First Randomized, Multicenter, Placebo-Controlled Study of Self-Administered Intranasal Etripamil for Acute Conversion of Spontaneous Paroxysmal Supraventricular Tachycardia (NODE-301).

Bruce S Stambler, Francis Plat, Philip T Sager, Silvia Shardonofsky, Douglas Wight, Diane Potvin, A Shekhar Pandey, James E Ip, Benoit Coutu, Blandine Mondésert, Laurence D Sterns, Matthew Bennett, Jeffrey L Anderson, Roger Damle, Ronald Haberman, A John Camm

Journal: Circulation. Arrhythmia and electrophysiology 2022;15(12):e010915

PMID: 36441560

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Abstract

BACKGROUND

Pharmacologic termination of paroxysmal supraventricular tachycardia (PSVT) often requires medically supervised intervention. Intranasal etripamil, is an investigational fast-acting, nondihydropyridine, L-type calcium channel blocker, designed for unsupervised self-administration to terminate atrioventricular nodal-dependent PSVT. Phase 2 results showed potential safety and efficacy of etripamil in 104 patients with PSVT.

METHODS

NODE-301, a phase 3, multicenter, double-blind, placebo-controlled study evaluated the efficacy and safety of etripamil nasal spray administered, unsupervised in patients with symptomatic sustained PSVT. After a medically supervised etripamil test dose while in sinus rhythm, patients were randomized 2:1 to receive etripamil 70 mg or placebo. When PSVT symptoms developed, patients applied a cardiac monitor and attempted a vagal maneuver; if symptoms persisted, they self-administered blinded treatment. An independent Adjudication Committee reviewed continuous electrocardiogram recordings. The primary efficacy endpoint was termination of adjudicated PSVT within 5 hours after study drug administration.

RESULTS

NODE-301 accrued 156 positively adjudicated PSVT events treated with etripamil (n=107) or placebo (n=49). The hazard ratio for the primary endpoint, time-to-conversion to sinus rhythm during the 5-hour observation period, was 1.086 (95% CI, 0.726-1.623; =0.12). In predefined sensitivity analyses, etripamil effects (compared with placebo) occurred at 3, 5, 10, 20, and 30 minutes (<0.05). For example, at 30 minutes, there was a 53.7% of SVT conversion in the treatment arm compared to 34.7% in the placebo arm (hazard ratio, 1.87 [95% CI, 1.09-3.22]; =0.02). Etripamil was well tolerated; adverse events were mainly related to transient nasal discomfort and congestion (19.6% and 8.0%, respectively, of randomized treatment-emergent adverse events.

CONCLUSIONS

Although the primary 5-hour efficacy endpoint was not met, analyses at earlier time points indicated an etripamil treatment effect in terminating PSVT. Etripamil self-administration during PSVT was safe and well tolerated. These results support continued clinical development of etripamil nasal spray for self-administration during PSVT in a medically unsupervised setting.

REGISTRATION

URL: https://www.

CLINICALTRIALS

gov; Unique identifier: NCT03464019.

Address: Piedmont Heart Institute, Atlanta, GA (B.S.S.).; Milestone Pharmaceuticals, Montréal, Québec, Canada (F.P., S.S., D.W.).; Cardiovascular Research Institute & Department of Medicine, Stanford University, Palo Alto, CA (P.T.S.).; Excelsus Statistics, Montréal, Québec' Canada (D.P.).; Cambridge Cardiac Care Centre, Cambridge, Ontario, Canada (A.S.P.).; Weill Cornell Medical Center, New York-Presbyterian Hospital, New York, NY (J.E.I.).; Centre Hospitalier de l' Université de Montréal Montréal, Québec, Canada (B.C.).; Montréal Heart Institute, Université de Montréal, Québec' Canada (B.M.).; Victoria Cardiac Arrhythmia Trials, Inc, Victoria, British Columbia' Canada (L.D.S.).; Centre for Cardiovascular Innovation' Division of Cardiology, University of British Columbia, Vancouver, Canada (M.B.).; Intermountain Medical Center, Murray, UT (J.L.A.).; South Denver Cardiology Associates, PC, Littleton, CO (R.D.).; Top Line Arrhythmia Contractors, LLC, Scottsdale, AZ (R.H.).; St. George's University of London, London, England (A.J.C.).

DOI: 10.1161/CIRCEP.122.010915