PMID- 24491642 OWN - NLM STAT- MEDLINE DCOM- 20140711 LR - 20220409 IS - 1549-4713 (Electronic) IS - 0161-6420 (Linking) VI - 121 IP - 5 DP - 2014 May TI - Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE extension study. PG - 1045-53 LID - S0161-6420(13)01167-6 [pii] LID - 10.1016/j.ophtha.2013.11.041 [doi] AB - OBJECTIVE: To evaluate long-term efficacy and safety profiles during 3 years of individualized ranibizumab treatment in patients with visual impairment due to diabetic macular edema (DME). DESIGN: Phase IIIb, multicenter, 12-month, randomized core study and 24-month open-label extension study. PARTICIPANTS: Of the 303 patients who completed the randomized RESTORE 12-month core study, 240 entered the extension study. METHODS: In the extension study, patients were eligible to receive individualized ranibizumab treatment as of month 12 guided by best-corrected visual acuity (BCVA) and disease progression criteria at the investigators' discretion. Concomitant laser treatment was allowed according to the Early Treatment Diabetic Retinopathy Study guidelines. Based on the treatments received in the core study, the extension study groups were referred to as prior ranibizumab, prior ranibizumab + laser, and laser. MAIN OUTCOME MEASURES: Change in BCVA and incidence of ocular and nonocular adverse events (AEs) over 3 years. RESULTS: Overall, 208 patients (86.7%) completed the extension study. In patients treated with ranibizumab during the core study, consecutive individualized ranibizumab treatment during the extension study led to an overall maintenance of BCVA and central retinal subfield thickness (CRST) observed at month 12 over the 2-year extension study (+8.0 letters, -142.1 mum [prior ranibizumab] and +6.7 letters, -145.9 mum [prior ranibizumab + laser] from baseline at month 36) with a median of 6.0 injections (mean, 6.8 injections; prior ranibizumab) and 4.0 (mean, 6.0 injections; prior ranibizumab + laser). In the prior laser group, a progressive BCVA improvement (+6.0 letters) and CRST reduction (-142.7 mum) at month 36 were observed after allowing ranibizumab during the extension study, with a median of 4.0 injections (mean, 6.5 injections) from months 12 to 35. Patients in all 3 treatment groups received a mean of <3 injections in the final year. No cases of endophthalmitis, retinal tear, or retinal detachment were reported. The most frequently reported ocular and nonocular adverse effects over 3 years were cataract (16.3%) and nasopharyngitis (23.3%). Eight deaths were reported during the extension study, but none were suspected to be related to the study drug/procedure. CONCLUSIONS: Ranibizumab was effective in improving and maintaining BCVA and CRST outcomes with a progressively declining number of injections over 3 years of individualized dosing. Ranibizumab was generally well tolerated with no new safety concerns over 3 years. CI - Copyright (c) 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved. FAU - Schmidt-Erfurth, Ursula AU - Schmidt-Erfurth U AD - Department of Ophthalmology, Medical University Vienna, Vienna, Austria. Electronic address: ursula.schmidt-erfurth@meduniwien.ac.at. FAU - Lang, Gabriele E AU - Lang GE AD - Division of Medical Retina and Laser Surgery, Department of Ophthalmology, University Eye Hospital Ulm, Ulm, Germany. FAU - Holz, Frank G AU - Holz FG AD - Department of Ophthalmology, University of Bonn, Bonn, Germany. FAU - Schlingemann, Reinier O AU - Schlingemann RO AD - Medical Retina Unit and Ocular Angiogenesis Group, Department of Ophthalmology, Academic Medical Center, Amsterdam, The Netherlands; Netherlands Institute for Neuroscience (NIN), Royal Academy of Sciences (KNAW), Amsterdam, The Netherlands. FAU - Lanzetta, Paolo AU - Lanzetta P AD - Department of Ophthalmology, University of Udine, Udine, Italy; Istituto Europeo di Microchirurgia Oculare (IEMO), Udine, Italy. FAU - Massin, Pascale AU - Massin P AD - Assistance Publique des