Intravitreal sirolimus for the treatment of geographic atrophy: results of a phase I/II clinical trial.

PURPOSE: To investigate the safety and effects of intravitreal sirolimus for the potential treatment of geographic atrophy (GA). METHODS: The study was a single-center, open-label, phase I/II trial enrolling six participants with bilateral GA treated with intravitreal sirolimus in only one randomly assigned eye, with the fellow eye as control. The primary efficacy outcome measure was the change in total GA area from baseline on color fundus photography (CFP); secondary outcomes included changes in GA area on fundus autofluorescence (FAF), visual acuity, central retinal thickness (CRT), and macular sensitivity from baseline. RESULTS: Although no systemic adverse events were attributed to treatment, two of six participants had ocular adverse events that were possibly associated. The treated eye of one participant developed abnormal paralesional changes on FAF that were associated with accelerated retinal thinning. This accelerated retinal thinning was also seen in the treated eye of a second participant. Because of concern that these events were associated with treatment, treatment was suspended. Comparisons of treated and fellow eyes for change in visual acuity, change in GA area, and change in CRT showed no evidence of treatment benefit and generally favored the untreated fellow eye. CONCLUSIONS: While paralesional FAF changes and rapid retinal thinning observed are potentially part of the natural course of GA, they may possibly be related to treatment. No general evidence of anatomical or functional benefit was detected in treated eyes. Further data on intravitreal sirolimus for GA treatment will be available from a larger phase II trial. (ClinicalTrials.gov number, NCT01445548.).

Treatment of geographic atrophy with subconjunctival sirolimus: results of a phase I/II clinical trial.

PURPOSE: To investigate the safety and effects of subconjunctival sirolimus, an mTOR inhibitor and immunosuppressive agent, for the treatment of geographic atrophy (GA). METHODS: The study was a single-center, open-label phase II trial, enrolling 11 participants with bilateral GA; eight participants completed 24 months of follow-up. Sirolimus (440 µg) was administered every 3 months as a subconjunctival injection in only one randomly assigned eye in each participant for 24 months. Fellow eyes served as untreated controls. The primary efficacy outcome measure was the change in the total GA area at 24 months. Secondary outcomes included changes in visual acuity, macular sensitivity, central retinal thickness, and total drusen area. RESULTS: The study drug was well tolerated with few symptoms and related adverse events. Study treatment in study eyes was not associated with structural or functional benefits relative to the control fellow eyes. At month 24, mean GA area increased by 54.5% and 39.7% in study and fellow eyes, respectively (P = 0.41), whereas mean visual acuity decreased by 21.0 letters and 3.0 letters in study and fellow eyes, respectively (P = 0.03). Substantial differences in mean changes in drusen area, central retinal thickness, and macular sensitivity were not detected for all analysis time points up to 24 months. CONCLUSIONS: Repeated subconjunctival sirolimus was well-tolerated in patients with GA, although no positive anatomic or functional effects were identified. Subconjunctival sirolimus may not be beneficial in the prevention of GA progression, and may potentially be associated with effects detrimental to visual acuity. (ClinicalTrials.gov number, NCT00766649.).

Central visual function and the NEI-VFQ-25 near and distance activities subscale scores in people with type 1 and 2 diabetes.

PURPOSE: To investigate relationships between clinical measures of central visual function and NEI-VFQ-25 Near and Distance Activities subscales in patients with diabetic retinopathy. DESIGN: Clinic-based, cross-sectional, observational study. METHODS: The NEI-VFQ-25 was administered to 170 people with type 1 or 2 diabetes before an ocular examination that included visual acuity, contrast sensitivity, and central visual fields. Multiple linear regression and exact multiple logistic regression were used to assess the relationship between poor acuity (<69 letters), poor contrast sensitivity (<1.5 log units), and abnormal visual fields (mean deviation < or = -5dB) and NEI-VFQ-25 subscale scores. RESULTS: Final multivariable linear models explained a beta = 4.7 letter difference (P < or = .001) for each 25-point Near Activities subscale score difference. Similar effects were observed for the Distance Activities subscale, although the magnitudes of regression and partial correlation coefficients were lower (beta = 3.3 letters, P < or = .01). Final logistic regression models on abnormal clinical categories of central visual function demonstrated relationships only with the Near Activities subscale. For a 1-point change in Near Activities subscale score, the odds of obtaining a poor score for visual acuity, central visual fields, and contrast sensitivity changed by 0.08 (P < or = .001), 0.07 (P < or = .05), and 0.12 (P < or = .001), respectively. CONCLUSIONS: NEI-VFQ-25 Near and Distance Activities subscales demonstrate utility as measures of central visual function in persons with type 1 or 2 diabetes. Low scores on the NEI-VFQ-25 may reflect poor central visual fields and contrast sensitivity in addition to poor visual acuity.