1. The Diabetic Retinopathy Clinical Research Network Treatment for Central-involved DME in Eyes with Very Good Visual Acuity Presenter: Carl W. Baker, MD 1

2. OCT CSF = 358 ETDRS VA Letter Score = 83 (20/25) 2

3. Clinical Question  What is the best treatment strategy for eyes with central-involved (CI) DME and good visual acuity?  Possible treatment approaches in clinical practice: Initiate intravitreal anti-VEGF promptly Initiate focal/grid laser promptly oIf VA worsens, begin anti-VEGF Observe oIf DME worsening on OCT, begin anti-VEGF or laser oIf VA worsens, begin anti-VEGF 3

4. What do we already know?  In Protocol I, ranibizumab + deferred or prompt laser for CI-DME provided VA outcomes superior to prompt focal/grid laser alone Only eyes with VA letter score ≤78 (20/32 or worse) were enrolled Anti-VEGF has not been evaluated in eyes that have CI-DME with VA 20/25 or better 4

5. What do we already know?  In ETDRS – 20/25 or better eyes with CI-DME that lost 5 or more letters at 2 years oFocal laser  27% oObservation  40% OCT not available to closely follow improvement or worsening of DME Clinical characteristics of the cohort may have changed since the time of ETDRS Deferred Anti-VEGF as a rescue treatment not evaluated as part of treatment approach 5

6. Available 2 Year Data Summary 6 ETDRS Focal ETDRS Observation Protocol I Ranibizumab + Deferred Laser Eyes with VA ≥20/25 or better at baseline VA = 20/32 at baseline N = 118N = 246N = 28 Visual Acuity Decrease by Letter Score of 5 or More 27%40%4% Visual Acuity Decrease by Letter Score of 10 or More 13%25%0 VA Change from Baseline Median (25 th, 75 th )-1 (-5, 2)-3 (-10, 1)5 (1, 9)

7. ETDRS and Protocol I Data*: Percent with VA loss ≥ 5 letters 7 *ETDRS study eyes with CI-DME and VA 20/25 or better at baseline. Protocol I study eyes with CI-DME and VA = 20/32 at baseline

8. Study Questions  In eyes with good VA, is deferring anti-VEGF similar, better, or worse than prompt anti-VEGF for long-term visual acuity outcomes? If similar or better, how long can you defer anti-VEGF? What % never need anti-VEGF?  If deferring anti-VEGF, is it better to observe or give focal/grid laser? Does one provide better VA outcomes? Does one allow for fewer anti-VEGF injections? 8

9. Study Questions  If prompt anti-VEGF is better, does it have enough of a benefit to warrant risks of repeated intravitreal injections? How many injections are needed to maintain 20/20 vision? Are fewer injections needed in the long run than if you wait until after VA or OCT decline to initiate anti-VEGF? 9

10. 10 Prompt laser + deferred anti-VEGF Observation + deferred anti-VEGF 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* Minimal prior treatment for DME ** Prompt anti-VEGF Study Design Randomized, multi-center clinical trial 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) **No more than 1 laser and/or 4 injections, at least 12 months ago

11. 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 11

12. Treatment Groups: Prompt Anti-VEGF  Treatment Group Description: Intravitreal anti-VEGF (2.0 mg aflibercept) at randomization DRCR.net retreatment criteria during follow-up  Rationale: Protocol I and other studies have demonstrated that anti-VEGF is well-tolerated and more effective than laser alone in increasing vision gain and decreasing vision loss in patients with CI DME, but this benefit has not been established in eyes that have good vision despite the presence of CI DME 12

13. Treatment Groups: Prompt Laser + Deferred Anti-VEGF  Treatment Group Description: Focal/grid laser at randomization Anti-VEGF only initiated if protocol criteria met  Rationale: The initial use of focal/grid laser could offer advantages over starting treatment with anti-VEGF in terms of reducing adverse events associated with intravitreal injections as well as fewer treatments given over time with potentially less frequent follow- up 13

