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Presently, acute pharmacological termination of paroxysmal supraventricular tachycardia (PSVT) unresponsive to patient-initiated vagal maneuvers requires in-hospital intervention. Etripamil, a fast-acting, nondihydropyridine, L-type calcium channel blocker, is formulated as an intranasal spray to rapidly terminate atrioventricular (AV) nodal-dependent PSVT in a medically unsupervised setting. The NODE-301 study did not meet its prespecified primary end point of PSVT conversion over 5 hours following a single dose of etripamil 70 mg. However, analysis at earlier time points demonstrated etripamil treatment effect during the first 30 minutes, consistent with its expected rapid onset and short duration of action. This led to the design of the RAPID study, which includes a new dosing regimen (up to 2 etripamil 70 mg doses separated by 10 minutes) to increase the exposure and pharmacodynamic effect of etripamil. The primary objective of RAPID (NCT03464019) is to determine if etripamil self-administered by patients is superior to placebo in terminating PSVT in an at-home setting. The secondary objective is to evaluate the safety of etripamil when self-administered by patients without medical supervision. Additional efficacy end points include the proportion of patients requiring additional medical intervention in an emergency department to terminate PSVT and patient-reported outcomes. After successfully completing a test dose to assess the safety of 2 70 mg doses of etripamil during sinus rhythm, approximately 500 patients will be randomized 1:1 to etripamil or placebo to accrue 180 positively adjudicated AV nodal-dependent PSVT events for treatment with the study drug. Etripamil may offer a new alternative to the current in-hospital treatment modality, providing for safe and effective at-home termination of PSVT.

Paroxysmal supraventricular tachycardia (PSVT) is a common episodic arrhythmia characterized by unpredictable onset and burdensome symptoms including palpitations, dizziness, chest pain, distress, and shortness of breath. Treatment of acute episodes of PSVT in the clinical setting consists of intravenous adenosine, beta-blockers, and calcium channel blockers (CCBs). Etripamil is an intranasally self-administered L-type CCB in development for acute treatment of AV-nodal dependent PSVT in a nonmedical supervised setting. This paper summarizes the rationale and study design of NODE-303 that will assess the efficacy and safety of etripamil. In the randomized, double-blinded, placebo-controlled, Phase 3 RAPID trial, etripamil was superior to placebo in the conversion of single PSVT episodes by 30 minutes post initial dose when administered in the nonhealthcare setting; this study required a mandatory and observed test dosing prior to randomization. The primary objective of NODE-303 is to evaluate the safety of symptom-prompted, self-administered etripamil for multiple PSVT episodes in real-world settings, without the need for test dosing prior to first use during PSVT. Secondary endpoints include efficacy and disease burden. Upon perceiving a PSVT episode, the patient applies an electrocardiographic monitor, performs a vagal maneuver, and, if the vagal maneuver is unsuccessful, self-administers etripamil 70 mg, with an optional repeat dose if symptoms do not resolve within 10 minutes after the first dose. A patient may treat up to four PSVT episodes during the study. Adverse events are recorded as treatment-emergent if they occur within 24 hours after the administration of etripamil. Efficacy endpoints include time to conversion to sinus rhythm within 30 and 60 minutes after etripamil administration, and the proportion of patients who convert at 3, 5, 10, 20, 30, and 60 minutes. Patient-reported outcomes are captured by the Brief Illness Perception Questionnaire, the Cardiac Anxiety Questionnaire, the Short Form Health Survey 36, the Treatment Satisfaction Questionnaire for Medication and a PSVT survey. Overall, these data will support the development of a potentially paradigm-changing long-term management strategy for recurrent PSVT.