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

Abstract Introduction Safe, rapid, and efficacious drugs for acute cardioversion of paroxysmal AF (PAF) are needed. In an open-label, Phase 2 study (INSTANT), orally inhaled flecainide was safe and efficacious for acute conversion of PAF to sinus rhythm (SR).[1, 2] Purpose Evaluate the efficacy and safety of flecainide acetate inhalation solution (FlecIH-103) compared to placebo in patients with short-duration, symptomatic, newly diagnosed, or recurrent PAF. Methods RESTORE-1 was a multicentre, randomized, double-blind, placebo-controlled trial in patients with symptomatic PAF (≤48 hours). Patients received FlecIH-103 at an estimated total lung dose of 120 mg or placebo (3:1) over 8 minutes using a breath-actuated nebulizer and were continuously monitored for 90 minutes (observation period), using a single-lead patch ECG electrode. Results The study was stopped prematurely after 55 of the expected 400 patients had been enrolled due to lower-than-expected flecainide peak plasma levels (197.8 ng/mL; 1.85-fold lower than those observed with the same target dose in INSTANT) and modest efficacy. The Data Monitoring Committee confirmed that there were no safety risks. Fifty-four of the enrolled patients (42 active; 12 placebo) were in AF at the start of inhalation. Baseline characteristics were well-balanced between treatment groups; overall mean age was 59.6 years (SD: 13.5) and 31.5% of patients were female. Cardioversion rates during the observation period in the efficacy population (n=51; 39 active, 12 placebo) were 30.8% (95% CI: 18.5-46.5%) in the active group and 0% (95% CI: 0.0-28.2%) in the placebo group (p=0.04; figure 1). In the active group, the median time to conversion from start of inhalation was 12.8 minutes (IQR: 7.8-25.0 minutes), which includes an 8-minute inhalation period. Among the 12 patients whose AF converted to SR, only 1 (8.3%) still had AF-related symptoms compared to 71.8% of patients whose AF did not convert to SR (p<0.001). Time to discharge-eligible status was 1.6h for patients whose AF cardioverted and 3.3h for those whose AF did not (p=0.002; figure 2). The most common adverse events (AEs; ≥8%) occurring more frequently in the active than the placebo group were the following: dyspnoea (14.3%), dysgeusia (14.3%) and cough (11.9%). No serious AEs or cardiovascular events of special interest (hypotension, ventricular tachycardia, bradycardia, sinus pause, atrial flutter 1:1, other arrhythmias) were reported. Conclusions Orally inhaled flecainide, at approximately half of the targeted dose, was modestly effective and safe. The 1.5-fold lower conversion rate observed in this study, compared to the same dose in the INSTANT trial, is consistent with the lower plasma levels of flecainide achieved. Future studies will be designed to improve drug delivery to yield peak plasma levels of flecainide associated with higher conversion rates.