14. Treatment Groups: Observation + Deferred Anti-VEGF  Treatment Group Description: Observation Anti-VEGF only initiated if protocol criteria met (to be discussed)  Rationale: Deferral of immediate treatment might result in decreased inconvenience, adverse events and costs associated with anti-VEGF treatments that are performed as often as once a month while potentially preserving vision in eyes with CI DME with good vision 14

15. 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 Minimal history of prior DME treatment oNo more than 1 laser, 4 injections at least 12 months ago  Non-study eye: Investigator must be willing to use (or switch to using) study aflibercept on the non-study eye if needed 15

16. VA and OCT Variability  There is inherent measurement variability  There may also be day to day actual variability, particularly in patients with diabetes  Two separate measurements are required to confirm the eye truly has good vision with DME Randomization criteria slightly relaxed for OCT central subfield thickness (~5% less than screening cutoff), however investigator must still confirm DME on clinical exam 16

17. 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 intravitreal anti-VEGF for an ocular condition other than DME in last 6 months or anticipated in next 6 months 17

18. OCT CSF = 400 VA Letter Score = 89 ERM present 18 EXCLUDED

19. Baseline Testing Procedures  Visual acuity and OCT eligibility must be confirmed at 2 visits within 1 to 28 days  Screening Visit Refraction followed by E-ETDRS visual acuity testing using the refraction obtained in the study eye OCT in the study eye oCirrus and Spectralis only Ocular exam may be done to rule out exclusions; however, data collection and official eligibility assessment occurs at randomization Fundus photography may be done at screening or randomization 19

20. Baseline Testing Procedures  Randomization Visit Refraction followed by E-ETDRS visual acuity testing using the refraction obtained in both eyes Low-contrast visual acuity in the study eye (select sites) OCT in the study eye Ocular exam in both eyes Fundus photographs in the study eye (if not done at screening visit) Measurement of blood pressure HbA1c oThe same lab or DCA Vantage must be used at baseline and follow-up 20

21. FA Sub-study  Certification – each investigator will indicate whether they routinely perform FA prior to focal/grid laser and whether they would be willing to collect FA in this study  Randomization Visit – For investigators who indicate FA will be collected FA will be obtained on all participants at baseline  Follow-up Visits – For investigator who indicate FA will be collected FA will be obtained at following prior to repeat focal/grid treatment for eyes randomized to laser group 21

22. Randomization Form  Before submitting, investigator MUST Confirm eligibility Confirm patient’s willingness to accept any of the treatment assignments and to complete all treatment/follow-up oThis is particularly important in this study since the treatment approaches are so varied (no treatment vs injection in the eye) oInvestigator is responsible for making sure patient has been properly informed of potential risks/benefits via consent process Be available to perform whatever the randomized treatment is THAT DAY as applicable 22

23. Randomization  Approximately 702 study eyes (one per participant) assigned to one of the three treatment groups  Stratified by site and fellow-eye DME treatment If the fellow eye is being seen more frequently than the study eye, it may influence the number of treatments performed in the study eye Rather than excluding patients that are already receiving DME treatment in the non-study eye, this will be used as a stratification factor during randomization 23

24. 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 24

25. Follow-up Testing All Protocol Visits:  Protocol refraction in the study eye followed by E- ETDRS VA testing in each eye  OCT on the study eye (same device as at baseline)  Ocular exam on the study eye at each visit and on the non-study eye only if study anti-VEGF treatment has been given Additional Annual Visit Procedures:  Non-study eye refraction prior to visual acuity  Low-contrast visual acuity (at select sites)  Fundus photography in the study eye  HbA1c (also at 16 weeks) The same lab or DCA Vantage that was used at baseline should be used

