Efficacy and Safety of Etripamil for the Termination of Spontaneous Paroxysmal Supraventricular Tachycardia (PSVT).

NODE-301 was a three-part, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of etripamil NS self-administered by participants who experienced an episode of PSVT in an at-home setting. Each episode was documented by an ambulatory Cardiac Monitoring System (CMS) that was placed on the chest by the participants or caregiver when symptoms begin and recorded at least 5 hours of continuous electrocardiogram (ECG).

This was an event-driven study. The study comprised of three parts: Parts 1, 2, and 3.

NODE-301 Part 1 included participants that received the randomized study drug to treat an episode of PSVT until the 150th positively adjudicated PSVT episode (January 15th, 2020). Participants were randomized to etripamil 70 mg or placebo in a 2:1 ratio. Participants had a Test Dose Randomization Visit where they received 70 mg etripamil in sinus rhythm and a Treatment Period during which they could administer the randomized study drug during a perceived episode of PSVT.

Part 2 (also referred as the RAPID study) included participants that did not use the randomized study drug to treat a perceived episode of PSVT before the Part 1 data cutoff and newly enrolled participants. Before randomization in the RAPID study, all participants received a Test Dose of etripamil consisting of an initial dose of etripamil 70 mg followed by a second dose of etripamil 70 mg 10 minutes later to evaluate tolerability and to train participants on the study procedures. After a successful Test Dose, participants in Part 2 were randomized to etripamil or placebo in a 1:1 ratio. When experiencing a PSVT episode, participants were instructed to administer a first dose of randomized study drug (70 mg etripamil or placebo) followed 10 minutes later, if PSVT symptoms persisted, by a second dose of study drug (70 mg etripamil or placebo). After having administered the randomized study drug for a perceived episode of PSVT, participants could enter an open-label period during which they had the possibility to treat a second episode of PSVT with open-label etripamil (70 mg etripamil with optional second dose of 70 mg etripamil).

Part 2 continued until the 180th positively adjudicated PSVT episode (the data on which the primary efficacy analysis of RAPID was conducted) (July 20th 2022). The study continued for approximately 6 months after the 180th positively adjudicated PSVT episode in Part 2 and this extension is referred to as Part 3 (also referred to as RAPID Extension). The design of Parts 2 and 3 were the same and therefore their results are combined in this publication.

NODE-301 study comprised 6 arms:

* 2 arms consisting of participants enrolled in Part 1 that treated a perceived episode of PSVT with randomized study drug (etripamil NS 70 mg or placebo) in a 2:1 ratio.
* 1 arm consisting of participants that only received the Test Dose in Part 1.
* 2 arms consisting of participants enrolled in Parts 2 and 3 that treated a perceived episode of PSVT with randomized study drug (etripamil NS 70 mg with optional second dose of 70 mg etripamil or placebo) in a 1:1 ratio and could be enrolled in the open-label period to treat an additional PSVT episode with etripamil
* 1 arm consisting of participants that only received the Test Dose in Parts 2 and 3.

• Etripamil (Drug), also known as MSP-2017: Etripamil administered via the Aptar Pharma Nasal Spray Bidose System, supplied as prefilled devices packaged into child-resistant boxes with instructions for use provided in the study drug box.
• Placebo (Drug): Placebo administered via the Aptar Pharma Nasal Spray Bidose System, supplied as prefilled devices packaged into child-resistant boxes with instructions for use provided in the study drug box.
• Etripamil Test Dose (Drug), also known as MSP-2017 Test Dose: During the Test Dose, etripamil administered via the Aptar Pharma Nasal Spray Bidose System, supplied as prefilled devices packaged into child-resistant boxes with instructions for use provided in the study drug box.

Primary outcomes

• The Time to Conversion of an Episode of PSVT to Sinus Rhythm (SR) After Study Drug Administration. [NODE-301 Part 1: Within 5 hours of start of study drug dosing. NODE-301 Parts 2 and 3: Within 30 minutes of start of study drug dosing.]: The primary efficacy endpoint is defined as an adjudicated termination of a positively adjudicated episode of PSVT (AV nodal reentrant tachycardia or AV reentrant tachycardia determination if possible) and conversion to sinus rhythm (SR) for at least 30 seconds within 5 hours (NODE-301 Part 1), or 30 minutes (NODE-301 Parts 2 and 3) of start of study drug dosing.

Sex: All, ages: 18 Years to any

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.

Participant flow

Outcome results

• The Time to Conversion of an Episode of PSVT to Sinus Rhythm (SR) After Study Drug Administration. (Primary), Count of participants, Participants: Part 1 - Placebo Single Dose 36; Part 1 - Etripamil 70 mg 80; Parts 2 and 3 - Placebo With Optional Second Dose of Placebo ; Parts 2 and 3 - Etripamil 70 mg With Optional Second Dose of Etripamil 70 mg (p 0.1212)

Adverse events

Time frame: Average of 9.4 months, adverse events were monitored from the time of test dose administration (i.e.,Test Dose Randomization Visit) until study participation was completed (i.e., after the Final Study Visit).

Serious adverse events by term

Other adverse events by term

61 more sites not listed.

• Results publication: Stambler BS, Camm AJ, Alings M, Dorian P, Heidbuchel H, Houtgraaf J, Kowey PR, Merino JL, Mondesert B, Piccini JP, Pokorney SD, Sager PT, Verma A, Wharton JM, Bharucha DB, Plat F, Shardonofsky S, Chen M, Ip JE; RAPID Investigators. Self-administered intranasal etripamil using a symptom-prompted, repeat-dose regimen for atrioventricular-nodal-dependent supraventricular tachycardia (RAPID): a multicentre, randomised trial. Lancet. 2023 Jul 8;402(10396):118-128. doi: 10.1016/S0140-6736(23)00776-6. Epub 2023 Jun 15. PMID 37331368
• Results publication: Stambler BS, Plat F, Sager PT, Shardonofsky S, Wight D, Potvin D, Pandey AS, Ip JE, Coutu B, Mondesert B, Sterns LD, Bennett M, Anderson JL, Damle R, Haberman R, Camm AJ. First Randomized, Multicenter, Placebo-Controlled Study of Self-Administered Intranasal Etripamil for Acute Conversion of Spontaneous Paroxysmal Supraventricular Tachycardia (NODE-301). Circ Arrhythm Electrophysiol. 2022 Dec;15(12):e010915. doi: 10.1161/CIRCEP.122.010915. Epub 2022 Nov 28. PMID 36441560
• Results publication: 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 Nov;253:20-29. doi: 10.1016/j.ahj.2022.06.005. Epub 2022 Jun 18. PMID 35728658

• Study Protocol: The RAPID study (NODE-301 Parts 2 and 3) (PDF, 2022-01-14)
• Study Protocol: NODE-301 Part 1 (PDF, 2019-07-09)
• Statistical Analysis Plan: The RAPID study (NODE-301 Parts 2 and 3) (PDF, 2022-06-06)
• Statistical Analysis Plan: NODE-301 Part 1 (PDF, 2020-01-13)

• David Bharucha, MD, Study director, Milestone Pharmaceuticals

NIH grants: 2018