Dosing Regimens of Intravitreal Aflibercept for Diabetic Macular Edema Beyond the First Year: VIOLET, a Prospective Randomized Trial

Justus G Garweg, Jana Štefanickova, Carel Hoyng, Tobias Niesen, Thomas Schmelter, Sergio Leal, Sobha Sivaprasad, VIOLET Investigators, Ursula Schmidt-Erfurth, Andreas Wedrich, Fareed Ali, David Chow, John Dickinson, Michel Giunta, Jesia Hasan, Jaroslava Dusova, Jan Hamouz, Laurent Kodjikian, Eric Souied, Claudia Dahlke, Karl-Heinz Emmerich, Nicolas Feltgen, Frank Holz, Frank Koch, Dirk Sandner, Walter Sekundo, Agnes Kerenyi, Andras Papp, Andras Seres, Attila Vajas, Balazs Varsanyi, Francesco Bandello, Francesco Boscia, Chiara Eandi, Edoardo Midena, Massimo Nicolo, Enrico Peiretti, Federico Ricci, Francesco Viola, Gianni Virgili, Vilma-Jurate Balciuniene, Andrius Cimbalas, Ewa Graczynska, Andrzej Grzybowski, Jakub Kaluzny, Zofia Michalewska, Dorota Raczynska, Marek Rekas, Bozena Romanowska-Dixon, Slawomir Teper, Tomasz Zarnowski, Miguel Amaro, João Castro Sousa, Manuel Falcão, João Pereira Figueira, Sara Vaz-Pereira, Mikulas Alexik, Monika Gajdosova, Gabriela Pavlovicova, Jana Štefanickova, Katarina Struharova, Alfredo Adan, Lluis Arias Barquet, Anniken Bures, Carlos Cava Valenciano, Enrique Cervera, Laura Sararols, Justus Garweg, Ioannis Petropoulos, Andrew Lotery, Martin McKibbin, Sobha Sivaprasad, Deepali Varma, Justus G Garweg, Jana Štefanickova, Carel Hoyng, Tobias Niesen, Thomas Schmelter, Sergio Leal, Sobha Sivaprasad, VIOLET Investigators, Ursula Schmidt-Erfurth, Andreas Wedrich, Fareed Ali, David Chow, John Dickinson, Michel Giunta, Jesia Hasan, Jaroslava Dusova, Jan Hamouz, Laurent Kodjikian, Eric Souied, Claudia Dahlke, Karl-Heinz Emmerich, Nicolas Feltgen, Frank Holz, Frank Koch, Dirk Sandner, Walter Sekundo, Agnes Kerenyi, Andras Papp, Andras Seres, Attila Vajas, Balazs Varsanyi, Francesco Bandello, Francesco Boscia, Chiara Eandi, Edoardo Midena, Massimo Nicolo, Enrico Peiretti, Federico Ricci, Francesco Viola, Gianni Virgili, Vilma-Jurate Balciuniene, Andrius Cimbalas, Ewa Graczynska, Andrzej Grzybowski, Jakub Kaluzny, Zofia Michalewska, Dorota Raczynska, Marek Rekas, Bozena Romanowska-Dixon, Slawomir Teper, Tomasz Zarnowski, Miguel Amaro, João Castro Sousa, Manuel Falcão, João Pereira Figueira, Sara Vaz-Pereira, Mikulas Alexik, Monika Gajdosova, Gabriela Pavlovicova, Jana Štefanickova, Katarina Struharova, Alfredo Adan, Lluis Arias Barquet, Anniken Bures, Carlos Cava Valenciano, Enrique Cervera, Laura Sararols, Justus Garweg, Ioannis 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.

Keywords: Aflibercept; Diabetic retinopathy; Intravitreal injections; Macular edema; Treatment outcome; Vascular endothelial growth factor.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Patient disposition. aTwo patients in each of the fixed and T&E groups and one patient in the PRN group had no post-baseline assessments available and were excluded from the full analysis set. bReasons for withdrawal in the category “Other” were patient withdrawal by sponsor and lack of efficacy. AE adverse event, IVT-AFL intravitreal aflibercept, PRN pro re nata, T&E treat-and-extend
Fig. 2
Fig. 2
Mean change in BCVA from baseline to Week 100a. Full analysis set; last observation carried forward. The apparent spike at Week 52 and Week 100 is because this was a mandatory visit for all patients. aPatients had previously received 1 year of IVT-AFL treatment prior to the VIOLET study baseline. bAt Week 52 (primary endpoint), compared with IVT-AFL fixed, IVT-AFL T&E, and IVT-AFL PRN groups achieved a non-inferior outcome in mean BCVA change for the prespecified margin of 4 letters (p < 0.0001 for both comparisons). BCVA best-corrected visual acuity, ETDRS Early Treatment Diabetic Retinopathy Study, IVT-AFL intravitreal aflibercept, PRN pro re nata; SD standard deviation, T&E treat-and-extend

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Source: PubMed

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