Safety Study of Etripamil Nasal Spray for Patients With Paroxysmal Supraventricular Tachycardia. NODE-303

The NODE-303 Study: Multi-Centre, Multi-National,Open Label, Safety Study of Etripamil Nasal Spray for Patients With Paroxysmal Supraventricular Tachycardia.

NODE-303 was a multi-center, open label study to evaluate the safety of etripamil NS in participants with Paroxysmal Supraventricular Tachycardia (PSVT). Participants were provided with an ambulatory Cardiac Monitoring System (CMS) to help document PSVT episodes. The CMS was self-applied by the participant, when they felt the onset of PSVT symptoms. Participants self-administered etripamil NS if vagal maneuver was ineffective. After an episode of PSVT where study drug was administered, the participant returned to the investigative site and had the option to continue in NODE-303 and manage up to three subsequent episodes of PSVT with etripamil NS for a maximum of four episodes.

NODE-303 was a multi-center, open label study to evaluate the safety of etripamil NS in participants with PSVT. Participants were provided with an ambulatory CMS to help document PSVT episodes. The CMS was self-applied by the participant, when they felt the onset of PSVT symptoms. Participants self-administered etripamil NS 70 mg if vagal maneuver (VM) was ineffective. Approximately 2 years after study initiation, a protocol amendment was implemented to allow participants to administer a second dose of etripamil 70 mg 10 minutes after the first dose, if PSVT symptoms persisted. After an episode of PSVT where study drug was administered, the participant returned to the investigative site and had the option to continue in NODE-303 and manage up to three subsequent episodes of PSVT with etripamil NS for a maximum of four episodes.

The study included:

A Screening Visit during which the Investigator verified that the participant met the eligibility criteria of the NODE-303 study, obtained the signed informed consent, took blood and urine for laboratory evaluations, and conducted other screening procedures. The informed consent for NODE-303 was applicable for the initial and all subsequent PSVT episodes. A Baseline Visit during which the site confirmed eligibility, concomitant medications, trained the participant on study procedures, and gave the participant study drug, participant reported outcome (PRO) materials, and the CMS materials. A Treatment Period during which the participant completed the monthly PRO survey, self-identified symptoms of PSVT, used the CMS during 60 minutes, performed a VM, and self-administered etripamil NS if the symptoms did not resolve after the VM. Participants could be contacted during this period for reminders and training on what to do during a PSVT episode. Participants also completed a per episode survey after any PSVT episode they experience. During the Treatment Period, Follow-up Visits occurred at the study site up to 14 days after each episode of PSVT treated with etripamil NS, and during which the Investigator evaluated the results of the last usage of etripamil NS and reassessed participant's eligibility to continue in the study based on study inclusion and exclusion criteria. Participants who were eligible to continue in the study received additional study medication.

A Final Study Visit occurred when a participant discontinued or withdrew from the study, or when the overall study was completed, or the participant had completed the maximum number of doses. NODE-303 continued until enough documented self-administrations of etripamil NS were included in the safety database to meet regulatory requirements for the etripamil NS development program. The common study end date (CSED) for the entire study depended on the rate of accrual of the primary endpoint, unique participants with an episode. When the criteria for concluding the study were met, the Sponsor announced the CSED for the entire study and sites were informed in advance to schedule all final participant visits prior to the CSED.

Inclusion Criteria:

A participant was eligible for study participation if they met all of the following criteria:

1. Had been diagnosed with PSVT by a medical professional, and reported having at least one previous episode of PSVT. For clarity, PSVT referred to episodic Supraventricular Tachycardia (SVT) that included the atrioventricular (AV) node as a critical part of reentrant circuit.
2. Was at least 18 years of age;
3. Signed NODE-303 written informed consent
4. Women of childbearing potential had to be willing to use at least 1 form of contraception during the trial, and had to be willing to discontinue from the study should they have become or planned to become pregnant. Postmenopausal females were defined as having amenorrhea for at least 12 months prior to Screening without an alternative medical cause.
5. Willing and able to comply with study procedures

Exclusion Criteria:

A participant was excluded from the study if they met any of the following criteria:

1. Participants with only a history of atrial arrhythmia that did not involve the atrioventricular (AV) node as part of the tachycardia circuit (e.g. atrial fibrillation, atrial flutter, intra-atrial tachycardia) were not eligible. Participants with a history of these tachycardias who were also diagnosed with PSVT were eligible.

2. History of allergic reaction to verapamil

3. Current therapy with digoxin, or any Class I or III antiarrhythmic drug. Participants could be eligible if these drugs were stopped at least five half-lives before the administration of etripamil NS. The only exception was amiodarone which had to be stopped 30 days before enrollment.

4. History or evidence of ventricular pre-excitation, e.g., delta waves, Wolff- Parkinson-White syndrome

5. History or evidence of a second- or third-degree AV block

6. History or evidence of severe ventricular arrhythmia (e.g., torsades de pointes, ventricular fibrillation, or sustained ventricular tachycardia).

7. Symptoms of congestive heart failure New York Heart Association Class II to IV

8. SBP < 90 mmHg at Screening, Baseline or any Follow-up Visit.

9. Severe symptoms of hypotension experienced during PSVT episodes.

10. Significant physical or psychiatric condition including alcoholism or drug abuse, which, in the opinion of the Investigator, could jeopardize the safety of the participant, or impede the participant's capacity to follow the study procedures

11. History of syncope due to an arrhythmic etiology at any time, or history in last 5 years of unexplained syncope

12. Was pregnant or breastfeeding

13. Previously enrolled in a clinical trial for etripamil and received study drug or participation in any clinical trial for other investigational products or medical devices within 30 days of Screening.

14. History of Acute Coronary Syndrome (ACS) or stroke within 6 months of screening

15. Evidence of renal dysfunction as determined by an estimated glomerular filtration rate assessed at the Screening Visit as follows:

    1. <60mL/min/1.73m2 for participants <60 years of age;
    2. <40mL/min/1.73m2 for participants ≥60 and <70 years of age
    3. <35mL/min/1.73m2 for participants ≥70 years of age