Patients were recruited from two participating centers (Hospital de Olhos de Araraquara and Department of Ophthalmology at the University of São Paulo, Ribeirão Preto) from August through November 2005. All patients who met the following inclusion criteria were offered study participation: patients with neovascular AMD with logarithm of minimum angle of resolution (logMAR) Early Treatment Diabetic Retinopathy Study (ETDRS) best corrected visual acuity (BCVA) between 0.3 (Snellen equivalent, 20/40) and 1.64 (Snellen equivalent, 20/800
−2) due to subfoveal CNV diagnosed by fluorescein angiography within the prior 96 hours. Diagnosis of neovascular (exudative) AMD was based on the criteria of the International ARM Epidemiologic Study Group.
55 For inclusion in the study, it was mandatory that the CNV caused by AMD extend under the geometric center of the foveal avascular zone and that the neovascular complex demonstrate
some occult CNV component by fluorescein angiography. Lesions characterized angiographically by the presence of only classic CNV could also be included if logMAR ETDRS BCVA was worse than 1.0 (Snellen equivalent, 20/200). The neovascular complex could be of any size, and no restrictions existed with respect to the presence of associated serous pigment epithelial detachment and thick blood. Because of the local unavailability of pegaptanib at the time of this study, patients with the aforementioned lesion and/or BCVA criteria were not eligible for approved treatments, including photodynamic therapy with verteporfin.
Exclusion criteria included: pathologic myopia, defined as a spherical equivalent of −6 D or more, or an ocular axial length of ≥26.5 mm, or retinal abnormalities consistent with pathologic myopia (such as lacquer cracks)
56 ; angioid streaks; traumatic choroidal rupture; peripapillary changes with atrophic or pigmented “punched out” chorioretinal lesions; uveitis; or any other ophthalmic disorder, other than mild cataract, that might affect visual function. Patients were also excluded if they had (1) an allergy to fluorescein; (2) an ocular media opacity that might interfere with visual acuity, assessment of toxicity, or photographic fundus documentation of the macular area; (3) a history of vitrectomy; (4) any major surgery within the prior 6 months or planned within the next 28 days; (5) any history of a thromboembolitic event (including myocardial infarction and/or coronary disease associated with clinical symptoms or cerebral vascular accident); (6) uncontrolled systemic arterial hypertension (according to guidelines of the seventh report of the joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [JNC-7]); (7) an active infection, bleeding disorders, or peptic ulcer disease with bleeding; and (8) known coagulation abnormalities or current use of anticoagulative medication other than aspirin. Of the 51 patients offered study participation, 6 (11.8%) declined because of the estimated endophthalmitis risk of approximately 1%.
A comprehensive ophthalmic evaluation was performed at the participating center responsible for performing the intravitreal bevacizumab treatments. This evaluation included a medical history, blood pressure measurement, ETDRS BCVA testing, color fundus photography, fluorescein angiography, and third-generation OCT evaluation. Best corrected visual acuity was measured according to a standardized refraction protocol using a retroilluminated Lighthouse for the Blind distance visual acuity test chart (using modified ETDRS charts 1, 2, and R). Stereoscopic digital color fundus photography and fluorescein angiography were performed with certified fundus camera systems (UVi-60/EyeQ Pro; Canon, Tokyo, Japan, and TRC-50IA/IMAGEnet; Topcon, Tokyo, Japan). Third–generation OCT evaluation (Stratus Tomographer, model 3000; Carl Zeiss Ophthalmic Systems Inc., Humphrey Division, Dublin, CA) consisted of six linear 6.00-mm high-density (512 A-scans) scans oriented at intervals of 30° and centered on the foveal region.
Fifteen patients were enrolled per dose group, with enrollment in each escalating dose group only if there was no evidence of any dose-limiting toxicity at the lower dose(s)
(Table 1) . The protocol specified that enrollment would be stopped if three or more patients within a dose group experienced dose-limiting toxicity within 7 days after intravitreal injection of bevacizumab. No more than three patients could be enrolled into the study on any day, and no more than six patients could be enrolled into the study per week.