The Diabetic Retinopathy Clinical Research Network Worsening of Diabetic Retinopathy in a Randomized Clinical Trial Evaluating Ranibizumab and Triamcinolone: Exploratory Analysis 1

FINANCIAL DISCLOSURE Financial support: Additional Network support: National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, U.S. Department of Health and Human Services EY14231, EY14229, EY018817. Additional Network support: Genentech: ranibizumab and funding for clinical sites. Allergan: triamcinolone and funding for clinical sites. Additional Author support: Genentech: Grant

Background Phase III trial: Intravitreal Ranibizumab or Triamcinolone Acetonide in Combination With Laser Photocoagulation for Diabetic Macular Edema (LRT for DME)*: Sham intravitreal injection + prompt focal/grid laser group Ranibizumab + prompt focal/grid laser group Ranibizumab + deferred (for at least 24 weeks) focal/grid laser group Triamcinolone acetonide + prompt focal/grid laser group *Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010 June;117(6):1064-1077.e35

Retinopathy Worsening During First Year of Follow-up Sham N = 293 Ranibizumab N = 375 Triamcinolone N = 186 Reported vitreous hemorrhage OR received PRP 8% 3% P Value for comparison with sham -- 0.002 0.02

Background (continued) Other relevant reports: anti-VEGF therapy causing regression of PDR: Retina 2006;26:275-8. Am J Ophthalmol 2006;142:155-8. Am J Ophthalmol 2006;142:685-8. Ophthalmology 2006;113:23-8.

Purpose To further evaluate the effect of intravitreal ranibizumab or intravitreal triamcinolone acetonide on worsening of diabetic retinopathy up to 3 years in the LRT for DME trial AN EXPLORATORY ANALYSIS

Outcome Definition Worsening of retinopathy in eyes with non-PDR at baseline included any of the following: Worsening from non-PDR (Level 53 or lower) to PDR (Level 60 or higher) as determined by reading center grading of standard fundus photographs) Worsening by ≥ 2 levels on ETDRS diabetic retinopathy severity scale on reading center grading of fundus photographs Application of PRP Vitreous hemorrhage Vitrectomy for PDR

Outcome Definition (continued) Worsening of retinopathy in eyes with PDR at baseline included any of the following occurrence: Application of PRP Vitreous hemorrhage Vitrectomy for PDR Too few eyes with fundus photographs at year 2 to evaluate for retinopathy improvement

Statistical Methods Cumulative probability of the outcome at each study visit up to the 3-year visit were calculated using life-table method. Data were included only up to and including the first visit when all investigators were unmasked to primary outcome results of this protocol (since knowledge of 1 year results could bias results, e.g., decision to apply PRP) Proportional hazards model adjusting for baseline visual acuity and baseline retinopathy severity was used to compare treatment groups.

Statistical Methods (continued) The outcome was evaluated in 2 subgroups based on absence or presence of PDR at baseline: Non-PDR (DR severity levels 10, 12, 14, 20, 35, 43, 47, 53, 53E), PDR (DR severity levels 60, 61, 65, 71, 75).   No substantial deviations from proportional hazards assumption were detected.

Baseline Characteristics: Eyes with Non-PDR   Sham +Prompt Laser N = 191 Ranib +Prompt N =119 Ranib +Deferred N = 117 Triam +Prompt N = 111 Women, no. (%) 80 (42%) 54 (45%) 44 (38%) 49 (44%) Age, Median yrs 64 Race White 143 (75%) 88 (74%) 82 (70%) 80 (72%) Black 32 (17%) 21 (18%) 20 (17%) 19 (17%) Hispanic 13 (7%) 9 (8%) 13 (11%) Diabetes Type Type 1 11 (6%) 3 (3%) 5 (5%) Type 2 176 (92%) 113 (95%) 107 (91%) 102 (92%)

