A Randomized Trial of Peribulbar Triamcinolone Acetonide with and without Focal Photocoagulation for Mild Diabetic Macular Edema: A Pilot Study

Diabetic Macular Edema (DME)  DME-most common cause of visual loss in patients with diabetes  ETDRS- focal/grid laser reduced 3- year rate of moderate visual loss by 50%  Only 17% of patients with baseline acuity worse than 20/40 experienced moderate visual gain

Treatments for DME  Laser-Standard of care  Tight Glycemic Control  Corticosteroids-intravitreal, peribulbar  Anti-VEGF agents  Vitrectomy

Studies with Peribulbar Steroids DME  Bakri and Kaiser (2005)-63 eyes, 40 mg, VA improved from 20/80 to 20/63 at 12 months  Entezari et. al. (2005)-randomized trial, 64 eyes, 40 mg vs placebo injection, no benefit VA or OCT thick  Tunc et. al. (2005)-randomized trial, 60 pts, focal laser vs laser plus 20 mg, mild benefit in VA (2.5 lines in combined group vs 1.5 lines in laser group)  Cardillo et. al. (2005)-randomized trial, 24 eyes in 12 pts, 40 mg vs IVK (4 mg), short term impt greater in IVK grp (VA impt and decrease OCT thick  Bonini-Filho et. al. (2005)-randomized trial, 36 eyes, 40 mg vs IVK (4 mg), IVK has sign greater impt VA and decrease OCT thick  Ozdek et. al. (2006)-retrospective study, 126 eyes in 95 pts, 20 mg vs IVK (4 mg), both grps had sign impt in VA and decrease OCT thick with greater impt in IVK group Benefits of Peribulbar Steroids are Inconclusive

Potential Advantages of Peribulbar Steroids  Lower incidence of adverse effects compared with intravitreal steroids  Particular interest in eyes with good VA and mild DME  Combination with focal/grid laser may be beneficial

6 Study Design Anterior Peribulbar 20 mg Anterior Peribulbar 20 mg Posterior Peribulbar 40 mg Posterior Peribulbar 40 mg Phase 2 randomized, multi-center clinical trial Major Eligibility Criteria Assessed:  >18 years old  Best corrected electronic-ETDRS letter score ≥ 69 (20/40 or better)  Retinal thickening due to DME on clinical exam  OCT CST≥ 250 microns  IOP < 24 mm Hg with no history of open-angle glaucoma Anterior Peribulbar 20mg+Laser Anterior Peribulbar 20mg+Laser Laser Posterior Peribulbar 40mg+Laser Posterior Peribulbar 40mg+Laser

Protocol Overview 7 4 Weeks 8 Weeks 17 Weeks 34 Weeks 2 Year 1 Year Safety Follow-up to two years  Primary Outcome: change in OCT- Measured central subfield thickening  After the primary outcome treatment was at the investigator’s discretion  Secondary outcome: frequency of retreatment and change in VA  Safety outcomes – elevated IOP, cataract, ptosis, other complications  IOP measured at each visit  Peribulbar injection repeated at if DME was still present

Study Design  One study eye-equal probability of randomization to one of 5 groups  Two study eyes-focal laser in one eye; other eye to one of 4 other treatment groups  Subjects masked to injection type; not to focal laser  VA testers, OCT techs/readers masked; Investigators not masked

Treatment Protocol-Steroid Injection  Standard injection technique  Anesthesia at investigator’s discretion  27-g 5/8 inch needle  Anterior (20 mg)-bulbar conj, lower lid  Posterior (40 mg)- subtenon’s space, ST quad, 10 mm post to limbus

Examination Procedures  BCVA with electronic ETDRS-all visits with standard refraction at baseline and 34 weeks  Clinical exam at each visit  Lens assessment, HbA1c-baseline, 17 wks, 34 weeks  OCT-all visits, University of Wisconsi- Madison Reading Center for grading  EDTRS fundus photos – 7-fields baseline, 8 mo, 24 mo, 3-fields 4 mo, 12 mo  FA-baseline and 4 mo (if part of standard care)

Treatment Protocol-Focal Laser  Modified ETDRS  Laser burns-50 microns, gray intensity  Multiple settings (all completed in single setting)

Results

Baseline Characteristics AnteriorAnterior + laser PosteriorPosterior + laser Laser N=23N=25N=21N=22N=28 Women 22%32%62%18%45% Age 60±863±1358±1264±758±11 White 91%76% 86%82% VA <20/30 26%44%57%45%66% OCT 342 ± ± ± ± ±70

Mean Change in Central Subfield at 34 weeks From Baseline Anterior + laser Posterior Posterior + laser Laser -50 ± ± ± ± ± 62

Mean Central Subfield Thickness (Microns)

Mean Change in Vision at 34 weeks from Baseline Anterior + laser Posterior Posterior + laser Laser -1 ± 5-1 ± 7-3 ± 9-1 ± 9-1 ± 6

Results  No significant differences in primary outcome of central subfoveal thickness  No differences in visual acuity outcomes at 34 weeks.

Safety Phase Visit Completion Visit1 Year2 Year Follow-up rates (not including deaths) 92%76%

Treatments for DME Post 34 Weeks AnteriorPosteriorLaser focal/grid Laser23%25%4% Posterior Peribulbar2%0%8% Anterior Peribulbar0% Intravitreal Steroid9%5%7% Intravitreal Anti-VEGF4%3%5%

Subjects on IOP Lowering Medication or with IOP increase ≥ 10 mmHg VisitAnterior N=46 Posterior N=44 Laser N=42 17 Week9%2%0% 34 Week14%5%2% 1 Year19%8%0% 2 Year20%10%3%

Intraocular Pressure Elevation AnteriorPosteriorLaser 1 YearN = 43N = 38N = 41 IOP Lowering Meds9%0% ≥ 10 mmHg increase*10%8%0% ≥ 30 mmHg at F/U*5% 0% 2 YearN = 35N = 30N = 33 IOP Lowering Meds17%10%3% ≥ 10 mmHg increase*3%0% ≥ 30 mmHg at F/U*3%0% *Subjects not on IOP lowering medication at the visit

Cataract Extraction 1 Year2 Year Treatment Group N%N% Anterior380%3119% Posterior333%2512% Laser380%3010%

Adverse Effects-Ptosis  Anterior – 4/48 (8%)  Posterior – 3/47 (7%)  focal/grid - none

Discussion  No significant effect on central retinal thickness or VA from peribulbar triamcinolone ± laser compared with laser alone  Anterior and posterior subtenon’s injections were similar  Need for retreatment reduced in peribulbar with focal/grid laser  Investigators not masked to treatment group

Discussion  Significant complication rate (elevated IOP, cataract, ptosis) in peribulbar steroid group  Worse for Anterior vs. Posterior  Important to follow-up patients for at least 2 years for adverse side effects

Conclusion  No benefit from peribulbar steroids as a therapy for mild DME  No justification to warrant phase 3 trial  Demonstrates the need for long term studies (2 years) to evaluate potential adverse effects