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Phase 2 Evaluation of Intravitreal Bevacizumab for DME

Phase 2 Evaluation of Intravitreal Bevacizumab for DME. Sponsored by the National Eye Institute, National Institutes of Health, U.S. Department of Health and Human Services. Study Objectives.

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Phase 2 Evaluation of Intravitreal Bevacizumab for DME

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  1. Phase 2 Evaluation of IntravitrealBevacizumab for DME Sponsored by the National Eye Institute, National Institutes of Health, U.S. Department of Health and Human Services.

  2. Study Objectives • Assess the dose and dose interval related effects of intravitreal bevacizumab on central retinal thickness and VA in subjects with DME • Assess the effects of intravitreal bevacizumab combined with focal photocoagulation in DME • Assess the safety of intravitreal bevacizumab in subjects with DME

  3. 5 Treatment Groups Laser (0) Focal photocoagulation at baseline Bev 1.25 (0,6) 1.25 mg intravitreal bevacizumab at baseline and at 6 wks Bev 2.5 (0,6) 2.5 mg intravitreal bevacizumab at baseline and at 6 wks Bev 1.25 (0) 1.25 mg intravitreal bevacizumab at baseline with sham injection at 6 wks Bev 1.25 (0,6) + Laser (3) 1.25 mg intravitreal bevacizumab at baseline, focal photocoagulation at 3 wks, and 1.25 mg intravitreal bevacizumab at 6 wks

  4. Efficacy Outcomes Central subfield thickness on OCT

  5. Efficacy Outcomes Electronic-ETDRS Visual Acuity (EVA)

  6. Study Phases • Weeks 0-12: no other treatment was to be given for DME in the study eye (study visits every 3 weeks) • Weeks 13-24: treatment depended on response to treatment given during the first 12 wks (study visits every 6 weeks) • After 24 weeks: follow-up for safety (study visits at 41 and at 70 weeks)

  7. Study Results • Enrollment completed in 2 months • 121 eyes of 121 subjects randomized • 109 eyes included in efficacy analyses • Exclusions: • 5 baseline CSF <275 um • 1 nongradable baseline OCT • 1 hx of laser 3 mos prior to randomization • 2 CNV with diabetic retinopathy • 2 no follow-up • 1 endophthalmitis • 19-24 subjects in each group

  8. Baseline Characteristics • Median age: 65 yrs • Women: 39% • Caucasian: 76% • Diabetes type: 1 – 7%, 2 – 93% • Median duration of diabetes: 17 yrs • No prior DME treatment: 31%

  9. Baseline Characteristics • Visual Acuity Median (quartiles) letter score: 64 (71,56) approx. Snellen equivalent 20/50 (20/40,20/80) • Central Subfield Thickness Median (quartiles) microns : 411 (334, 505)

  10. 1. Does 1.25 mg bevacizumab have a positive effect on DME? • Compare Laser (0) vs. Bevacizumab 1.25 mg (0,6) at 3, 6, 9, and 12 weeks

  11. OCT Central Subfield ThicknessMedian Change (microns) from Baseline

  12. OCT Central Subfield Thickness <250 microns or >50% Decrease in Thickening

  13. Visual Acuity Letter Score Median Change from Baseline

  14. Visual Acuity Letter ScoreIncrease > 10 from Baseline

  15. 2. Does 2.5 mg bevacizumab have a positive effect on DME? • Compare Laser (0) vs. Bevacizumab 2.5 mg (0,6) at 3, 6, 9, and 12 weeks

  16. OCT Central Subfield ThicknessMedian Change (microns) from Baseline

  17. OCT Central Subfield Thickness <250 microns or >50% Decrease in Thickening

  18. Visual Acuity Letter Score Median Change from Baseline

  19. Visual Acuity Letter ScoreIncrease > 10 from Baseline

  20. 3. Does 2.5 mg bevacizumab produce a greater short-term reduction in DME than 1.25 mg? • Compare Bevacizumab 1.25 mg (0,6) vs. Bevacizumab 2.5 mg (0,6) at 3, 6, 9, and 12 weeks

