The Diabetic Retinopathy Clinical Research Network Exploratory Analysis of Diabetic Retinopathy Progression through 3 Years in a Randomized Clinical Trial Comparing Intravitreal Triamcinolone with Focal/Grid Photocoagulation Sponsored by the National Eye Institute, National Institutes of Health, U.S. Department of Health and Human Services

Background Current treatments for reducing the risk of progression of retinopathy: Glycemic control PRP – associated with side effects and potential complications Identification of other treatments is desirable Rationale for corticosteroids: Down regulates VEGF and reduces breakdown of blood-retinal barrier Anti-angiogenic properties Intravitreal triamcinolone shown to prevent retinal neovascularization in animal and clinical studies

DRCR.net Protocol B: Laser vs. Intravitreal Triamcinolone for DME 840 eyes (693 subjects) at 88 sites Laser group: N = 330 1 mg IVT group: N = 256 4 mg IVT group: N = 254 Major Eligibility Criteria: VA 20/40 to 20/320 CSF >= 250 microns on OCT Visits (and retreatment assessment) every 4 months through 3 years Primary Outcome: VA at 2 years

Primary Results Focal/Grid Laser was more effective (VA and CSF) with fewer side effects (IOP and cataract) than 1 mg or 4 mg IVT at 2 years Longer term 3 year results were consistent with 2 year results Change in retinopathy level was a planned secondary outcome An exploratory analysis was pursued to evaluate effect of IVT on a multilevel definition of progression of retinopathy

Outcome Definition Progression of retinopathy up to 3 years (any of the following): Progressed from NPDR at baseline to PDR during follow-up* Received PRP between baseline and follow-up Reported a vitreous hemorrhage between baseline and follow-up Worsened 2 or more levels on the ETDRS diabetic retinopathy scale* *Based on Reading Center grading of annual fundus photos

Cumulative Probability* of Progression of Retinopathy Months 0 4 8 12 16 20 24 28 32 36 *calculated using the life-table method Note: 14% were censored prior to 2 yr visit and an additional 34% between the 2 and 3 yr visits (of which only 7% had the potential to complete the 3 yr visit due to early closeout of the study) 6 6

Treatment Group Comparisons at 1, 2, and 3 Years P value* Laser v 1 mg 0.71 1 Year Laser v 4 mg 0.03 1 mg v 4 mg 0.08 0.64 2 Years 0.005 0.73 3 Years 0.02 0.07 *From a proportional hazards model adjusting for baseline VA, history of prior macular photocoagulation, and baseline retinopathy severity

Cumulative Probability* of Progression of Retinopathy up to 2 Years Additional Probability (not counted in prior row) Laser N=330 1mg N=256 4mg N=254 NPDR to PDR 15% 11% 8% PRP 9% 6% 5% Vitreous hemorrhage Worsened 2 levels 1% 3% Combined definition 31% 29% 21% *calculated using the life-table method 8 8

Cumulative Probability* of Progression of Retinopathy up to 2 Years Total Probability for Each Criteria Laser N=330 1mg N=256 4mg N=254 NPDR to PDR 15% 11% 8% PRP 14% 10% 9% Vitreous hemorrhage 16% Worsened 2 levels Combined definition 31% 29% 21% *calculated using the life-table method 9 9

Cumulative Probability* of Progression of Retinopathy up to 3 Years Additional Probability (not counted in prior row) Laser N=330 1mg N=256 4mg N=254 NPDR to PDR 19% 14% 16% PRP 10% 7% 6% Vitreous hemorrhage 12% 5% Worsened 2 levels 2% 3% Combined definition 37% 35% 30% *calculated using the life-table method 10 10

Cumulative Probability* of Progression of Retinopathy up to 3 Years Total Probability for Each Criteria Laser N=330 1mg N=256 4mg N=254 NPDR to PDR 19% 14% 16% PRP 18% 11% 12% Vitreous hemorrhage 20% 15% Worsened 2 levels 17% Combined definition 37% 35% 30% *calculated using the life-table method 11 11

Discussion 4 mg IVT can reduce the risk of progression of retinopathy at 1, 2, and 3 years Difference cannot be explained by an increase in retinopathy caused by focal/grid laser Similar risk in laser group and 1 mg group Similar risk of development of PDR in ETDRS immediate laser group (11.1%) and deferred laser group (10.8%) Results in Fluocinolone Acetonide Implant Study Group trial support DRCRnet results Lower rate of retinopathy worsening compared to standard of care group (P<0.002, P=0.012, and P<0.015 at 1, 2, and 3 years, respectively)

Conclusions Use of IVT to reduce risk of progression of retinopathy is not warranted at this time IVT is associated with cataract and elevated IOP PDR can be treated relatively safely with PRP Further investigation of treatments to reduce risk of progression of retinopathy safely is needed