Ranibizumab for Treatment of Neovascular Age-Related Macular Degeneration A Phase I/II Multicenter, Controlled, Multidose Study Jeffrey S. Heier, MD, 1 Andrew N. Antoszyk, MD, 2 Peter Reed Pavan, MD, 3 Steven R. Leff, MD, 4 Philip J. Rosenfeld, MD, PhD, 5 Thomas A. Ciulla, MD, 6 Richard F. Dreyer, MD, 7 Ronald C. Gentile, MD, 8 Judy P. Sy, PhD, 9 Gary Hantsbarger, PhD, 9 Naveed Shams, MD, PhD 9 Objective: To assess safety of repeated intravitreal injections of ranibizumab in treating neovascular age- related macular degeneration (AMD), and to assess changes in visual acuity (VA) and AMD lesion characteristics. Design: Multicenter, controlled, open-label, clinical trial. Participants: Sixty-four patients with subfoveal predominantly or minimally classic AMD-related choroidal neovascularization. Methods: In part 1, subjects were randomized to monthly intravitreal ranibizumab for 3 months (4 injections of 0.3 mg or 1 injection of 0.3 mg followed by 3 injections of 0.5 mg; n = 53) or usual care (UC; n = 11). In part 2, subjects could continue their regimen for 3 additional months or cross over to the alternative treatment. Main Outcome Measures: Adverse events (AEs), intraocular pressure (IOP), VA, and lesion characteristics assessed by fluorescein angiography and fundus photography. Results: Of the 64 randomized subjects, 62 completed the 6-month study. Twenty of 25 subjects (80%) randomized to 0.3 mg, and 22 of 28 subjects (79%) randomized to 0.5-mg ranibizumab in part 1 continued on that treatment in part 2; 9 of 11 (82%) subjects randomized to UC in part 1 crossed over to ranibizumab treatment in part 2. The most common AEs with ranibizumab were reversible inflammation and minor injection-site hemorrhages. Serious AEs were iridocyclitis, endophthalmitis, and central retinal vein occlusion (1 subject each). Postinjection, IOP increased transiently in 22.6% of ranibizumab-treated eyes in parts 1 and 2. After 4 ranibizumab injections (day 98), mean ( standard deviation) VA had increased 9.413.3 and 9.117.2 letters in the 0.3- and 0.5-mg groups, respectively, but had decreased 5.19.6 letters with UC. In part 2 (day 210), VA increased from baseline 12.814.7 and 15.014.2 letters in subjects continuing on 0.3 and 0.5 mg, respectively. Visual acuity improved from baseline 15 letters in 26% (day 98) and 45% (day 210) of subjects initially randomized to and continuing on ranibizumab, respectively, and areas of leakage and subretinal fluid decreased. No UC subject had a 15-letter improvement at day 98. Conclusions: Repeated intravitreal injections of ranibizumab had a good safety profile and were associated with improved VA and decreased leakage from choroidal neovascularization in subjects with neovascular AMD. Ophthalmology 2006;113:633– 642 © 2006 by the American Academy of Ophthalmology. Overexpression of vascular endothelial growth factor-A (VEGF-A), a diffusible cytokine that stimulates vascular permeability and angiogenesis, 1 is thought to play a key role in age-related macular degeneration (AMD), 2,3 diabetic ret- inopathy, and other retinal disorders associated with neo- vascularization. 4 Inhibitors of VEGF-A activity may there- fore be useful in the treatment and management of these disorders. 5,6 Originally received: May 24, 2005. Accepted: October 20, 2005. Manuscript no. 2005-448. 1 Ophthalmic Consultants of Boston, Boston, Massachusetts. 2 Charlotte Eye, Ear, Nose, & Throat Associates, Charlotte, North Carolina. 3 University of South Florida College of Medicine, Tampa, Florida. 4 Retina Vitreous Center, New Brunswick, New Jersey. 5 Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida. 6 Midwest Eye Institute, Indianapolis, Indiana. 7 Retina Northwest, Portland, Oregon. 8 New York Eye and Ear Infirmary, New York, New York. 9 Genentech, Inc., South San Francisco, California. Presented in part at: American Society of Retinal Specialists Annual Meeting, August, 2003; New York, New York, and American Academy of Ophthalmology Annual Meeting, November, 2003; Anaheim, California. This study was supported by Genentech, Inc., South San Francisco, California. Financial disclosure/conflict of interest: Drs Heier, Antoszyk, Rosenfeld, and Gentile have served on the Lucentis Advisory Board; Dr Pavan has served as a consultant to Genentech for Lucentis; and Drs Sy, Hantsbarger, and Shams are employees of Genentech, Inc. Reprint requests to Jeffrey S. Heier, MD, Ophthalmic Consultants of Boston, 50 Staniford Street, Suite 600, Boston, MA 02114. 633 © 2006 by the American Academy of Ophthalmology ISSN 0161-6420/06/$–see front matter Published by Elsevier Inc. doi:10.1016/j.ophtha.2005.10.052