Key Points
-The RAPID study achieved its primary efficacy endpoint of terminating PSVT with self-administered Etripamil using a symptom-based optimal repeat dosing.
-Pooled analysis with the NODE-301 study showed that self-administered etripamil showed a significant reduction in emergency department utilization and medical intervention.
-This Phase III trial showed a favorable safety and tolerability profile of etripamil consistent with prior etripamil trials.
Sustained paroxysmal supraventricular tachycardia (PSVT) affects almost 400,000 American adults, and often requires presentation to a medical facility for treatment. About 50,000 emergency department visits annually are attributable to PSVT. Etripamil (Milestone Pharmaceuticals, Saint-Laurent, QC, Canada) is a novel intra-nasal short-acting L-type calcium-channel blocking agent which has shown good tolerability and potential efficacy for the out-of-hospital treatment of PSVT. The drug carries a safety profile that makes it an acceptable therapy for unsupervised self-administration. Two phase I studies and one Phase II randomized, placebo-controlled, double-blinded studies have been previously completed. These early studies demonstrated rapid absorption (Tmax ≤ 7mins) and elimination of the drug with dose-dependent PR prolongation. Additionally, plasma levels and pharmacodynamics outcomes were similar between Caucasians and persons of Japanese descent. Adverse events related to the drug were often mild respiratory tract irritative symptoms, with one episode of transient high-grade atrioventricular block with hypotension occurring at the higher dosing (140mg).
In a late-breaking presentation at the 2022 AHA Scientific Sessions today, Dr. James Ip (Weill Cornell Medicine, New York, NY) and his team presented their study: “Self-Administered Etripamil for Termination of Spontaneous Paroxysmal Supraventricular Tachycardia: Primary Analysis from the Rapid Study”.
The RAPID study (NCT03464019) was a multi-center, randomized, double-blind, placebo-controlled, parallel assignment study to evaluate the efficacy and safety of etripamil NS self-administered by patients who experience an episode of paroxysmal ventricular tachycardia (PSVT) in an at-home setting. The RAPID study is a Part 2 of the NODE-301 study which also assessed the efficacy and safety of etripamil NS following a similar study design. The key differences being that Part 2 includes a repeat dosing option during the randomized treatment phase, as well as during an added open-label treatment phase. The inclusion criteria comprised adults ≥18 years who had an electrocardiographically documents history of PSVT of sustained episodes of PSVT (lasting ~ twenty (20) minutes or longer). Patients with a history of pre-excitation of prior high-degree atrioventricular block were excluded. Patients who had a history of PSVT post prior ablation met eligibility criteria.
A total of 692 patients were randomized to etripamil versus placebo. Before randomization, all patients received a test dose of an etripamil NS dosing regimen in sinus rhythm (an initial dose of etripamil NS 70 mg followed by a second dose of etripamil NS 70 mg between 10-15 minutes, after the first dose) to evaluate tolerability and to train patients on the study procedures. When patients experienced a PSVT event at-home, they applied a cardiac monitor, attempted a vagal maneuver before administering the double-blinded study drug if symptoms continued. If symptoms continued for more than 10 minutes they administered the second dose of the study drug. A total of 120 patients in the placebo arm had a perceived PSVT event versus 135 patients in the etripamil arm (the Safety population). After blinded adjudication of the events, 72% of the safety population had verified PSVT (85 in the placebo vs 99 treated with etripamil). The characteristics in safety group were similar with a mean age was 54 years, and 71% of patients were female. About two-thirds of the population was taking a concurrent beta-blocker or calcium channel blocker.
The primary outcome was the time to conversion of an adjudicated episode of PSVT to sinus rhythm (SR) after study drug administration at 30 minutes, was noted in 64.3% of the etripamil arm versus 31.2% in the placebo [HR 2.62 (95% CI, 1.659-4.147); p <0.001]. The median time to conversion of PSVT to sinus rhythm was significantly reduced in the etripamil arm compared to placebo (17.2 minutes in the etripamil arm vs 53.5 minutes in placebo). Consistent benefit of etripamil was sustained over several subgroup analyses. The pre-specified pooled analysis with the NODE-301 study, demonstrated a statistically significant reduction in patients seeking medical interventions and emergency department utilization in the etripamil arm vs placebo. The RAPID study showed continued safety with self-administered etripamil NS use, with most treatment emergent adverse events (TEAE) being limited to mild nasal irritative symptoms.
When discussing the clinical implications of the study at AHA, Dr. Ip stated: “these results demonstrate a potential management strategy for patients to self-treat episodes with etripamil in a medically unsupervised setting.”