Macular Degeneration: Quinlan E

Shah SM, Tatlipinar S, Quinlan E, Sung JU, Tabandeh H, Nguyen QD, Fahmy AS, Zimmer-Galler I, Symons RC, Cedarbaum JM, Campochiaro PA. · Retinal Imaging Research and Reading Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA. · Invest Ophthalmol Vis Sci. · Pubmed #17122137 links to  free full text

Abstract: PURPOSE: In this study, the authors sought to develop and characterize techniques for measuring changes in choroidal neovascularization (CNV) lesion size and fluorescence over time for quantitative analysis of fluorescein angiograms. METHODS: Initial assessment of the quantitative technique was made by retrospectively analyzing digital fluorescein angiograms taken before and 3 months after photodynamic therapy (PDT) for CNV (6 patients, group 1). The method was then applied prospectively to digital fluorescein angiograms (baseline and day 71) obtained on 12 patients taking part in a clinical trial investigating the effect of vascular endothelial growth factor (VEGF) Trap in CNV (group 2). Two masked observers, with the use of image processing, measured the area of hyperfluorescence and fluorescence intensity above background. Values for each image were plotted against time after dye injection to generate curves, and each area under the curve (AUC) was calculated. RESULTS: The physician who treated the patients in group 1 judged the condition of three patients to be improved and of three to be worse 3 months after PDT. Masked retrospective grading of fluorescein angiograms showed an 11% decrease in AUC for fluorescence area and a 32% decrease in AUC for fluorescence intensity in the three patients whose conditions clinically improved but increases of 131% and 292% in the three patients whose conditions clinically worsened. In group 2, a 38% decrease in AUC for fluorescence intensity and a 19% decrease in AUC for fluorescence area were observed in patients who received VEGF Trap compared with increases of 66% (P = 0.004, Mann-Whitney U test) and 21% (P = 0.07) for patients who received placebo. Macular volume decreased by 11% in VEGF Trap-treated patients and increased by 10% in placebo-treated patients (P = 0.03). CONCLUSIONS: This study reports a technique for analysis of change in fluorescence area and intensity over time during fluorescein angiography (FA) using a continuous scale and its application in a clinical setting and a clinical trial. Compared with previous techniques making use of categorical scales, this approach provides an advantage for evaluating responses to treatment that may improve the value of FA as an outcome measure in clinical trials.

Nguyen QD, Tatlipinar S, Shah SM, Haller JA, Quinlan E, Sung J, Zimmer-Galler I, Do DV, Campochiaro PA. · The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA. · Am J Ophthalmol. · Pubmed #17046701 No free full text.

Abstract: PURPOSE: The role of vascular endothelial growth factor (VEGF) in diabetic macular edema (DME) was tested with ranibizumab, a specific antagonist of VEGF. DESIGN: A nonrandomized clinical trial. METHODS: Ten patients with chronic DME received intraocular injections of 0.5 mg of ranibizumab at baseline and at one, two, four, and six months. The primary outcome was change in foveal thickness between baseline and seven months, and the secondary outcome measures were changes from baseline in visual acuity and macular volume. RESULTS: Mean values at baseline were 503 microm for foveal thickness, 9.22 mm3 for macular volume, and 28.1 letters (20/80) read on an Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart. At seven months (one month after the fifth injection), the mean foveal thickness was 257 microm, which was a reduction of 246 microm (85% of the excess foveal thickness present at baseline; P = .005 by Wilcoxon signed-rank test for likelihood that this change is due to ranibizumab rather than chance). The macular volume was 7.47 mm3, which was a reduction of 1.75 mm3 (77% of the excess macular volume at baseline; P = .009). Mean visual acuity was 40.4 letters (20/40), which was an improvement of 12.3 letters (P = .005). The injections were well-tolerated with no ocular or systemic adverse events. CONCLUSION: Intraocular injections of ranibizumab significantly reduced foveal thickness and improved visual acuity in 10 patients with DME, which demonstrated that VEGF is an important therapeutic target for DME. A randomized, controlled, double-masked trial is needed to test whether intraocular injections of ranibizumab provide long-term benefit to patients with DME.

