Two-Year Safety and Efficacy of Ranibizumab 0.5 mg in Diabetic Macular Edema Interim Analysis of the RESTORE Extension Study Gabriele E. Lang, MD, 1 András Berta, MD, PhD, 2 Bora M. Eldem, MD, 3 Christian Simader, MD, 4 Dianne Sharp, FRANZCO, 5 Frank G. Holz, MD, 6 Florian Sutter, MD, 7 Ortrud Gerstner, MSc, 8 Paul Mitchell, MD, PhD, 9 on behalf of the RESTORE Extension Study Group* Objective: To evaluate the 2-year safety and efficacy of ranibizumab 0.5 mg in diabetic macular edema (DME). Design: Twenty-four-month, open-label, multicenter, Phase IIIb extension study. Participants: Two hundred forty of 303 patients with visual impairment due to DME who completed the RESTORE core study and entered the extension. Methods: All patients were eligible to receive ranibizumab 0.5 mg pro re nata (PRN) from month 12 (end of core study) to month 36 based on best-corrected visual acuity (BCVA) stability and disease progression retreatment criteria. Patients were also eligible to receive laser PRN according to Early Treatment Diabetic Retinopathy Study guidelines. A preplanned interim analysis was performed at month 24, stratifying by treatment groups as in the RESTORE core study and referred to as prior ranibizumab, ranibizumab plus laser, or laser groups in the extension. Main Outcome Measures: Incidence of ocular and nonocular adverse events (AEs) and mean change in BCVA. Results: Two hundred twenty patients (92%) completed the month 24 visit. Over 2 years, the most frequent ocular serious AE (SAE) and AE were cataract (2.1%) and eye pain (14.6%), respectively. The main nonocular AEs were nasopharyngitis (18.8%) and hypertension (10.4%). There were no cases of endophthalmitis, and the incidences of nonocular SAEs were low. Of the patients entering the extension, 4 deaths were reported in the second year, none of which were related to study drug or procedure. Mean BCVA gain, central retinal thickness (CRT) decrease, and National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) composite score observed at month 12 were maintained at month 24 (prior ranibizumab: þ7.9 letters, e140.6 mm, and 5.6, respectively; prior ranibizumab plus laser: þ6.7 letters, e133.0 mm, and 5.8, respectively), with an average of 3.9 (prior ranibizumab) and 3.5 ranibizumab injections (prior ranibizumab plus laser). In patients treated with laser alone in the core study, the mean BCVA, CRT, and NEI VFQ-25 composite score improved from month 12 to month 24 (þ5.4 letters, e126.6 mm, and 4.3, respectively), with an average of 4.1 ranibizumab injections. Conclusions: Ranibizumab 0.5 mg administered according to prespecified visual stability and disease progression criteria was well tolerated, with no new safety concerns identified over 2 years. Overall, an average of 3.8 ranibizumab injections was sufficient to maintain (prior ranibizumab) or improve (prior laser) BCVA, CRT, and NEI VFQ-25 outcomes through the second year. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2013;120:2004e2012 ª 2013 by the American Academy of Ophthalmology. *Group members listed online in Appendix 1 (available at http://aaojournal.org). Ranibizumab (Lucentis; Novartis Pharma AG, Basel, Switzerland, and Genentech, Inc., South San Francisco, CA) is a humanized monoclonal antibody Fab fragment that binds to and inhibits all isoforms of vascular endothelial growth factor (VEGF)-A. 1 Ranibizumab, specifically designed for in- travitreal use, was approved in European countries in 2007 for the treatment of neovascular age-related macular degener- ation (AMD), in 2010 for the treatment of visual impairment due to diabetic macular edema (DME), and in 2011 for the treatment of visual impairment due to macular edema secondary to retinal vein occlusion. 2 The randomized clinical trial Ranibizumab for Edema of the Macula in Diabetes (READ-2) and that of the Diabetic Retinopathy Clinical Research Network (DRCR.net) along with pivotal studies RESOLVE and RESTORE in >1000 patients have established the efficacy and safety of ranibizumab in DME. 3e8 The READ-2 (N ¼ 126) and DRCR.net (N ¼ 691) studies were the first to demonstrate that ranibizumab alone or 2004 Ó 2013 by the American Academy of Ophthalmology ISSN 0161-6420/13/$ - see front matter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ophtha.2013.02.019