The Diabetic Retinopathy Clinical Research Network Treatment for Central-involved DME in Eyes with Very Good Visual Acuity (DRCR.net Protocol V)

DRCR.net Overview Objective: Collaborative network to facilitate multicenter clinical research of 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

DRCR.net Status (as of 1/6/14) Active Total Sites (Community & Academic Centers) 119 179 Community Sites 80 (67%) 120 (67%) Investigators 363 786 Other Personnel 979 2746 States 37 41

Current 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 include: Initiating intravitreal anti-VEGF promptly Initiating focal/grid laser promptly If VA worsens, begin anti-VEGF Observing If DME worsening on OCT, begin anti-VEGF or laser

What do we already know? In the DRCR.net LRT for DME Study (Protocol I), ranibizumab + deferred or prompt laser for CI-DME provided VA outcomes superior to prompt focal/grid laser alone However… 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

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

Available 2 Year Data Summary ETDRS Focal Observation Protocol I Ranibizumab + Deferred Laser Eyes with VA ≥20/25 or better at baseline VA = 20/32 at baseline N = 118 N = 246 N = 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% VA Change from Baseline Median (25th , 75th) -1 (-5, 2) -3 (-10, 1) 5 (1, 9)

ETDRS and Protocol I Data*: Percent with VA loss ≥ 5 letters *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

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?

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?

Study Design Randomized, multi-center clinical trial (N=702) 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 or minimal** 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) **No more than 1 laser and/or 4 injections, at least 12 months ago

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

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

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

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) No or minimal history of prior DME treatment No more than 1 laser, 4 injections at least 12 months ago Non-study eye: Patient must be willing to use (or switch to using) study aflibercept on the non-study eye if needed 15

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 need in next 6 months

Study Follow-Up Treatment Visit Schedule Outcome Visit Schedule Prompt anti-VEGF Group: visits every 4 weeks during the first 24 weeks, every 4-16 weeks thereafter Deferred anti-VEGF groups (focal and observation)*: visits at 8 and 16 weeks, followed by every 16-week visits thereafter All participants will have visits at 1 and 2 years for outcome assessment *For the deferred groups, if vision and/or OCT are worsening or anti-VEGF is initiated, visits will be every 4, 8 or 16 weeks depending on disease progression and treatment

Study Treatment Prompt Anti-VEGF Injection at baseline Evaluation at each visit for re-injection based on protocol criteria Focal/grid laser at baseline Evaluation at each visit for initiating anti-VEGF based on visual acuity loss Retreatment with laser if protocol criteria are met Laser + Deferred Anti-VEGF Observe + Deferred Anti-VEGF No treatment at baseline Evaluation at each visit for initiating anti-VEGF based on visual acuity loss

Referrals We Need Your Help! Please consider any eyes with DME involving the center of the macula and vision ~20/32 or better on clinic charts Study participants must be willing to be randomized to laser, injections, or observation to start and continue follow-up for 2 years Consenting/Screening/Randomization will be split into several visits An optional “Observational Phase” is also available for patients not ready for randomized treatment

Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net) Dedicated to multicenter clinical research of diabetic retinopathy, macular edema and associated disorders. 20