Efficacy and Safety of Etripamil for the Termination of Spontaneous PSVT. NODE 301 [Part 1 and Part 2 (The RAPID Study)]

Inclusion Criteria:

Participants who met all of the following criteria were eligible to participate in the study:

1. Male or female participants at least 18 years of age;
2. Electrographically documented history of PSVT (e.g., electrocardiogram \[ECG\] obtained during an episode of PSVT, Holter monitoring, loop recorder, etc). If participant had a prior ablation for PSVT, participant had to have documented ECG evidence of PSVT post-ablation;
3. History of sustained episodes of PSVT (i.e., typically lasting approximately 20 minutes or longer);
4. Females of childbearing potential who were sexually active with a male partner who were not surgically sterile (i.e., vasectomy) had to agree to use a highly effective form of contraception from the time of signed informed consent until 30 days after the last administration of study drug. Females of childbearing potential had to have a negative serum pregnancy test result at the Screening Visit and at the Final Study Visit, a negative urine pregnancy test at the Test Dose Randomization Visit and had to use a highly effective form of contraception between the visits.

The following categories defined females who were NOT considered to be of childbearing potential:
* Premenopausal females with 1 of the following:

1. Documented hysterectomy,
2. Documented bilateral salpingectomy or tubal ligation; or
3. Documented bilateral oophorectomy, or
* Postmenopausal females, defined as having amenorrhea for at least 12 months without an alternative medical cause;
5. Male participants, except those who were surgically sterile, had to use an approved highly effective form of contraception during the 3 days after any study drug administration; and
6. Signed written informed consent.

Exclusion Criteria:

Participants who met any of the following criteria were excluded from participation in the study:

1. Systolic blood pressure \<90 mmHg after a 5-minute rest in sitting position at the Screening Visit or before the Test Dose. In participants treated with a chronic prophylactic drug for PSVT (e.g., beta-blockers, verapamil, and diltiazem), the drug could be stopped for at least the equivalent of 5 half-lives, participants could be rescreened once, and chronic use of the drug could not be restarted after randomization;
2. History of severe symptoms of hypotension, especially syncope, during episodes of PSVT;
3. History of atrial arrhythmia that did not involve the AV node as part of the tachycardia circuit (e.g., atrial fibrillation, atrial flutter, intra-atrial tachycardia);
4. History of allergic reaction to verapamil;
5. Current therapy with digoxin or any Class I or III antiarrhythmic drug, except if these drugs were stopped at least the equivalent of 5 half-lives before the Test Dose Randomization Visit;
6. Current chronic therapy with oral amiodarone, or had taken oral amiodarone within 30 days prior to the Test Dose Randomization Visit;
7. Evidence of ventricular pre-excitation (e.g., delta waves, short PR interval \<100 msec, Wolff-Parkinson-White syndrome) on the ECG performed at the Screening Visit or before the Test Dose administration;
8. Evidence of a second- or third-degree AV block on the ECG performed at the Screening Visit or before the Test Dose administration;
9. History or evidence of severe ventricular arrhythmia (e.g., torsades de pointes, ventricular fibrillation, or ventricular tachycardia);
10. Current congestive heart failure defined by the New York Heart Association Class II to IV;
11. History of Acute Coronary Syndrome or stroke within 6 months of screening;
12. Evidence of hepatic dysfunction defined as alanine aminotransferase or aspartate aminotransferase \>3 × the upper limit of normal (ULN) or total bilirubin \>2 × ULN at the Screening Visit, unless due to Gilbert syndrome;
13. Evidence of End-Stage Renal Disease as determined by an estimated glomerular filtration rate assessed at the Screening Visit of \<15 mL/min/1.73m2, or requiring hemodialysis;
14. Females who were pregnant or lactating;
15. Evidence or history of any significant physical or psychiatric condition including drug abuse, which, in the opinion of the Investigator, could jeopardize the safety of participants, or affect their participation in the study. Additionally, the Investigator had the ability to exclude a participant if for any reason the Investigator judged the participant was not a good candidate for the study or would not be able to follow study procedures;
16. Participation in any investigational drug or device study or the use of any investigational drug or device within 30 days of the Screening Visit; or
17. Previously enrolled in a clinical trial for etripamil and received study drug during a perceived episode of PSVT.

Before randomization in the study, all participants received a Test Dose of an etripamil NS dosing regimen (etripamil 70 NS mg in Part 1 and in Parts 2 and 3 an initial dose of etripamil NS 70 mg followed by a second dose of etripamil NS 70 mg not earlier than 10 minutes and not later than 15 minutes after the first dose) to evaluate tolerability and to train participants on the study procedures. Participants who passed the Test Dose were randomized in the NODE-301 (2:1) or RAPID and RAPID Extension (2:1) study. A failure of the Test Dose was considered if participants met any of the following criteria occurring after administration of the either the first or second dose of etripamil NS 70 mg:

1. Any symptoms consistent with clinically severe hypotension such as pre-syncope, medically significant lightheadedness, syncope, nausea, or vomiting;
2. For participants with a pre-Test Dose Systolic Blood Pressure above 100 mmHg:

1. Decrease in SBP ≥40 mmHg after Test Dose; or
2. Post-Test Dose SBP \<80 mmHg;
3. For participants with a pre-Test Dose SBP between 90 mmHg and 100 mmHg (inclusive):

a) Post-Test Dose SBP \<75 mmHg;
4. Third-degree AV block, Mobitz II second-degree AV block, or Wenckebach with bradycardia ≤40 bpm;
5. New, significant sinus bradycardia Heart Rate ≤40 bpm or sinus pauses (≤3 seconds), if considered by the Investigator to put the participant's safety at risk if either were to occur while not under medical supervision;
6. Any new ventricular arrhythmia considered significant by the Investigator; or
7. Atrial fibrillation, atrial flutter or atrial tachycardia (event lasting longer than 30 seconds);
8. Refusal of second dose of etripamil Test Dose regimen.

Participants who failed the Test Dose proceeded in the study as follows:

* If the Investigator identified a possible reversible cause of the initial Test Dose failure (e.g., concomitant medication such as beta-blocker), a re-challenge with a new Test Dose of etripamil dose regimen was possible after elimination of the reversible cause (e.g., withdrawal of concomitant therapy with the appropriate washout period). Participants could be randomized if they passed the second Test Dose and the cause of the Test Dose failure was eliminated for the duration of the study; or
* If the Investigator could not identify a reversible cause of the initial Test Dose failure, or if the potential cause could not be modified (e.g., necessary antihypertensive drug to control blood pressure), participants could not be randomized and completed a Final Study Visit. Participants who failed the Test Dose are part of the Test Dose Only Population.