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Laser-RanibizumabTriamcinolone for DME Study DRCR.net Protocol I Michael J. Elman, M.D. Protocol Chair Protocol Summary Study Objective 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 laser2 Protocol Summary Major Eligibility Criteria Age >=18 years. Type 1 or type 2 diabetes Center involved DME responsible for VA of 20/32 or worse OCT central subfield thickness >250µ 3 Protocol Summary Sample Size Minimum of 842 eyes Subjects may have one or two study eyes. 701 subjects assuming 20% have 2 study eyes 4 Protocol Summary Treatment Groups Randomization to one of the following 4 groups: Group A: Sham injection + focal laser Group B: 0.5 mg injection of intravitreal Ranibizumab + focal laser Group C: 0.5 mg injection of intravitreal Ranibizumab + deferred focal laser Group D: 4 mg injection of intravitreal Triamcinolone + focal laser 5 Protocol Summary Efficacy Outcomes Primary Outcome: • VA at 1 year Secondary Outcomes: • Change in OCT CSF and retinal volume • # of injections in first year 6 Protocol Summary Main Safety Outcomes Injected-related: • Endophthalmitis, retinal detachment Ocular drug-related: • Inflammation, cataract, cataract surgery, increased IOP, glaucoma medications, glaucoma surgery Systemic drug-related: • Cardiovascular events 7 Protocol Summary Follow-up Schedule First Year Visits every 4 weeks Second and Third Years Visit schedule depends on treatment group If failure met, visits occur every 4 months regardless of trt group 8 Retreatment Criteria: Injections During Follow-Up Group A - sham Groups B and C - ranibizumab 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 Everyone gets an injection (Drug or Sham) • Visual acuity score does not matter • OCT score does not matter Injection can only be skipped if an adverse event occurs Rationale: ensures that enough treatment is given to accurately assess efficacy 10 Retreatment Criteria for Injection at 16 and 20-week Visits VA letter score >=84 or OCT < 250: • Can defer injection 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 ≥13w 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 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 No focal photocoagulation before 24 weeks 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 Subjects are unmasked to treatment grp Eyes assigned to Sham and Triamcinolone groups start every 16 wk visits and discontinue sham injections 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 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) ≥13w since last laser treatment with no improvement since the last laser treatment and VA 10 or more worse than baseline OR 2) ≥ 29w since last laser with no improvement since the last laser treatment • The eye can be treated at investigator discretion.