1. The Diabetic Retinopathy Clinical Research Network Effects of Intravitreal Ranibizumab or Triamcinolone on Diabetic Retinopathy Jennifer K. Sun, MD, MPH Sponsored by the National Eye Institute, National Institutes of Health, U.S. Department of Health and Human Services 1

2. 2  840 eyes (693 subjects) 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 DRCR.net Protocol B: Laser vs. Intravitreal Triamcinolone for DME

3. 3  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* Outcome Definition *Based on Reading Center grading of annual fundus photos

4. 4 Cumulative Probability* of Progression of Retinopathy *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) Months 0 4 8 12 16 20 24 28 32 36

5. 5 Treatment Group Comparisons at 1, 2, and 3 Years ComparisonP value* Laser v 1 mg0.71 1 YearLaser v 4 mg0.03 1 mg v 4 mg0.08 Laser v 1 mg0.64 2 YearsLaser v 4 mg0.005 1 mg v 4 mg0.03 Laser v 1 mg0.73 3 YearsLaser v 4 mg0.02 1 mg v 4 mg0.07 *From a proportional hazards model adjusting for baseline VA, history of prior macular photocoagulation, and baseline retinopathy severity ComparisonP value* Laser v 1 mg0.71 1 YearLaser v 4 mg0.03 1 mg v 4 mg0.08 Laser v 1 mg0.64 2 YearsLaser v 4 mg0.005 1 mg v 4 mg0.03 Laser v 1 mg0.73 3 YearsLaser v 4 mg0.02 1 mg v 4 mg0.07

6. 6 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 PDR15%11%8% PRP9%6%5% Vitreous hemorrhage6%9%5% Worsened 2 levels1%3% Combined definition31%29%21% *calculated using the life-table method

7. 7 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 PDR15%11%8% PRP14%10%9% Vitreous hemorrhage16% 11% Worsened 2 levels15%11% Combined definition31%29%21% *calculated using the life-table method

8. 8 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 PDR19%14%16% PRP10%7%6% Vitreous hemorrhage6%12%5% Worsened 2 levels2% 3% Combined definition37%35%30% *calculated using the life-table method

9. 9 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 PDR19%14%16% PRP18%11%12% Vitreous hemorrhage19%20%15% Worsened 2 levels17%15%17% Combined definition37%35%30% *calculated using the life-table method

10. 10 Conclusions  As compared with laser, 4 mg IVT may 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 IVT group Similar risk of development of PDR in ETDRS immediate laser group (11.1%) and deferred laser group (10.8%)  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

11. 11  854 eyes (691 subjects) Sham + Prompt Laser: N = 293 Ranibizumab + Prompt Laser: N = 187 Ranibizumab + Deferred Laser: N = 188 Triamcinolone + Prompt Laser: N = 186  Major Eligibility Criteria: VA ~ 20/32 to 20/320 Definite retinal thickening due to DME involving the center of the macula CSF ≥ 250 microns on OCT DRCR.net Protocol I: Ranibizumab+ Prompt or Deferred Laser or Tiamcinolone + Prompt Laser for DME

12. 12 Progression/Regression in Diabetic Retinopathy at 1 Year by Baseline Severity Change from baseline to 1-year visit* Sham +Prompt Laser Ranibizumab +Prompt Laser or Deferred Laser Triamcinolone +Prompt Laser Baseline Severity: Moderately Severe NPDR or Better N = 150N = 182N = 80 Improved by ≥2 levels4%25% Worsened by ≥2 levels7%3% P value for comparison with Sham P = 0.08P =0.17 *Photos were missing or ungradeable for 61 eyes in the sham+prompt laser group, 72 eyes in the ranibizumab groups, and 33 eyes in the triamcinolone+prompt laser group

13. 13 Progression/Regression in Diabetic Retinopathy at 1 Year by Baseline Severity Change from baseline to 1-year visit* Sham +Prompt Laser Ranibizumab +Prompt Laser or Deferred Laser Triamcinolone +Prompt Laser Baseline Severity: Severe NPDR or worse N = 83N = 121N = 70 Improved by ≥2 levels19%28%13% Worsened by ≥2 levels8%1%3% P value for comparison with Sham P = 0.03P = 0.17 *Photos were missing or ungradeable for 61 eyes in the sham+prompt laser group, 72 eyes in the ranibizumab groups, and 33 eyes in the triamcinolone+prompt laser group

14. Retinopathy Progression During 1 Year of Follow-up 14 Sham N = 293 Ranibizumab N = 375 Triamcinolone N = 186 Reported vitreous hemorrhage OR received PRP 8%3% P Value for comparison with sham --0.0020.02

15. Conclusions  During the first year, eyes assigned to Ranibizumab groups or Triamcinolone group compared with Laser group were: More likely to show retinopathy regressionMore likely to show retinopathy regression Less likely to show retinopathy progressionLess likely to show retinopathy progression Less likely to have a VH or receive PRPLess likely to have a VH or receive PRP  Limitations of this study include large numbers of missing or ungradable photos  Future investigations are needed to definitively demonstrate effect of anti-VEGF therapy or steroid on retinopathy severity 15