Nguyen QD, Shah SM, Hafiz G, Quinlan E, Sung J, Chu K, Cedarbaum JM, Campochiaro PA, Anonymous00330. · Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland MD 21287-9277, USA. · Ophthalmology. · Pubmed #16876249 No free full text.

Abstract: OBJECTIVES: To assess the safety, pharmacokinetics, and biological activity of IV administration of vascular endothelial growth factor trap (VEGF Trap), a recombinant protein containing the binding domains of VEGF receptors 1 and 2, in patients with neovascular age-related macular degeneration (AMD). DESIGN: Randomized, multicenter, placebo-controlled clinical trial. PARTICIPANTS: Twenty-five patients were enrolled (11 male, 14 female); 19 received VEGF Trap (0.3 [n = 7], 1.0 [n = 7], or 3.0 mg/kg [n = 5]), and 6 received a placebo. METHODS: Patients were randomized to receive a placebo or 0.3-, 1.0-, or 3.0-mg/kg VEGF Trap--a single IV dose followed by a 4-week observation period and then 3 doses 2 weeks apart. MAIN OUTCOME MEASURES: Safety and biological activity, including change in excess retinal thickness and volume assessed by optical coherence tomography and visual acuity (VA) measured by the Early Treatment Diabetic Retinopathy Study protocol. RESULTS: The majority of adverse events attributable to VEGF Trap were mild to moderate in severity, but 2 of 5 patients treated with 3.0 mg/kg experienced dose-limiting toxicity (1 with grade 4 hypertension and 1 with grade 2 proteinuria); therefore, all patients in the 3.0 mg/kg-dose group were withdrawn from the study. The mean percent changes in excess retinal thickness were -12%, -10%, -66%, and -60%, respectively, for the placebo and 0.3-, 1.0-, and 3.0-mg/kg groups at day 15 (P<0.02 by analysis of covariance [ANCOVA]) and -5.6%, +47.1%, and -63.3% for the placebo and 0.3- and 1.0-mg/kg groups at day 71 (P<0.02, ANCOVA). A significant change in VA was not noted in this small study. CONCLUSIONS: The maximum tolerated dose of IV VEGF Trap in this study population was 1.0 mg/kg. This dose resulted in elimination of about 60% of excess retinal thickness after either single or multiple administrations. Alternative routes of delivery to increase the therapeutic window are being explored.

Campochiaro PA, Hafiz G, Shah SM, Nguyen QD, Ying H, Do DV, Quinlan E, Zimmer-Galler I, Haller JA, Solomon SD, Sung JU, Hadi Y, Janjua KA, Jawed N, Choy DF, Arron JR. · Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA. · Mol Ther. · Pubmed #18362932 No free full text.

Abstract: Macular edema is a major cause of vision loss in patients with central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO). It is not clear how much of the edema is due to hydrodynamic changes from the obstruction and how much is due to chemical mediators. Patients with macular edema due to CRVO (n = 20) or BRVO (n = 20) were randomized to receive three monthly injections of 0.3 or 0.5 mg of ranibizumab. At the primary endpoint, month 3, the median improvement in letters read at 4 m was 17 in the 0.3-mg group and 14 in the 0.5-mg group for CRVO, and 10 and 18, respectively for the BRVO group. Optical coherence tomography (OCT) showed that compared to injections of 0.3 mg, injections of 0.5 mg of ranibizumab tended to cause more rapid reductions of central retinal thickening that lasted longer between injections, but in 3 months, excess central retinal thickening which is a quantitative assessment of the macular edema, was reduced by approximately 90% in all four treatment groups. There was no correlation between the amount of improvement and duration of disease or patient age at baseline, but there was some correlation between the aqueous vascular endothelial growth factor (VEGF) level at baseline and amount of improvement. These data indicate that excess production of VEGF in the retinas of patients with CRVO or BRVO is a major contributor to macular edema and suggest that additional studies investigating the efficacy of intraocular injections of ranibizumab are needed.