diabetic retinopathy clinical research network糖尿病视网膜病变临床研究网络（ppt40）课件

The Diabetic Retinopathy Clinical Research Network Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema Michael Elman, MD 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 Background: Protocol B IVT vs Laser 2 Intravitreal triamcinolone was evaluated previously as a “monotherapy” treatment for DME in a randomized trial conducted by DRCR.net (): Results suggested that IVT without laser was not superior to focal/grid photocoagulation Focal/grid photocoagulation in eyes with center- involved DME produces gradual visual acuity improvement of 2 lines in about 30% of eyes after 2 years, although approximately 20% of laser treated eyes worsen by 2 lines 3 Laser-Ranibizumab-Triamcinolone Randomized Clinical Trial for DME: Study Objective Evaluate efficacy and safety of: 0.5-mg intravitreal ranibizumab plus prompt laser (within 1 week); or 0.5-mg intravitreal ranibizumab plus deferred laser (24 weeks); or 4-mg intravitreal triamcinolone plus prompt (within 1 week) laser, in comparison with sham plus prompt laser for treatment of diabetic macular edema. 4 Study Design Primary outcome: Change in visual acuity from baseline to 1 year (intent to treat analysis) Randomized, multi-center clinical trial At least one eye meeting all of the following criteria: Electronic-ETDRS best corrected visual acuity letter score of 78 to 24 (20/32 to 20/320) Definite retinal thickening due to diabetic macular edema involving the center of the macula on clinical examination Central subfield (Stratus OCT) 250 m Visit/Treatment Schedule: Year 1 the “4:2:7” Guide 5 Sham+Prompt Laser Ranibizumab +Prompt Laser Ranibizumab +Deferred Laser Triamcinolone +Prompt Laser 04812 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 10% or visual acuity letter score improved by 5. Sham+prompt laser Ranibizumab+promt laser Ranibizumab+deferred laser Triamcinolone+prompt laser Follow-up Visits at and After 52 Week Visit if Ranibizumab Injection Given 6 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. 606468104 *Success: Visual acuity letter score 84 (20/20) or OCT CSF 10% or visual acuity letter score improved by 5. DrugDrugDrugDrugDrug VisitVisit*Visit*Visit*Visit*Visit* Follow-up Visits at and After 52 Week Visit if Ranibizumab Not Given (4 to 8 to 16 Weeks) 7 Ranibizumab +deferred or Prompt Laser No Drug 5256 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 DrugNo DrugNo Drug VisitVisitVisitSkip VisitVisit Skip 16 wks Visit Study Enrollment and Completion 8 Ranibizumab +Prompt Laser N = 187 Ranibizumab +Deferred Laser N = 188 Sham +Prompt Laser N = 293 Triamcinolone +Prompt Laser N = 186 Eyes Randomized: N = 854 (691 Participants) 1 Year Visit (Primary Outcome) Completion: 94%* 2 Year Visit Completion: 87%* * Includes deaths * Includes deaths and excludes pending and dropped who are not yet in window 9 Baseline Characteristics Sham +Prompt Laser Ranibizumab +Prompt Laser Ranibizumab +Deferred Laser Triamcinolone +Prompt Laser Median age 63626462 Diabetes type Type I 9%6%8%8% Type II 89%92%90%89% Uncertain 3%2%2%3% Median E-ETDRS visual acuity letter score (Snellen equivalent) 65 (20/50)66 (20/50)66 (20/50)66 (20/50) Median OCT CSF thickness (m) 407371382374 10 Injections/Sham Prior to 1 Year Sham +Prompt Laser N = 274 Ranibizumab +Prompt Laser N = 171 Ranibizumab +Deferred Laser N = 178 Triamcinolone +Prompt Laser N =176 Maximal possible # of sham/injections 13 sham*13 drug13 drug9 sham/ 4 drug Median number of sham/study drug injections to 1 year 11*895 sham/ 3 drug AE Precluding Study Drug Injection NA2%2%15% Compliance with sham/drug injection when required by protocol 96%95%97%97% Masked participant with 1 study eye identified correct assignment at 1 year 10%88%90%44% *Excludes 56 eyes among 163 participants with 2 study eyes unmasked at baseline when assigned ranibizumab + deferred laser. % of visits reported; 12% of eyes in the triamcinolone group compared with 3% and 4% in the ranibizumab groups 11 Additional Information On Injections/Sham to 2 Yrs Sham +Prompt Laser N = 274 Ranibizumab +Prompt Laser N = 171 Ranibizumab +Deferred Laser N = 178 Triamcinolone +Prompt Laser N = 176 % of eyes meeting failure criteria* at 1- year study visit 4%2%1%2% Maximal # of drug injections prior to 2 years n/a25258 Median drug injections prior to 1 year n/a893 Median drug injections prior to 2 years n/a11134 * Failure is defined as: VA 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 Out of 26 maximum Out of 26 maximum 12 Laser Treatments Prior to 1 Year Sham +Prompt Laser Ranibizumab +Prompt Laser Ranibizumab +Deferred Laser* (permitted starting at 24- week visit) Triamcinolone +Prompt Laser Median number of laser treatments including baseline 3202 Proportion of eyes receiving laser at 48-week visit 26%16%8%21% No, only 1, only 2 or 3 more lasers after baseline 13%,27%,31%,32%,70%, 20%,26%,30%, 40%,20%27%,11%10%,1%28%,15% * 3 eyes deviated from the protocol and received laser prior to 24 weeks (2 were given laser at the 1 week safety visit and 1 at the 20 week visit). Out of 4 maximum Out of 4 maximum Out of 2 maximum Out of 4 maximum Visual Acuity 13 Mean Change in Visual Acuity (Letters)* at Follow-up Visits 14 * 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 24 weeks So what is your Standard Care for Center Involved DME? 36 37 Intravitreal Ranibizumab Summary If ranibizumab is to be given as it was in this study, the data indicate a need to follow eyes continuously undergoing this treatment Additional ranibizumab and/or laser were needed in most eyes through 2 years, even if success criteria were met early in the course of treatment. So how are you following patients and determining when to re-treat? 37 38 Intravitreal Ranibizumab Treatment Protocol Results are based on rigorous adherence to a detailed retreatment protocol on a web-based real- time data entry system that provided feedback to the treating physician regarding the treatment to be prescribed at each follow-up visit. The underlying rationale of the treatment algorithm is to place 4 mandatory injections and then continue treatment, as needed, until stabilization or lack of further improvement is noted. 39 Intravitreal Ranibizumab Treatment Protocol Once a retreatment is withheld, the algorithm is designed to identify when there is a need to re- initiate treatment. The goal was to avoid substantial vision loss while also avoiding a regimen which requ