26. Criteria for Initiating Anti-VEGF in Deferred Groups  Visual acuity worsening of at least 10 letters at one visit or 5 to 9 letters at 2 consecutive visits If VA loss of 5 to 9 letters, subject is seen in 4 (±2) weeks to check for continued vision loss Requiring a second confirmation visit for 5 to 9 letter loss will minimize initiation of treatment unnecessarily due to measurement error or other variability Delaying treatment for 2 to 6 weeks is not likely to be harmful to the participant  OCT worsening alone will not warrant anti-VEGF However, subject will be seen more frequently to check for vision loss and delaying treatment in this case is not likely to be harmful to the participant 26

27. Retreatment Criteria Once Anti- VEGF Initiated (either at baseline or when criteria met) 27  Improving on OCT or VA  Inject Improving = OCT CSF thickness decreased by ≥ 10% or VA letter score improved by ≥ 5  Worsening on OCT or VA  Inject Worsening = OCT CSF thickness increased by >10% or VA letter score decreased by >5  Stable: not improving or worsening on OCT or VA  Inject unless stable since last 2 injections OR it is before 24-wk visit and OCT is > machine-specific threshold (250 µm equivalent) or VA worse than 20/20

28.  An eye will be considered a “failure” if after 24 weeks of anti-VEGF and at least 13 weeks since “complete” laser has been given, DME is still present on OCT and clinical exam, VA letter score is ≥ 10 letters worse than baseline at 2 consecutive visits and there has been no improvement from prior injections or laser  Once “failure” is met, treatment is at investigator discretion Principles of DRCR.net DME Intravitreal Anti-VEGF Treatment

29.  If the investigator’s desired treatment plan deviates from the retreatment protocol, the Protocol Chair or designee must be contacted prior to deviating from retreatment protocol, including: Desire to defer an injection when injection indicated by protocol Desire to inject when injection should be deferred per protocol Principles of DRCR.net DME Intravitreal Anti-VEGF Treatment

30. Injection Preparation Reminders  Two individuals must confirm the study eye and drug number against the printout or website  Mark the eye for injection  Apply topical anesthetic  Place the lid speculum  Apply povidone iodine directly over and surrounding the injection site (allowing sufficient time for the povidone iodine to dry) DRCR.net injections must NOT be given without the use of povidone iodine in any circumstance  Pre- and post-injection topical antibiotics can be applied at the discretion of the investigator 30

31. Focal/Grid Laser Treatment Criteria after Anti-VEGF initiated  Once anti-VEGF is initiated, laser can be added at investigator discretion if: ≥24 weeks since first anti-VEGF injection OCT CSF is ≥machine-specific threshold or there is edema threatening the fovea AND The eye has not improved on OCT or VA compared with either of the last two consecutive injections  After 24 weeks, if OCT or VA are worsening from the last two injections, laser should be given

32. Focal/Grid Laser Re-Treatment  Once focal/grid laser has been initiated (either at baseline for laser group or when criteria are met), retreatment with laser will be performed unless one of the following is present: Laser has been given in <13 weeks The OCT CSF is < machine-specific threshold (250 micron equivalent) and there is no edema threatening the fovea Complete focal/grid laser has been given The OCT or VA has improved since last laser

33. Complete the Visit Instructions 33 Because the eye is stable for only one visit or is worsening since the last visit, an injection of Aflibercept in the right eye must be given at this visit. Focal/grid photocoagulation should not be performed at this visit.

34. Intravitreal Anti-VEGF Treatment in the Non-study Eye  If the non-study eye is treated for any condition which requires treatment with an anti-VEGF agent, study aflibercept must be used  The DRCR.net CC will provide drug for the non- study eye  If non-study eye and study eye will be injected on the same day, the study eye must be injected first

35. Use of Intravitreal Anti-VEGF in the Study Eye for Non-DME Tx  Use of study aflibercept for an FDA approved indication other than DME is at investigator discretion  Any off-label use of anti-VEGF for an ocular condition other than DME (e.g. PDR, vitreous hemorrhage) will require discussion with and approval by the protocol chair or designee  Study aflibercept must be used for any anti- VEGF treatment in the study eye 35

