Phase 3, Multicenter, Placebo‑Controlled Study of Intranasal Etripamil for Rapid Ventricular Rate Control in Atrial Fibrillation (ReVeRA‑301)

The primary objective is to demonstrate the efficacy of etripamil nasal spray compared with placebo in participants diagnosed with atrial fibrillation presenting with a rapid ventricular rate. Secondary objectives include:

• Evaluation of the safety profile of etripamil nasal spray when administered in an at‑home setting.
• Characterization of the overall clinical benefit of etripamil in this patient population.

Approximately 550 participants were enrolled, comprising adult men and women aged 18 years and older with documented symptomatic atrial fibrillation (paroxysmal, persistent, or permanent) and a ventricular rate ≥110 bpm. All subjects had experienced at least two symptomatic episodes of ≥20 minutes duration within the preceding 12 months and were receiving guideline‑directed antithrombotic or anticoagulation therapy. Both sexes were represented, and the trial included individuals classified as vulnerable, defined as patients meeting the clinical criteria. Enrollment required written informed consent, ability to comply with study procedures, and, for women of child‑bearing potential, a negative pregnancy test and use of effective contraception throughout the study period. No specific dietary, physical‑activity, or habit restrictions were stipulated in the provided information.

The ReVeRA-301 trial is a multi‑center, randomized, double‑blind, placebo‑controlled Phase III study evaluating the efficacy and safety of a single intranasal dose of etripamil nasal spray (140 mg) versus matching placebo in adults with symptomatic atrial fibrillation and a rapid ventricular rate (≥110 bpm). Participants are screened for eligibility, provide written informed consent, and undergo a screening visit to confirm inclusion criteria and baseline assessments. Eligible subjects are then randomized in a 1:1 ratio and receive the study drug during a documented AF episode; this constitutes the baseline/treatment visit. Post‑dose evaluations include electrocardiographic recordings and electronic patient‑reported outcomes at 30, 45, and multiple additional time points up to 300 minutes to assess the primary ventricular‑rate reduction and secondary symptom‑improvement endpoints. A safety follow‑up visit is performed 24–48 hours after dosing, and an end‑of‑study visit occurs at approximately 7 days to collect final safety data and study completion assessments. Participant involvement therefore spans roughly 1 week from screening to end of study. Early termination may occur if a participant experiences a serious adverse event, requires rescue therapy, becomes pregnant, withdraws consent, or fails to comply with protocol‑required procedures.

The investigational product is Etripamil, supplied as a nasal spray for intranasal administration. Each dose contains 140 mg of the active substance etripamil and is delivered as a single spray into each nostril. The dosing regimen consists of one administration at the onset of a qualifying episode of atrial fibrillation with rapid ventricular response; repeat dosing is not permitted within a 24‑hour period.

The comparator is a matching placebo formulated as a nasal spray without active pharmaceutical ingredient. The placebo is identical in appearance, volume, and administration procedure to the active product and is delivered using the same intranasal route and single‑dose schedule.

Study medication is provided in pre‑filled, single‑use devices that are labeled with a unique identifier. Participants receive instruction on proper spray technique and are required to document the time of administration in an electronic diary. Compliance monitoring includes device count at each study visit and review of electronic diary entries to confirm adherence to the dosing window and to detect any prohibited additional dosing.

The primary efficacy assessment is the maximum reduction in ventricular rate measured from ECG continuous monitoring system (CMS) recordings within 30 minutes after the first dose of study drug.

Key secondary efficacy variables include improvement in participant symptoms assessed by a 7‑unit anchored Likert scale administered via ePRO at 30 minutes, and a repeat measurement at 45 minutes. Additional secondary measures comprise participant satisfaction with symptom relief captured by ePRO at 30 and 45 minutes, change in heart rate from baseline to 30 minutes, and the proportion of participants achieving predefined heart‑rate reductions (≥10 % reduction, ≥20 % reduction, ≥20 bpm reduction, and <100 bpm) at the 30‑minute timepoint, analyzed using chi‑square tests. Further analyses evaluate the proportion of participants requiring medical interventions, the proportion converting to sinus rhythm and time to conversion, and the time to achieve the defined heart‑rate reductions. Efficacy estimators are also repeated at extended observation windows of 15, 45, 60, 90, 120, 150, 180, 240, and 300 minutes.