Dosing Regimens of Intravitreal Aflibercept for Diabetic Macular Edema Beyond the First Year: VIOLET, a Prospective Randomized Trial
Justus G. Garweg, Jana Štefaničková, Carel B. Hoyng, Tobias Niesen, Thomas Schmelter, Sérgio Leal, Sobha Sivaprasad, the VIOLET Investigators, Ursula Schmidt‐Erfurth, Andreas Wedrich, Fareed Ali, David R. Chow, John D. Dickinson, Michel Giunta, Jesia Hasan, Jaroslava Dusova, Jan Hamouz, Laurent Kodjikian, Eric H. Souied, Claudia Dahlke, Karl-Heinz Emmerich, Nicolas Feltgen, Frank G. Holz, Frank Koch, Dirk Sandner, Walter Sekundo, Ágnes Kerényi, András Papp, András Seres, Attila Vajas, Balázs Varsányi, Francesco Bandello, Francesco Boscia, Chiara M. Eandi, Edoardo Midena, Massimo Nicolò, Enrico Peiretti, Federico Ricci, Francesco Viola, Gianni Virgili, Vilma Jūratė Balčiūnienė, Andrius Cimbalas, Ewa Graczyńska, Andrzej Grzybowski, J Kałuzný, Zofia Michalewska, Dorota Raczyńska, Marek Rękas, Bożena Romanowska‐Dixon, Sławomir Teper, Tomasz Żarnowski, Miguel Amaro, João Paulo Castro Sousa, Manuel Falcão, João Figueira, Sara Vaz-Pereira, Mikulas Alexik, Monika Gajdošová, Gabriela Pavlovičová, Jana Štefaničková, K. Struharova, Alfredo Adán, L. Arias Barquet, Anniken Burés, Carlos Cava Valenciano, Enrique Cervera, Laura Sararols, Justus G. Garweg, Ioannis N. Petropoulos, Andrew Lotery, Martin McKibbin, Sobha Sivaprasad, Deepali Varma
Abstract
INTRODUCTION: The purpose was to compare two flexible regimens of intravitreal aflibercept (IVT-AFL) with fixed dosing every 8 weeks, beyond the first year of treatment, in patients with diabetic macular edema (DME). VIOLET was a 100-week, randomized, Phase IIIb, non-inferiority study in patients with center-involving DME previously treated with IVT-AFL for ≥ 1 year according to the European label. METHODS: Patients received an initial dose of IVT-AFL at study baseline and were randomly assigned (1:1:1) to treat-and-extend (T&E), pro re nata (PRN), or fixed regimens. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline (randomization) to Week 52. RESULTS: Full analysis set comprised 458 patients (baseline mean BCVA: 72.5, 71.0, and 72.7 letters in the T&E, PRN, and fixed-dose groups, respectively). Patients received a mean (min-max) of 10.0 (2-14; T&E), 11.5 (1-25; PRN), and 12.3 (3-13; fixed) injections over 100 weeks, with 13.3 (4-23), 25.0 (3-29), and 16.1 (5-25) clinic visits, respectively. At Week 52, mean (± standard deviation) BCVA changes from baseline were + 0.5 ± 6.7 (T&E), + 1.7 ± 6.8 (PRN), and + 0.4 ± 6.7 (fixed-dosing) letters (least squares mean difference [95% confidence interval]: T&E 0.01 [- 1.46, 1.47] and PRN 0.95 (- 0.52, 2.42) letters versus fixed dosing; p < 0.0001 for both non-inferiority tests [4-letter margin]). The IVT-AFL safety profile was consistent with previous studies. CONCLUSION: The treatment burden associated with intravitreal injections for DME is lowest with T&E regimens, but there are a range of flexible IVT-AFL dosing regimens, allowing physicians to adopt an individualized treatment plan. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02818998.