Hopitaux de Paris, Universite Paris Diderot, Ophthalmology Department, Hopital Lariboisiere, Paris, France. FAU - Gerstner, Ortrud AU - Gerstner O AD - Novartis Pharma AG, Basel, Switzerland. FAU - Bouazza, Abdelkader Si AU - Bouazza AS AD - Novartis Pharma AG, Basel, Switzerland. FAU - Shen, Haige AU - Shen H AD - Beijing Novartis Pharmaceuticals Co., Ltd., Shanghai, China. FAU - Osborne, Aaron AU - Osborne A AD - Novartis Pharma AG, Basel, Switzerland. FAU - Mitchell, Paul AU - Mitchell P AD - Centre for Vision Research (Westmead Millennium Institute), University of Sydney, Sydney, Australia. CN - RESTORE Extension Study Group LA - eng SI - ClinicalTrials.gov/NCT00906464 PT - Clinical Trial, Phase III PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20140201 PL - United States TA - Ophthalmology JT - Ophthalmology JID - 7802443 RN - 0 (Angiogenesis Inhibitors) RN - 0 (Antibodies, Monoclonal, Humanized) RN - ZL1R02VT79 (Ranibizumab) SB - IM MH - Angiogenesis Inhibitors/adverse effects/*therapeutic use MH - Antibodies, Monoclonal, Humanized/adverse effects/*therapeutic use MH - Diabetes Mellitus, Type 1/complications MH - Diabetes Mellitus, Type 2/complications MH - Diabetic Retinopathy/*drug therapy/physiopathology MH - Female MH - Humans MH - Intravitreal Injections MH - Laser Coagulation MH - Macular Edema/*drug therapy/physiopathology MH - Male MH - Middle Aged MH - Precision Medicine MH - Ranibizumab MH - Retina/pathology MH - Retreatment MH - Sickness Impact Profile MH - Surveys and Questionnaires MH - Time Factors MH - Treatment Outcome MH - Visual Acuity/physiology FIR - Papp, Andras IR - Papp A FIR - Seres, Andras IR - Seres A FIR - Berta, Andras IR - Berta A FIR - Pesztenlehrer, Norbert IR - Pesztenlehrer N FIR - Weber, Michel IR - Weber M FIR - Creuzot- Garcher, Catherine IR - Creuzot- Garcher C FIR - Emmerich, Karl-Heinz IR - Emmerich KH FIR - Engelmann, Katrin IR - Engelmann K FIR - Hansen, Lutz IR - Hansen L FIR - Kellner, Ulrich IR - Kellner U FIR - Kirchhof, Bernd IR - Kirchhof B FIR - Mohr, Andreas IR - Mohr A FIR - Spital, Georg IR - Spital G FIR - Wiedemann, Peter IR - Wiedemann P FIR - Schrage, Norbert IR - Schrage N FIR - Menchini, Ugo IR - Menchini U FIR - Balestrazzi, Emilio IR - Balestrazzi E FIR - Noci, Nicola Delle IR - Noci ND FIR - Ciriano, J P Martinez IR - Ciriano JP FIR - Kleverling, Bert Jeroen IR - Kleverling BJ FIR - Van Calster, Joachim IR - Van Calster J FIR - Devriendt, Marlene IR - Devriendt M FIR - Kurz-Levin, Malaika IR - Kurz-Levin M FIR - Jurgens, Inga IR - Jurgens I FIR - Schneider, Ulrike IR - Schneider U FIR - Garweg, Justus IR - Garweg J FIR - Tappeiner, Christoph IR - Tappeiner C FIR - Gerding, Heinrich IR - Gerding H FIR - Kloos, Patrik IR - Kloos P FIR - Eldem, Bora IR - Eldem B FIR - Sobaci, Gungor IR - Sobaci G FIR - Kapran, Ziya IR - Kapran Z FIR - Ergin, Mehmet IR - Ergin M FIR - Hasanreisoglu, Berati IR - Hasanreisoglu B FIR - Arumi, Josep Garcia IR - Arumi JG FIR - Ulla, Francisco Gomez IR - Ulla FG FIR - Imaz, Ramon Torres IR - Imaz RT FIR - Cervera, Enrique IR - Cervera E FIR - Civera, Alfredo Adan IR - Civera AA FIR - Moreno, Jose Ruiz IR - Moreno JR FIR - Gillies, Mark IR - Gillies M FIR - Lim, Lyndell IR - Lim L FIR - Vote, Brendan IR - Vote B FIR - Sharp, Dianne IR - Sharp D FIR - Gonder, John IR - Gonder J FIR - Kertes, Peter IR - Kertes P FIR - Maberley, David IR - Maberley D FIR - Boyd, Shelley IR - Boyd S FIR - Olivier, Sebastien IR - Olivier S FIR - Bailey, Clare IR - Bailey C EDAT- 2014/02/05 06:00 MHDA- 2014/07/12 06:00 CRDT- 2014/02/05 06:00 PHST- 2013/07/23 00:00 [received] PHST- 2013/11/19 00:00 [revised] PHST- 2013/11/26 00:00 [accepted] PHST- 2014/02/05 06:00 [entrez] PHST- 2014/02/05 06:00 [pubmed] PHST- 2014/07/12 06:00 [medline] AID - S0161-6420(13)01167-6 [pii] AID - 10.1016/j.ophtha.2013.11.041 [doi] PST - ppublish SO - Ophthalmology. 2014 May;121(5):1045-53. doi: 10.1016/j.ophtha.2013.11.041. Epub 2014 Feb 1.