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

Study Overview
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Brief Summary
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This is a two-part, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of etripamil NS self-administered by patients who experience an episode of paroxysmal ventricular tachycardia (PSVT) in an at-home setting. Part 1 comprised the conduct of the NODE-301 study up to the date of the adjudication of 150th positively adjudicated PSVT episode and Part 2 comprises the conduct of the NODE-301 study after the completion of Part 1. The RAPID Study (NODE-301 - Part 2) will enroll patients enrolled during Part 1 who had not dosed with the double-blind study drug, or had not discontinued the study before the adjudication of the 150th positively adjudicated PSVT episode in Part 1, and patients enrolled into the study following the completion of Part 1. Enrollment will continue until and for approximately 6 months after the date of the adjudication of the 180th positively adjudicated PSVT episode. The study will include the following visits: A Screening Visit, A Test Dose Randomization Visit, Monthly Follow-up Visits, A Randomized Treatment Period, A Randomized Treatment Period Follow-Up Visit, An Open-Label Treatment Period, and A Final Study Visit.

Detailed Description
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NODE-301 is a two-part, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of etripamil NS self-administered by patients who experience an episode of paroxysmal ventricular tachycardia (PSVT) in an at-home setting. Each episode will be documented by an ambulatory Cardiac Monitoring System (CMS) that will be placed on the chest by the patient or caregiver when symptoms begin and will record at least 5 hours of continuous electrocardiogram (ECG). This is an event-driven study. The study is comprised of 2 parts: Part 1 and Part 2. Part 1 comprised the conduct of NODE-301 up to the date of the adjudication of the 150th positively adjudicated PSVT episode (January 15th, 2020). Part 1 had the same general study design as Part 2 of the study, with the key differences being that Part 2 includes a repeat dosing option during the randomized treatment phase, as well as during an added open-label treatment phase. Part 2 (the RAPID Study) describes the conduct of NODE-301 following the completion of Part 1. RAPID will enroll patients enrolled during Part 1 who had not dosed with the double-blind study drug, or had not discontinued the study before the adjudication of the 150th positively adjudicated PSVT episode in Part 1, and patients enrolled into the study following the completion of Part 1. Before randomization in the RAPID study, all patients will receive a test dose of an etripamil NS dosing regimen (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 patients on the study procedures. The RAPID Study includes a Screening Visit, a Test Dose Randomization Visit, Monthly Follow-up Visits, a Randomized Treatment Period, a Randomized Treatment Period Follow-Up Visit, an Open-Label Treatment Period, and a Final Study Visit. Study comprised of 4 arms: 2 arms consisting of patients enrolled during Part 1 randomized 2:1 to a single dose of study drug (etripamil NS 70 mg or placebo) to treat a perceived episode of PSVT 2 arms consisting of newly enrolled patients who pass a test dose regimen of etripamil NS 70 mg, randomized 1:1 to a dosing regimen of etripamil or placebo that allows patients to self-administer a second dose (not earlier than 10 minutes and not later than 15 minutes after the first dose) of study drug if symptoms are still present at 10 minutes, to treat a perceived PSVT episode. Safety will be monitored during the treatment periods. To ensure the safety of trial participants in RAPID, new processes or modification of listed processes may be put in place to reduce the risks associated with the COVID-19 pandemic. These potential changes include, but are not limited to, the use of tele-medicine to conduct study visit procedures, conduct of study procedures outside of the clinical site (i.e., at a patient's home) by site personnel or by trained but non-study personnel, and the distribution of investigational products by alternative secure delivery methods.

Official Title
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Multi-Centre, Randomized, Double-Blind, Placebo-Controlled, Efficacy, and Safety Study of Etripamil Nasal Spray for the Termination of Spontaneous Episodes of Paroxysmal Supraventricular Tachycardia. NODE 301 Trial.

Conditions
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Paroxysmal Supraventricular Tachycardia

