A Multicenter, Phase 2, Randomized, Controlled Study of the Efficacy and Safety of Etripamil Nasal Spray for the Acute Reduction of Rapid Ventricular Rate in Patients with Symptomatic Atrial Fibrillation (ReVeRA-201).

Background: Despite chronic therapies, atrial fibrillation (AF) leads to rapid ventricular rates (RVR) often requiring intravenous treatments. Etripamil is a fast-acting, calcium-channel blocker administered intranasally affecting the atrioventricular-node within minutes. Methods: ReVeRA evaluated efficacy and safety of etripamil for the reduction of ventricular rate (VR) in patients presenting urgently with AF-RVR (VR ≥110 bpm), was randomized, double-blind, placebo-controlled, and conducted in Canada and Netherlands. Patients presenting urgently with AF-RVR were randomized (1:1, etripamil nasal spray (NS) 70 mg: placebo-NS). The primary objective was to demonstrate the effectiveness of etripamil in reducing VR in AF-RVR within 60 min of treatment. Secondary objectives assessed achievement of VR <100 bpm, reduction by ≥10 and ≥20%, relief-of-symptoms and treatment-effectiveness; adverse events (AEs); and additional measures to 360 min. Results: 69 patients were randomized, 56 dosed with etripamil (n=27) or placebo (n=29). The median age was 65 years; 39% were female; proportions of AF types were similar between groups. The difference of mean maximum reductions in VR over 60 min, etripamil vs placebo, adjusting for baseline VR, was -29.91 bpm (95% confidence interval: -40.31, -19.52; p <0.0001). VR reductions persisted up to 150 min. Significantly greater proportions of patients receiving etripamil achieved VR reductions <100 bpm (with longer median duration <100 bpm), or VR reduction by ≥10% or ≥20%, vs placebo. VR reduction ≥20% occurred in 66.7% of patients in the etripamil arm and no patients in placebo. Using the Treatment Satisfaction Questionnaire for Medication-9, there was significant improvement in satisfaction on symptom-relief and treatment-effectiveness with etripamil vs placebo. Serious AEs were rare; 1 patient in the etripamil arm experienced transient severe bradycardia and syncope, assessed as due to hyper-vagotonia. Conclusions: Intranasal etripamil 70 mg reduced VR and improved symptom-relief and treatment-satisfaction. These data support further development of self-administered etripamil for the treatment of AF-RVR. Clinical Trial Registration: ClinicalTrials.gov; Unique Identifier: NCT04467905.