Shardonofsky, Silvia

ABSTRACT Introduction Etripamil is a fast‐acting intranasally self‐administered calcium‐channel blocker developed for termination of paroxysmal supraventricular tachycardia (PSVT). Prior studies have demonstrated safety and efficacy of etripamil for PSVT termination following an initial medically supervised test dose during sinus rhythm. NODE‐303 is an open‐label, single‐arm study that evaluated etripamil for multiple, at‐home PSVT episodes, without test dose before first use. Methods Patients applied an ECG monitor at symptom onset and self‐administered etripamil (70 mg) if a vagal maneuver was unsuccessful. ECG monitoring occurred for ≥ 1 h following study drug administration. A repeat 70‐mg dose was introduced during the study for symptoms persisting 10 min after the first dose. Safety measures included treatment‐emergent adverse events (TEAEs) and ECG arrhythmia‐surveillance. Efficacy measures were captured for PSVT termination during treatment of each of the multiple episodes. Results 1054 perceived PSVT episodes were etripamil‐treated in 503 of 1116 patients enrolled. TEAEs within 24 h were mostly mild or moderate and localized: 30.2% of patients experienced nasal discomfort, nasal congestion (13.9%), rhinorrhea (13.1%), epistaxis (7.4%). TEAE frequencies decreased across multiple PSVT episodes and were similar for single versus repeat doses. For first PSVT episodes, 70.5% of patients converted to sinus rhythm by 60 min post etripamil (median time to conversion = 18.3 min [14.2–25.6]). Conversion in earlier episodes was consistently predictive of conversion in subsequent episodes. Conclusions Etripamil nasal spray self‐administered in a real‐world setting was well tolerated, effective, and had a consistent safety profile as a single‐ or repeat‐dose regimen across multiple PSVT episodes. Trial Registration: ClinicalTrials.gov NCT04072835

Background: Etripamil nasal spray (NS) is a fast acting, self-administered calcium channel blocker in development for the termination of AV-nodal-dependent supraventricular tachycardia (SVT). Prior randomized, placebo-controlled and open-label studies have demonstrated favorable safety and efficacy of etripamil in converting paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm (SR) self-administered without direct medical supervision. Research Question/Hypothesis: To assess patterns and annualized PSVT episode frequency among patients opting to self-administer acute treatment with etripamil. Methods: NODE-303 was an event-driven, multi-center, open-label Phase 3 study, conducted in North and South America to evaluate the safety and efficacy of etripamil in patients with documented PSVT over multiple episodes. Test dosing was not performed prior to at-home use. Enrolled patients, upon perceiving symptoms of PSVT: applied an ambulatory ECG monitor, performed a previously trained vagal maneuver and, if symptoms persisted, self-administered etripamil NS 70 mg. During the study, the protocol was amended to allow a repeat dose (70 mg) if symptoms persisted 10 min after the first dose. Each patient could self-treat up to 4 episodes. Results: Of 1,116 enrolled patients, 503 (45.1%) treated ≥1 perceived PSVT episode (safety population). Etripamil achieved conversion to SR in 60% of patients by 30 minutes and 70% by 60 minutes. A total of 220, 118, 62, and 103 patients completed the study with 1, 2, 3, and 4 etripamil-treated perceived episodes of PSVT, respectively, with an average time on study of 440 days. Among these patients, the average number of annualized etripamil-treated PSVT episodes was 3.2 (standard deviation 3.8). Annualized use: etripamil was self-administered for 0-2 PSVT episodes per year, 2-6 episodes, 6-12 episodes, and >12 episodes, in 54%, 32%, 10%, and 4% of patients, respectively (Figure). Conclusions: This analysis aimed to assess the annualized use of etripamil NS in a real-world setting, by analyzing how often patients would self-administer the drug for PSVT episodes. Of patients that self-administered etripamil (n=503), the majority treated >1 episode and the annualized frequency of episodes treated with etripamil was 3.2 episodes/yr.

Abstract Background Etripamil nasal spray (NS) is a fast-acting, self-administered calcium-channel blocker in development for the conversion of AV-nodal dependent paroxysmal supraventricular tachycardia (PSVT) in a medically unsupervised setting. Prior studies show favorable safety and efficacy in converting single episodes of PSVT to sinus rhythm (SR). Purpose In NODE-303, patient-reported outcome (PRO) instruments assessed quality of life (QoL) over multiple etripamil-treated episodes of PSVT. Methods NODE-303 was an event-driven, multi-center, open-label Phase 3 study in North and South American patients with documented PSVT that evaluated the safety and efficacy of etripamil in PSVT termination, over multiple episodes and without the need for prior test dosing. Enrolled patients who perceived PSVT symptoms applied an ambulatory ECG cardiac monitoring system (CMS), performed a pre-trained vagal maneuver and, if symptoms persisted, self-administered etripamil NS 70 mg. A study amendment allowed a repeat dose (etripamil NS, 70 mg) if symptoms persisted 10 min after the first dose. Each patient could self-treat up to 4 episodes. Safety was assessed through adverse events, clinical data, and ECG CMS recordings. The Treatment Satisfaction Questionnaire for Medication (TSQM; validated for acute episodic assessments) and other PROs were administered, and healthcare utilization data were acquired. Patients completed PROs at baseline (BL), monthly, and per PSVT episode, which collected information on symptoms, episode characteristics, rescue medications, and emergency room visits. Additional PROs were the Brief Illness Perception Questionnaire (BIPQ), Cardiac Anxiety Questionnaire (CAQ), and 36-Item Short Form Health Survey (SF-36). Results There were higher proportions of patients reporting mild, minimal or no disease severity, every 6 months, than at BL; extremely severe, severe, and moderate disease severity was reported by smaller proportions of patients than at BL, though incomplete surveys at later visits may limit this analysis. Anxiety and stress about future PSVT episodes were consistently reduced from BL. Measures of treatment satisfaction, effectiveness, and convenience were consistent across multiple episodes, and were at levels considered favorable for the TSQM instrument (Table 1). Rates of emergency-room visits and hospital admissions across multiple, treated PSVT episodes were similar to those observed in trials assessing single episodes (Table 2). The BIPQ, CAQ or SF-36 had no notable changes from BL. Conclusions Etripamil self-administration was associated with patient-reported improvements in degree of disease severity, decreased anxiety and stress over future PSVT episodes, and levels of treatment satisfaction, effectiveness, and convenience considered favorable for respective PRO instrument. Using a symptom-prompted, self-administered treatment for PSVT could potentially improve QoL measures and reduce healthcare resource utilization.