Intervention / Treatment
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* Drug: Etripamil
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who meet all of the following criteria will be eligible to participate in the study: Male or female patients at least 18 years of age; Electrographically documented history of PSVT (e.g., electrocardiogram [ECG] obtained during an episode of PSVT, Holter monitoring, loop recorder, etc). If patient had a prior ablation for PSVT, patient must have documented ECG evidence of PSVT post-ablation; History of sustained episodes of PSVT (i.e., typically lasting approximately 20 minutes or longer); Females of childbearing potential who are sexually active with a male partner who is not surgically sterile (i.e., vasectomy) must 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 should 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 must use a highly effective form of contraception between the visits. The following categories define females who are NOT considered to be of childbearing potential: Premenopausal females with 1 of the following: Documented hysterectomy, Documented bilateral salpingectomy or tubal ligation; or Documented bilateral oophorectomy, or Postmenopausal females, defined as having amenorrhea for at least 12 months without an alternative medical cause; Male patients, except those who are surgically sterile, must use an approved highly effective form of contraception during the 3 days after any study drug administration; and Signed written informed consent. Exclusion Criteria: Patients who meet any of the following criteria will be excluded from participation in the study: Systolic blood pressure <90 mmHg after a 5-minute rest in sitting position at the Screening Visit or before the test dose. In patients treated with a chronic prophylactic drug for PSVT (e.g., beta-blockers, verapamil, and diltiazem), the drug may be stopped for at least the equivalent of 5 half-lives, patients may be rescreened once, and chronic use of the drug cannot be restarted after randomization; History of severe symptoms of hypotension, especially syncope, during episodes of PSVT; History of atrial arrhythmia that does not involve the AV node as part of the tachycardia circuit (e.g., atrial fibrillation, atrial flutter, intra-atrial tachycardia); History of allergic reaction to verapamil; Current therapy with digoxin or any Class I or III antiarrhythmic drug, except if these drugs are stopped at least the equivalent of 5 half-lives before the Test Dose Randomization Visit; Current chronic therapy with oral amiodarone, or have taken oral amiodarone within 30 days prior to the Test Dose Randomization Visit; 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; Evidence of a second- or third-degree AV block on the ECG performed at the Screening Visit or before the test dose administration; History or evidence of severe ventricular arrhythmia (e.g., torsades de pointes, ventricular fibrillation, or ventricular tachycardia); Current congestive heart failure defined by the New York Heart Association Class II to IV; History of Acute Coronary Syndrome or stroke within 6 months of screening; 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; 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; Females who are pregnant or lactating; 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 patients, or affect their participation in the study. Additionally, the Investigator has the ability to exclude a patient if for any reason the Investigator judges the patient is not a good candidate for the study or will not be able to follow study procedures; 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 Previously enrolled in a clinical trial for etripamil and received study drug during a perceived episode of PSVT. Before randomization in the RAPID study, all patients will receive a test dose of an etripamil NS dosing regimen (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 patients on the study procedures. Both doses of the etripamil dosing regimen must be administered for the test dose to be considered evaluable. A failure of the test dose is considered if patients meet any of the following criteria occurring after administration of the either the first or second dose of etripamil NS 70 mg: Any symptoms consistent with clinically severe hypotension such as pre-syncope, medically significant lightheadedness, syncope, nausea, or vomiting; For patients with a pre-test dose Systolic Blood Pressure above 100 mmHg: Decrease in SBP ≥40 mmHg after test dose; or Post-test dose SBP <80 mmHg; For patients with a pre-test dose SBP between 90 mmHg and 100 mmHg (inclusive): a) Post-test dose SBP <75 mmHg; Third-degree AV block, Mobitz II second-degree AV block, or Wenckebach with bradycardia ≤40 bpm; New, significant sinus bradycardia Heart Rate ≤40 bpm or sinus pauses (≤3 seconds), if considered by the Investigator to put the patient's safety at risk if either were to occur while not under medical supervision; Any new ventricular arrhythmia considered significant by the Investigator; or Atrial fibrillation, atrial flutter or atrial tachycardia (event lasting longer than 30 seconds); Refusal of second dose of etripamil test dose regimen. Patients who fail the test dose will proceed in the study as follows: If the Investigator identifies 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 NS 70 mg will be possible after elimination of the reversible cause (e.g., withdrawal of concomitant therapy with the appropriate washout period). Patients may be randomized if they pass the second test dose and the cause of the test dose failure is eliminated for the duration of the study; or If the Investigator cannot identify a reversible cause of the initial test dose failure, or if the potential cause cannot be modified (e.g., necessary antihypertensive drug to control blood pressure), patients will not be randomized and will complete a Final Study Visit. Patients who fail the test dose will be part of the Test Dose Only Population.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Study comprised of 4 arms: 2 arms consisting of patients enrolled during Part 1 randomized 2:1 to a single dose of study drug (etripamil NS 70 mg or placebo) to treat a perceived episode of PSVT. 2 arms consisting of newly enrolled patients who pass a test dose regimen of etripamil NS 70 mg, randomized 1:1 to a dosing regimen of etripamil or placebo that allows patients to self-administer a second dose (not earlier than 10 minutes and not later than 15 minutes after the first dose) of study drug if symptoms are still present at 10 minutes, to treat a perceived PSVT episode.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Etripamil 70 mg Single Dose<br>Self- administration of a single dose of 70 mg of etripamil. | Drug: Etripamil<br>* Etripamil will be 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.<br>|
| Placebo Comparator: Placebo Single Dose<br>Self- administration of a single dose of placebo. | Drug: Placebo<br>* Placebo will be 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.<br>|
| Experimental: Etripamil 70 mg with Optional Second Dose<br>Dosing regimen that permits a second dose of etripamil 70 mg | Drug: Etripamil<br>* Etripamil will be 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.<br>|
| Placebo Comparator: Placebo with Optional Second Dose<br>Dosing regimen that permits a second dose of placebo. | Drug: Placebo<br>* Placebo will be 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The time to conversion of an episode of PSVT to sinus rhythm (SR) after study drug administration. | 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 30 minutes of start of study drug dosing. | Within 30 minutes of start of study drug dosing. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relief of specific symptoms (i.e., heart palpitations, rapid pulse feeling, chest pain, anxiety, shortness of breath, dizziness, and fainting) potentially associated with an episode of PSVT. |  | Completed as soon as possible after termination of the treated PSVT episode | 
| Rating of Treatment Satisfaction Questionnaire for Medication (TSQM). |  | Completed as soon as possible after termination of the treated PSVT episode | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cardiac monitoring, Paroxysmal supraventricular tachycardia, atrioventricular nodal reentrant tachycardia, atrioventricular reciprocating tachycardia, calcium channel blocker, conversion rate