NODE clinical trials of Etripamil nasal spray for PSVT

NODE clinical trials of Etripamil nasal spray for PSVT

Etripamil is a short-acting nondihydropyridine, L-type calcium channel blocker being evaluated for the rapid termination of paroxysmal supraventricular tachycardia (PSVT). Currently PSVT is terminated by intravenous adenosine in the emergency department if vagal maneuvers fail. Though ‘pill-in-the-pocket’ approaches with various drugs have been described for out-patient termination of PSVT, often that is not enough. If Etripamil nasal spray is established as modality for rapid termination of PSVT, that will be very useful.

Etripamil for the Conversion of PSVT to Sinus Rhythm (NODE-1) was a phase 2 clinical trial to assess the efficacy and safety of etripamil nasal spray [1]. Patients with sustained supraventricular tachycardia for five minutes received either a placebo nasal spray or one to four doses of the active compound. Primary endpoint was conversion of PSVT within 15 minutes of drug administration. Secondary endpoints included time to conversion and adverse events reported. There were 104 patients in the study and conversion rates in etripamil group was between 65% to 95%. Placebo group had a conversion rate of 35%. Median time to conversion was less than 3 minutes. Common adverse event was local irritation. Blood pressure reduction occurred predominantly with the highest etripamil dose.

However NODE-301, a phase 3, multicenter, double-blind, placebo-controlled, randomized study did not meet the prespecified primary end point of conversion of PSVT over five hours after a single 70 mg dose of etripamil [2]. But a secondary analysis showed treatment effect at 30 minutes, consistent with the rapid onset and short duration of action. It was also noted that more patients in the placebo group than the etripamil group sought other medical interventions to terminate PSVT during the 5-hour window. Recurrence rates of PSVT following initial conversion to sinus rhythm was less than 1% during the post administration 5 hour monitoring period.

This prompted the design of RAPID study with a new dosing regimen of up to two etripamil 70 mg doses separated by ten minutes. RAPID is a multicenter placebo controlled phase 3 trial [3]. Primary endpoint is to determine if etripamil self-administered by patients is superior to placebo in terminating PSVT in an at-home setting. After successfully completing a test dose of two 70 mg doses of etripamil to assess safety during sinus rhythm, about 500 patients will be randomized 1:1 to etripamil or placebo. It is hoped that etripamil may offer a new alternative to the current in-hospital treatment modality, providing for safe and effective at-home termination of PSVT.

References

1. Stambler BS, Dorian P, Sager PT, Wight D, Douville P, Potvin D, Shamszad P, Haberman RJ, Kuk RS, Lakkireddy DR, Teixeira JM, Bilchick KC, Damle RS, Bernstein RC, Lam WW, O’Neill G, Noseworthy PA, Venkatachalam KL, Coutu B, Mondésert B, Plat F. Etripamil Nasal Spray for Rapid Conversion of Supraventricular Tachycardia to Sinus Rhythm. J Am Coll Cardiol. 2018 Jul 31;72(5):489-497. doi: 10.1016/j.jacc.2018.04.082. PMID: 30049309.
2. BS Stambler, F Plat, PT Sager, et al. Etripamil nasal spray for acute termination of spontaneous episodes of paroxysmal supraventricular tachycardia. NODE-301 trial. Heart Rhythm, 17 (2020), p. 1200
   Abstract D-LBCT01-01.
3. Stambler BS, Plat F, Sager PT, Lubkov V, Shardonofsky S, Wight D, Chen M, Camm AJ. Rationale for and design of a multicenter, placebo-controlled, phase 3 study to assess efficacy and safety of intranasal etripamil for the conversion of paroxysmal supraventricular tachycardia. Am Heart J. 2022 Jun 18;253:20-29. doi: 10.1016/j.ahj.2022.06.005. Epub ahead of print. PMID: 35728658.