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

Paroxysmal Supraventricular Tachycardia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04072835
• Other study ID #: NODE-303
• Status: Completed
• Phase: Phase 3
• Start date: September 23, 2019
• Est. completion date: January 26, 2023

Study information

• Verified date: May 2024
• Source: Milestone Pharmaceuticals Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1116
• Est. completion date: January 26, 2023
• Est. primary completion date: January 26, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Paroxysmal Supraventricular Tachycardia
• Tachycardia
• Tachycardia, Supraventricular
• Tachycardia, Ventricular

Intervention

Drug:
• Etripamil NS
Participants were provided with an ambulatory Cardiac Monitoring System (CMS) to help document PSVT episodes. The CMS was self-applied by the participant, when PSVT symptoms begin. Participants self-administered etripamil NS if vagal maneuver was ineffective. After implementation of protocol amendment 2.1, participants had the option to administer a second dose of etripamil 70 mg 10 minutes after the first dose, if symptoms persisted. After an episode of PSVT where drug was administered, the participant returned to the investigative site for a study visit and was given 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.

Locations

Country	Name	City	State
Argentina	5106	Ciudad Autonoma de Buenos Aires	Buenos Aires
Argentina	5117	Ciudad Autonoma de Buenos Aires	Buenos Aires
Argentina	5125	Ciudad Autonoma de Buenos Aires
Argentina	5129	Ciudad Autónoma de Buenos Aires
Argentina	5116	Córdoba
Argentina	5118	Córdoba
Argentina	5123	Córdoba
Argentina	5134	Corrientes
Argentina	5102	La Plata
Argentina	5105	Mar Del Plata	Buenos Aires
Argentina	5112	Mar Del Plata	Buenos Aires
Argentina	5115	Quilmes	Buenos Aires
Argentina	5122	Ramos Mejía	Buenos Aires
Argentina	5132	Rosario
Argentina	5109	Salta
Argentina	5110	San Nicolas	Buenos Aires
Argentina	5130	San Nicolas
Argentina	5124	Temperley
Brazil	5221	Belo Horizonte	Reg1
Brazil	5228	Belo Horizonte
Brazil	5217	Brasília	Reg1
Brazil	5202	Campinas
Brazil	5215	Campinas	Reg1
Brazil	5222	Canoas	Reg1
Brazil	5207	Curitiba	Reg1
Brazil	5201	Goiânia
Brazil	5229	Jaú
Brazil	5227	Juiz de Fora	Reg1
Brazil	5209	Recife	Reg1
Brazil	5235	Rio De Janeiro
Brazil	5214	Salvador	Reg1
Brazil	5219	Santo André	Reg1
Brazil	5212	Sao Jose do Rio Preto	Reg1
Brazil	5220	São Paulo	Reg1
Brazil	5225	São Paulo	Reg1
Brazil	5232	São Paulo
Brazil	5204	Tatuí
Brazil	5205	Uberlândia	Reg1
Brazil	5231	Votuporanga
Canada	215	Cambridge	Ontario
Canada	2011	Greenfield Park	Quebec
Canada	202	Hamilton	Ontario
Canada	2017	Kelowna	British Columbia
Canada	2020	Levis	Quebec
Canada	203	Montreal	Quebec
Canada	205	Montréal	Quebec
Canada	2010	North Vancouver	British Columbia
Canada	2006	Oshawa	Ontario
Canada	2001	Ottawa	Ontario
Canada	2014	Québec	Quebec
Canada	2003	Saint-Jerome	Quebec
Canada	2019	Saskatoon	British Columbia
Canada	201	Sherbrooke	Quebec
Canada	2002	St Jean sur Richelieu	Quebec
Canada	2018	Surrey	British Columbia
Canada	212	Vancouver	British Columbia
Canada	213	Victoria	British Columbia
Colombia	5409	Armenia
Colombia	5404	Barranquilla
Colombia	5408	Bucaramanga
Colombia	5401	Medellín
Colombia	5407	Punta de Cartagena
Colombia	5403	San Gil
United States	1047	Austin	Texas
United States	1092	Austin	Texas
United States	1078	Boston	Massachusetts
United States	1042	Bradenton	Florida
United States	1010	Bridgeport	Connecticut
United States	1024	Canton	Ohio
United States	1065	Charlotte	North Carolina
United States	129	Charlotte	North Carolina
United States	123	Cincinnati	Ohio
United States	1115	Coeur d'Alene	Idaho
United States	142	Columbus	Ohio
United States	1123	Corvallis	Oregon
United States	1022	Cumming	Georgia
United States	1106	Daytona Beach	Florida
United States	1107	Edgewater	Florida
United States	1134	Elmer	New Jersey
United States	149	Fort Wayne	Indiana
United States	1016	Fort Worth	Texas
United States	1121	Fremont	California
United States	1077	Gilbert	Arizona
United States	1133	Haddon Heights	New Jersey
United States	1031	Hershey	Pennsylvania
United States	1032	Hialeah	Florida
United States	1017	Houston	Texas
United States	1062	Jackson	Tennessee
United States	1099	Kansas City	Missouri
United States	166	Lansing	Michigan
United States	101	Littleton	Colorado
United States	117	Lynchburg	Virginia
United States	137	Macon	Georgia
United States	1012	Memphis	Tennessee
United States	1026	Miami	Florida
United States	1055	Miami	Florida
United States	1008	Monroe	Louisiana
United States	1079	Mount Airy	North Carolina
United States	1064	Naples	Florida
United States	114	New York	New York
United States	1071	North Miami Beach	Florida
United States	1086	Oklahoma City	Oklahoma
United States	1009	Orlando	Florida
United States	1045	Peoria	Illinois
United States	1048	Plano	Texas
United States	122	Rapid City	South Dakota
United States	0116	Richmond	Virginia
United States	1076	Richmond	Virginia
United States	1004	Riverton	Utah
United States	119	Rochester	Minnesota
United States	1060	Saint Augustine	Florida
United States	1093	Saint Paul	Minnesota
United States	1007	Salisbury	Maryland
United States	1014	San Antonio	Texas
United States	1021	Southampton	New York
United States	1035	Stanford	California
United States	1018	Statesville	North Carolina
United States	1066	Trumbull	Connecticut
United States	1023	Vista	California
United States	1025	West Des Moines	Iowa
United States	1083	West Hills	California
United States	1082	Wyomissing	Pennsylvania
United States	105	Yardley	Pennsylvania
United States	1097	York	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Milestone Pharmaceuticals Inc.	IQVIA Biotech

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Canada,  Colombia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Adverse Events for Self-administered Etripamil NS Outside of the Clinical Setting.	Number of participants with any adverse events experienced from baseline up to the final study visit including the treatment of up to 4 perceived PSVT episodes.	From Baseline until a maximum of 4 episodes of perceived PSVT are treated with study drug, up to a maximum duration of 40 months.
Secondary	Time to Conversion	Kaplan-Meier estimates of time to conversion up to 60 minutes after etripamil administration for adjudicated conversion of confirmed episodes of PSVT to SR (Sinus Rhythm) reported at Follow-up Visit 1.	Time to conversion up to 60 minutes after etripamil administration.