LaserRanibizumab Triamcinolone for DME Study DRCR net Protocol

Laser-Ranibizumab. Triamcinolone for DME Study DRCR. net Protocol I Michael J. Elman, M. D. Protocol Chair

Protocol Summary Study Objective Ø To Evaluate safety and efficacy of the following in eyes with center-involved DME 1. intravitreal anti-VEGF treatment in combination with prompt focal laser 2. intravitreal anti-VEGF treatment with deferred focal laser 3. intravitreal corticosteroids in combination with prompt focal laser 2

Protocol Summary Major Eligibility Criteria Ø Age >=18 years. Ø Type 1 or type 2 diabetes Ø Center involved DME responsible for VA of 20/32 or worse Ø OCT central subfield thickness >250µ 3

Protocol Summary Sample Size Ø Minimum of 842 eyes Ø Subjects may have one or two study eyes. Ø 701 subjects assuming 20% have 2 study eyes 4

Protocol Summary Treatment Groups Randomization to one of the following 4 groups: Ø Group A: Sham injection + focal laser Ø Group B: 0. 5 mg injection of intravitreal Ranibizumab + focal laser Ø Group C: 0. 5 mg injection of intravitreal Ranibizumab + deferred focal laser Ø Group D: 4 mg injection of intravitreal Triamcinolone + focal laser 5

Protocol Summary Efficacy Outcomes Ø Primary Outcome: • VA at 1 year Ø Secondary Outcomes: • Change in OCT CSF and retinal volume • # of injections in first year 6

Protocol Summary Main Safety Outcomes Ø Injected-related: • Endophthalmitis, retinal detachment Ø Ocular drug-related: • Inflammation, cataract surgery, increased IOP, glaucoma medications, glaucoma surgery Ø Systemic drug-related: • Cardiovascular events 7

Protocol Summary Follow-up Schedule First Year Ø Visits every 4 weeks Second and Third Years Ø Visit schedule depends on treatment group Ø If failure met, visits occur every 4 months regardless of trt group 8

Retreatment Criteria: Injections During Follow-Up Ø Group A - sham Ø Groups B and C - ranibizumab Ø Group D - Triamcinolone injection is given if one has not been given in the prior 15 weeks; otherwise a sham injection is given. 9

Retreatment Criteria Through 12 -Week Visit Ø Everyone gets an injection (Drug or Sham) • Visual acuity score does not matter • OCT score does not matter Ø Injection can only be skipped if an adverse event occurs Ø Rationale: ensures that enough treatment is given to accurately assess efficacy 10

Retreatment Criteria for Injection at 16 and 20 -week Visits Ø VA letter score >=84 or OCT < 250: • Can defer injection Ø VA letter score <84 (worse than 20/20) AND OCT > 250: • Give injection Rationale: Ensures that eyes assigned to triamcinolone with vision less than 20/20 will receive at least 2 injections. 11

Retreatment Criteria for Injection 24 to 48 Week Visit Eyes are assigned to 1 of 4 categories: 1. VA letter score >=84 (20/20 or better) or OCT <250: • Decision to reinject at investigator discretion 2. Evidence of improvement at any visit since the last non-sham injection (or baseline for group A): • An injection is given 12

Retreatment Criteria for Injection 24 to 48 Week Visit 3. Failure criteria (next slide) not met, and no improvement at any visit since the last non-sham injection (or baseline for group A): • Decision to reinject is at investigator discretion. 13

Retreatment Criteria for Injection 24 to 48 Week Visit 4. Failure defined as: VA letter score 10 or more worse than baseline, OCT CSF >=250 microns, DME present on clinical exam that is the cause of the visual loss, complete laser given AND ≥ 13 w since last laser treatment with no improvement since the last laser treatment • The eye can be treated at investigator discretion. 14

Retreatment Criteria: Focal Photocoagulation Ø In general, focal photocoagulation will be given 3 to 10 days later following each injection unless one of the following is present: • Focal laser given in the previous 13 weeks • Maximal focal laser has already been given • The central subfield thickness is <250 microns and there is no edema threatening the fovea 15

Retreatment Criteria for Laser Group C – Laser Deferred Ø No focal photocoagulation before 24 weeks Ø At the 24 -week or later visit, if there is no evidence of improvement from the last 2 consecutive injections and the investigator believes that macular edema is present for which focal photocoagulation is indicated, the eye should receive focal photocoagulation. 16

Retreatment Criteria at and after 52 -Week Visit Ø Subjects are unmasked to treatment grp Ø Eyes assigned to Sham and Triamcinolone groups start every 16 wk visits and discontinue sham injections Ø Eyes assigned to ranibizumab continue every 4 week visits unless injections are deferred due to success or no improvement – visits then move to 8 or 16 wk intervals 17

Retreatment Criteria at and after 52 -Week Visit Ø Failure/futility defined as: VA letter score <84, OCT CSF >=250 microns, DME present on clinical exam that is the cause of the visual loss, complete laser given AND either 1) ≥ 13 w since last laser treatment with no improvement since the last laser treatment and VA 10 or more worse than baseline OR 2) ≥ 29 w since last laser with no improvement since the last laser treatment • The eye can be treated at investigator discretion.