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

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; P =0.12). In predefined sensitivity analyses, etripamil effects (compared with placebo) occurred at 3, 5, 10, 20, and 30 minutes ( P <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]; P =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.

Multicenter, Phase 2, Randomized Controlled Study of the Efficacy and Safety of Etripamil Nasal Spray for the Acute Reduction of Rapid Ventricular Rate in Patients With Symptomatic Atrial Fibrillation (ReVeRA-201)

“…15 Moreover, the currently reported findings can be viewed in the context of the efficacy demonstrated in phase 3 double-blind randomized, and open-label trials of self-administered intranasal etripamil 70 mg to rapidly terminate PSVT and to reduce tachycardia rate before termination. 12,13 These efficacy data in patients with PSVT and the currently reported data in patients with AF-RVR reflect the impact of etripamil on atrioventricular-nodal conduction and properties during tachycardic rates.…”

“…The efficacy, safety, and tolerability of the self-administered drug, have been studied in patients with paroxysmal supraventricular tachycardia (PSVT), demonstrating significant and rapid termination of PSVT with preceding slowing of the tachycardia rate and reduced emergency department care. [12][13][14] Preclinical and clinical data show that etripamil results in slower rates of tachycardias conducted utilizing the atrioventricular node soon after intranasal administration, illustrating the drug's action. 12 Furthermore, self-administered etripamil has been observed to slow the ventricular rate (VR) in a small cohort of patients with symptomatic AF-RVR.…”

“…[12][13][14] Preclinical and clinical data show that etripamil results in slower rates of tachycardias conducted utilizing the atrioventricular node soon after intranasal administration, illustrating the drug's action. 12 Furthermore, self-administered etripamil has been observed to slow the ventricular rate (VR) in a small cohort of patients with symptomatic AF-RVR. 15 Clinical data show general tolerability and limited AEs in >1600 patients with PSVT, supporting the likely safety of investigating etripamil in patients with AF-RVR.…”

Advances in Clinical Cardiology 2022: A Summary of Key Clinical Trials

“…Etripamil is a novel non-dihydropyridine calcium channel blocker, which may be given as a nasal spray, for acute treatment of patients with paroxysmal supraventricular tachycardia (PSVT) or AF. The RAPID (Efficacy and Safety of Etripamil for the Termination of Spontaneous PSVT) study [76] screened 706 patients with PSVT ultimately assigning in random fashion 135 patients to etripamil versus 120 to placebo. Etripamil was associated with more than double the primary outcome of conversion to sinus rhythm within 30 min (64.3% vs. 31.2%; HR 2.62; 95% CI 1.66-4.15) and a median time to conversion of 17 min (almost 3 times quicker than placebo).…”

“…Previous studies have shown the selective cardiac myosin activator Omecamtiv Mecarbilon may improve CV outcomes in HFrEF patients [1,76]. To assess functional impact, the METEORIC-HF (Effect of Omecamtiv Mecarbil on Exercise Capacity in Chronic Heart Failure With Reduced Ejection Fraction) trial [78] randomised 276 patients with LVEF B 35%; NYHA II-III (in 2:1 fashion) to Omecamtiv Mecarbilon versus placebo for 20 weeks, in addition to standard therapy.…”