Baseline Characteristics: Eyes with PDR   Sham +Prompt Laser N = 78 Ranib +Prompt N = 57 Ranib +Deferred N = 53 Triam +Prompt N =66 Women, no. (%) 31 (40%) 24 (42%) 24 (45%) 30 (45%) Age, Median yrs 60 64 59 Race White 51 (65%) 41 (72%) 42 (79%) 50 (76%) Black 15 (19%) 9 (16%) 4 (8%) 11 (17%) Hispanic 9 (12%) 4 (7%) 5 (9%) 3 (5%) Diabetes Type Type 1 12 (15%) 8 (14%) 6 (11 %) 9 (14%) Type 2 63 (81%) 48 (84%) 46 (87%) 55 (83%) Prior PRP 50 (64%) 42 (74%) 33 (62%) 40 (61%)

Cumulative Probability of Worsening of Retinopathy for Eyes with Non-PDR at Baseline 1-Year 2-Years 3-Years

Cumulative Probability of Worsening of Retinopathy for Eyes with PDR at Baseline 1-Year 2-Years 3-Years

Results (continued) 100 bilateral non-PDR eyes with 1 eye randomized to sham+prompt laser, and 1 eye randomized to ranibizumab (plus prompt or deferred laser) or triamcinolone+laser. Subgroup with systemic control of diabetes and all other systemic (non-study eye) and environmental variables that might affect worsening of retinopathy is the same among eyes assigned to sham+prompt laser treatment and eyes assigned to intravitreal injections Results mirrored non-PDR eyes in entire study group for all 3 injection assignments. Too few bilateral PDR eyes to evaluate (26 eyes).

Cumulative Probability of Worsening of Retinopathy for Bilateral Non-PDR Study Eyes at Baseline 1-Year 2-Years 3-Years

Median (Quartile) # of Injections Eyes with Non-PDR at Baseline   Ranibizumab + prompt laser Ranibizumab + deferred laser Traimcinolone + prompt laser Non-Proliferative Diabetic Retinopathy at Baseline Year 1* 8 (6, 10) 3 (2, 3) Year 2† 2 (0, 3) 2 (0, 5) 1 (0, 2) Year 3§ 1 (0, 4) Total§ 12 (9, 14) 10 (8, 16) 5 (3, 8) *Only included eyes that completed 1-year visit †Only included eyes that completed 2-year visit prior to protocol change §Only included eyes that completed 3-year visit prior to protocol change

Median (Quartile) # of Injections Eyes with PDR at Baseline   Ranibizumab + prompt laser Ranibizumab + deferred laser Traimcinolone + prompt laser Proliferative Diabetic Retinopathy at Baseline Year 1* 9 (6, 11) 10 (8, 11) 3 (2, 4) Year 2† 1 (0, 6) 5 (1, 8) 1 (0, 2) Year 3§ 0 (0, 2) 1 (0, 4) 0 (0, 1) Total§ 11 (7, 19) 17 (9, 22) 5 (3, 7) *Only included eyes that completed 1-year visit †Only included eyes that completed 2-year visit prior to protocol change §Only included eyes that completed 3-year visit prior to protocol change

Conclusions Ranibziumab reduces risk of worsening of retinopathy as reported in other trials evaluating ranibizumab in the treatment of DME Intravitreal triamcinolone also reduces risk of worsening of diabetic retinopathy in eyes with PDR The study protocol was not designed primarily to determine the effect of intravitreal ranibizumab or triamcinolone on preventing worsening of retinopathy

Conclusions (continued) Comparing to reports of RIDE and RISE trial with ranibizumab q4 weeks for at least 2 years, worsening of retinopathy in DRCR.net study was decreased without fixed (required) q4 week ranibizumab Frequency of injections necessary to slow retinopathy worsening requires further study Intravitreal ranibizumab appears to reduce risk of worsening of diabetic retinopathy in eyes with DME and with or without PDR

Conclusions (continued) Further study seems necessary to further assess the risks and benefits of this approach before considering routine use of these treatments to reduce the rates of worsening of diabetic retinopathy

THANK YOU DRCR.net (as of 1/5/12) Active Total Sites (Community & Academic Centers) 125 254 Community Sites 76 (61%) 157 (62%) Investigators 345 891 Other Personnel 889 2748 States 38 48