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

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.

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

Mean change in BCVA from baseline to Week 100^a. 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