Oral levosulpiride adjuvant to intravitreal ranibizumab for diabetic macular oedema: A 24-week randomized placebo-controlled trial

Background/Objective: Diabetic macular oedema (DMO) is a leading cause for visual impairment primarily managed with intravitreal anti-VEGF agents such as ranibizumab (RBZ). Levosulpiride (LSP), a prokinetic medication, was recently repositioned as a safe oral treatment for naive DMO. Here, we investigated the adjuvant effect of oral LSP in combination with intravitreal RBZ injections for treating persistent DMO. Subjects/Methods: Double-blinded, dual-centre, phase 2 trial in patients with centre-involving DMO randomly assigned to be orally treated with placebo (15 patients, 18 eyes) or LSP (18 patients, 19 eyes) along with 3 successive (4 weeks apart) RBZ intravitreal injections and a 24-week follow-up. Results: Baseline best-corrected visual acuity (BCVA) improved (p[≤]0.04) at week 12 in both RBZ+placebo and RBZ+LSP, but improvement was maintained (p=0.009) at week 24 only in RBZ+LSP. In agreement, longitudinal changes from baseline in BCVA from weeks 12 to 24 defined superior (p=0.02) visual gains measured by the Area Under the Curve (AUC) in RBZ+LSP vs. RBZ+placebo. The baseline value of mean central foveal thickness (CFT) decreased (p[≤]0.002) in both groups at week 12 and CFT reduction was significant (p=0.006) at week 24 only in RBZ+LSP. Also, longitudinal changes from baseline in CFT resulted in a higher AUC reduction (p[≤]0.04) at weeks 4 to12 in RBZ+LSP vs. RBZ+placebo. No significant adverse side effects were detected. Conclusions: Adjunctive LSP showed functional and anatomical benefits over the first-line therapy with RBZ. Adjuvant properties may involve the LSP-induced intraocular upregulation and downregulation of vasoinhibin and VEGF, respectively. Larger clinical trials are warranted.