 weeks since last laser  When should focal/grid laser be repeated after initiation? 22

23. Anti-VEGF Treatment Concepts Clinical Practice Considerations DRCR.net Study Once initiated, focal/grid was re-applied if 1) edema was present, 2) eye did not have “complete” laser, and 3) it had been at least 13 weeks since last laser  When should focal/grid laser be repeated after initiation? 23 Focal/grid laser generally should be repeated at any time that edema persists or is not improving while giving anti-VEGF therapy (as long as it is believed that additional laser may be of benefit)

24. Summary  Given that duplication of the treatment approach used within the DRCR.net trial with its elaborate infrastructure may not be practical in all clinical settings  This presentation provides guidelines based on DRCR.net investigators’ opinion for a simplified retreatment approach when using intravitreal ranibizumab to treat center-involved DME with vision impairment  However, it is unknown whether these or other modifications to the DRCR.net protocol would result in better, same or worse outcomes 24