36. Case Example: Prompt Anti-VEGF Group 481216202428360 Week OCT VA I = improved: OCT CSF decreased by >10% or VA LS improved by >5 W= worsened: OCT CSF increased by >10% or VA LS worsened by >5 St = stable: did not improve or worsen (according to above definitions) Su = success: stable (according to above definition) AND visual acuity letter score >84 (~20/20) and OCT CSF <250µ or SD equivalent 300 245 249242245 249275245 247 245 20/25 20/20 20/32 20/20 A-VEGF Laser Category 32 404448 --I Su W 249 20/20 Su 249 20/20 Su Required due to improvement Deferred while Success Required due to worsening Required 1 st time success I Required due to improvement Required 1 st time success Su Deferred while Success

37. Case Example: Laser+Def Anti-VEGF 816360 Week OCT VA I = improved: OCT CSF decreased by >10% or VA LS improved by >5 W= worsened: OCT CSF increased by >10% or VA LS worsened by >5 St = stable: did not improve or worsen (according to above definitions) Su = success: stable (according to above definition) AND visual acuity letter score >84 (~20/20) and OCT CSF <250µ or SD equivalent 300 275 325 255 20/25 20/32 20/20 A-VEGF Laser Category 32 404448 -- 260 20/20 255 20/20 St Return in 4 weeks to re- check VA VA still decreased; initiate anti- VEGF -- I Required 1 st time stable 2 nd time stable but <24w

38. Case Example: Observe+Def Anti-VEGF 816360 Week OCT VA I = improved: OCT CSF decreased by >10% or VA LS improved by >5 W= worsened: OCT CSF increased by >10% or VA LS worsened by >5 St = stable: did not improve or worsen (according to above definitions) Su = success: stable (according to above definition) AND visual acuity letter score >84 (~20/20) and OCT CSF <250µ or SD equivalent 300 325400 300260 250 20/25 20/20 A-VEGF Laser Category 32 404448 -- 260 20/20 255 20/20 St > 10% worsening on OCT; return in 8 weeks -- II I Required 1 st time stable Defer 2 nd time stable ≥24w 400 20/40 24 -- 325 20/32 28 I VA decreased 10 letters; initiate anti- VEGF Inject due to improvement

39. Observational Phase  Objective To collect additional data on the natural history of eyes with good VA and DME (when the RCT is declined)  Summary Potential participants who are not ready/willing to be randomized but meet certain criteria can enroll Collect data every 4 months while the eye is being observed Follow-up will continue until… oThe eye is randomized oTreatment is given outside of the study OR oThe patient reaches 2 years from enrollment 39

40. Enter RCT or Observational Phase? Screening Visit (OCT/VA) Randomize Ready/Eligible to Randomize? Eligible Observational Phase No Yes No Ready/ Eligible to Randomize? Completed Receive DME Trt Observational Phase Follow-up 40

41. Stay Out of Trouble: Use the Computer!  All visits must be entered in real time! Menu includes required exams and visit reminders. Forms include visit specific instructions (i.e. required on study eye only or both eyes)  DME treatment and visit schedule are determined for you!  Contact CC prior to any deviations from protocol treatment

42. ***CRITICAL*** Investigator AND Coordinator Role Enrolling the Correct Participants  Educate patient with a thorough ICF process so that they understand: Time commitment Treatment requirements  Assess likelihood that patient will adhere to protocol  Listen to the coordinator  Verify patient has reliable means of transportation to study site  Consider travel distance and patient’s other health conditions 42

43. Certification Requirements  Site Specific IRB approval of protocol and ICF Contract addendum  Investigator Completed 1572 Protocol Q+A (80% correct or higher) Protocol acceptance form Protocol review teleconference w/in 2 months Investigator brochure acknowledgment (PI only) Competing studies form  Coordinator Requirements Completed mock informed consent with investigator