  21. OCT Central Subfield ThicknessMedian Change (microns) from Baseline

  22. OCT Central Subfield Thickness <250 microns or >50% Decrease in Thickening

  23. Visual Acuity Letter Score Median Change from Baseline

  24. Visual Acuity Letter Score Increase> 10 from Baseline

  25. 4. What is the duration of effect of the initial injection? • Among eyes with a decrease in CSF thickness of >11% (the reliability limit for real change) from baseline to 3 weeks, evaluate change from 3 weeks to 6 weeks

  26. Duration of Initial Injection Pooling 1.25 mg Groups [Bev 1.25 (0,6) and Bev 1.25 (0)]

  27. Duration of Initial InjectionBevacizumab 2.5 mg (0,6) Group

  28. 5. What is the duration of effect of the second injection? • Among eyes with a decrease in CSF thickness of at least 11% from 6w to 9w, evaluate change from 9 weeks to 12 weeks

  29. Duration of Second InjectionBevacizumab 1.25 mg (0,6) Group

  30. Duration of Second InjectionBevacizumab 2.5 mg (0,6) Group

  31. 6. Is there a greater effect with bevacizumab followed by focal laser compared with bevacizumab alone? • Compare (at 12 weeks) bevacizumab 1.25 mg alone vs. bevacizumab 1.25 mg plus laser

  32. Effect of Combining Focal Photocoagulation with Bevacizumab at 12 Weeks

  33. Subgroup Analyses at 3 Weekspooling all bevacizumab groups

  34. Subgroup Analyses at 3 Weekspooling all bevacizumab groups

  35. Subgroup Analyses at 3 Weeks pooling all bevacizumab groups

  36. Subgroup Analyses at 3 Weekspooling all bevacizumab groups • Change in CSF thickness and change in VA from baseline to 3 weeks did not significantly vary according to: • Age, gender, baseline retinopathy severity, baseline clinical characterization of DME as focal or diffuse

  37. Outcome during weeks 13-24 • Among eyes meeting deferral criteria at 12 weeks, deferral criteria were also met at 18 weeks in: • 2 of 4 eyes in Laser (0) Group • 5 of 7 eyes in Bev 1.25 (0,6) Group • 1 of 8 eyes in Bev 2.5 (0,6) Group • 2 of 3 eyes in Bev 1.25 (0) Group • 3 of 5 eyes in Bev 1.25 (0,6) + Laser (3) Group

  38. Ocular Adverse Events • 1 eye in the Bev 1.25 (0,6) + Laser (3) Group with endophthalmitis

  39. Cardiovascular Adverse Events • Fatal MI at 16 wks (1.25 inj at 0, 6 wks) • Non-fatal MI at 1 wk (2.5 inj at 0 wks) • CHF at 12 wks (1.25 inj at 0, 7 wks)

  40. Other Systemic Adverse Events • Of the 107 subjects treated with bevacizumab • Death due to cancer (N=1) • Peripheral vascular disease (N=1) • Syncope (N=1) • Elevated BP (N=3) • Worsening renal function (N=3) • Anemia (N=4) • Of the 12 subjects receiving only focal photocoagulation • Peripheral vascular disease (N=2) • Elevated BP (N=1) • Worsening renal function (N=1) • Anemia (N=1)

  41. Comparison of APTC events in Protocols H and B (IVT Study) • B: 11 of 693 (1.6%) subjects reported an APTC event over the first 24 weeks of follow-up • H: 2 of 107 (1.9%) subjects treated with bevacizumab reported an APTC event during the first 24 weeks of follow-up

  42. Conclusions • There is an apparent effect of 1.25 mg and 2.5 mg of bevacizumab when compared with focal photocoagulation, although the effect appears to be modest • It does not appear that 2.5 mg of bevacizumab has an appreciably larger effect on DME than 1.25 mg

  43. Conclusions • Injection intervals of 4 weeks are probably more appropriate than intervals of 6 weeks 4. A study arm with combination treatment (bevacizumab plus focal photocoagulation) is feasible from a logistical standpoint

  44. Conclusions The study was designed to evaluate short term effect. No conclusions should be made regarding clinical benefit. A large phase 3 randomized clinical trial is needed for this purpose.

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