Flecainide acetate inhalation solution for cardioversion of recent-onset, symptomatic atrial fibrillation: results of the phase 3 RESTORE-1 trial

Abstract

Aims: Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia. New treatments are needed to cardiovert recent-onset paroxysmal AF quickly and safely. RESTORE-1 was a multicentre, randomized, double-blind, placebo-controlled trial of a 120 mg orally inhaled solution of flecainide acetate (FlecIH-103) for cardioversion of symptomatic, recent-onset (≤48 h) paroxysmal AF. The study aim was to evaluate the efficacy and safety of FlecIH-103 administered via oral inhalation.

Methods and results: Patients experiencing a recent-onset paroxysmal AF episode were randomized to receive a single dose of FlecIH-103 or placebo delivered over two 3.5 min inhalation periods, while patients were monitored using 12-lead electrocardiograms and Holter. The trial was stopped prematurely after treating 55 patients, due to lower-than-expected conversion rates and plasma levels. Mean age was 59.6 years, 31.5% of patients were female, and 59.2% were having their first AF episode. Conversion rate was 30.8% (95% confidence interval: 14.7-43.8) for the active group (n = 39) and 0.0% for the placebo group (n = 12) (P = 0.04). Median time to conversion was 12.8 min (IQR: 17.2). In the active group, the mean flecainide plasma level was 198 ng/mL (SD: 156), which is ∼50% lower than in the previous studies. The most common adverse events (AEs) were dysgeusia, dyspnoea, and cough. All AEs were short-lasting and of mild or moderate intensity.

Conclusion: Despite early termination of the trial, FlecIH-103 was significantly more effective than placebo in cardioverting AF. Safety data did not show any serious AEs. Further studies of FlecIH-103 are needed to optimize the combination of drug formulation and inhalation delivery platform.

Clinical trial registration: URL: https://clinicaltrials.gov, unique identifier: NCT05039359.

Keywords: Atrial fibrillation; Cardioversion; Flecainide; Oral inhalation.

Graphical Abstract

Figure 1

Patient disposition. Flowchart of patients assessed for trial participation, population disposition, and criteria for exclusion from study populations.

Figure 2

Time to conversion of AF to SR. Cumulative percentage of patients by treatment group whose AF converted to SR within the observation period. The period of inhalation comprises the first 8 min in the plot.

Figure 3

AF symptoms at 90 min. Percentage of patients who reported no symptoms at the end of the observation period based on treatment group (A) and conversion status (B).

Figure 4

Time to discharge-eligible status by treatment group and conversion status. Cumulative percentage of patients who became eligible for discharge following drug administration for the following three groups: (1) patients who received FlecIH-103 and whose AF converted (light blue), (2) patients who received FlecIH-103 and whose AF did not convert (black), and (3) patients who received the placebo solution (red). The inset shows the time to discharge-eligible status based only on treatment group (FlecIH-103 vs. placebo).

Figure 5

Comparison between plasma levels of flecainide and conversion rates. Plot of peak plasma levels and conversion rates from both the INSTANT-1 and RESTORE-1 trials. Each INSTANT-1 data point represents a different dose of FlecIH. The 120 mg eTLD INSTANT-1 data point is composed of patients who received two FlecIH solutions (FlecIH-102 and FlecIH-103). The data point for RESTORE-1 shows that the plasma levels achieved were similar to those of the 60 mg eTLD of INSTANT-1, which is consistent with the conversion rate in the range of 30–35%. The Pearson’s correlation coefficient was 0.85 (P = 0.07).