Efficacy and Safety of Etripamil for the Termination of Spontaneous Paroxysmal Supraventricular Tachycardia (PSVT). (NODE-301)

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 and RAPID Studies

This was a three-part, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of etripamil nasal spray (NS) self-administered by participants who experienced an episode of paroxysmal supraventricular tachycardia (PSVT) in an at-home setting.

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. Part 2 (also referred as the RAPID study) included participants that did not receive the randomized study drug in Part 1 and newly enrolled participants until the 180th positively adjudicated PSVT episode in Part 2. 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).

Study Overview

• Status: Terminated
• Conditions: Paroxysmal Supraventricular Tachycardia
• Intervention / Treatment: Drug: Etripamil; Drug: Placebo; Drug: Etripamil Test Dose

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 1097
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Arlon, Belgium, 6700
    • Clinique Du Sud- Luxembourg
  • Bonheiden, Belgium, 2820
    • Imelda Hospital
  • Bruxelles, Belgium, 1070
    • Universite Libre de Bruxelles (ULB) - Hopital Erasme
  • Bruxelles, Belgium, 1020
    • UVC Brugmann University Hospital - Centre Hospitalier Universitaire (CHU)
  • Edegem, Belgium, 2650
    • Antwerp University Hospital (UZA)
  • Gilly, Belgium, 6060
    • Grand Hopital de Charleroi (GHdC) - Site Saint-Joseph
  • Hasselt, Belgium, 3500
    • Pharmacy Campus Virga Jesse (losplaats 7)
  • Leuven, Belgium, 3000
    • University Hospital (UZ) Leuven
  • Liège, Belgium, 3000
    • Regional Hospital Centre Citadelle
  • Mons, Belgium, 7000
    • CHU Ambroise Pare
  • Yvoir, Belgium, 5530
    • CHU UCL Namur - Site Godinne
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • Libin Cardiovascular Institute of Alberta - University of Calgary
    • Edmonton, Alberta, Canada, T5H 3V9
      • Royal Alexandra Hospital
  • British Columbia
    • North Vancouver, British Columbia, Canada, V5Z 0A9
      • Medical Arts Health Research Group - North Vancouver
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Vancouver Coastal Health Research
    • Victoria, British Columbia, Canada, V8T 1Z4
      • Victoria Cardiac Arrhythmia Trials, Inc.
  • Manitoba
    • Winnipeg, Manitoba, Canada, R2H 2A6
      • University of Manitoba, St Boniface General Hospital
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • Dalhousie University - QEII Health Sciences Centre
  • Ontario
    • Cambridge, Ontario, Canada, N1R 6V6
      • Cambridge Cardiac Care Centre
    • Guelph, Ontario, Canada, N1H 1B1
      • Dawson Road Medical Centre
    • Hamilton, Ontario, Canada, L8L 0A6
      • Hamilton Health Sciences
    • London, Ontario, Canada, N6A 5A5
      • London Health Sciences Centre
    • Newmarket, Ontario, Canada, L3Y 2P6
      • Partners in Advanced Cardiac Evaluation (PACE) Cardiology Clinic
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital
  • Quebec
    • Montreal, Quebec, Canada, H1T 1C8
      • The Montreal Heart Institute
    • Montreal, Quebec, Canada, H2X 0A9
      • CHUM Recherche Cardiologie
    • Montréal, Quebec, Canada, H3G 1A4
      • McGill University Health Center - Research Institute
    • Québec, Quebec, Canada, G1V 4G5
      • Institut Universitaire De Cardiologie Et De Pneumologie De Québec
    • Saint-Jean-sur-Richelieu, Quebec, Canada, J3A 1J2
      • CardioVasc HR
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • CIUSSS de l'Estrie - CHUS
    • Terrebonne, Quebec, Canada, J6V 2H2
      • CSSS du Sud de Lanaudiere - Hopital Pierre Le Gardeur
• France
  • Brest, France, 29609
    • CHRU de Brest - Hopital de la Cavale Blanche
  • Bron, France, 69677
    • HCL Hôpital Louis Pradel
  • La Rochelle, France, 17000
    • Hopital Saint-Louis de La Rochelle
  • Lille, France, 59037
    • CHU de Lille - Institut coeur poumon
  • Pau, France, 64000
    • Centre Hospitalier de Pau
  • Besancon
    • Besançon, Besancon, France, 25030
      • CHRU Besancon - Hopital Jean Minjoz
  • Grenoble
    • La Tronche, Grenoble, France, 38043
      • CHU Grenoble-Alpes - Hopital Michallon
• Germany
  • Berlin, Germany, 12351
    • Vivantes Klinikum Neukoelln
  • Dresden, Germany, 01099
    • FAZ Dresden-Neustadt GbR
  • Dresden, Germany, 04779
    • Kardiologische Praxis
  • Papenburg, Germany, 26871
    • Kardiologische Gemeinschaftspraxis Papenburg
  • Siegen, Germany, 57072
    • Zentrum fuer Praevention und Rehabilitation
  • Ludenscheid
    • Lüdenscheid, Ludenscheid, Germany, 58515
      • Maerkische Gesundheitsholding GmbH - Klinikum Luedenscheid
  • Munchen
    • München, Munchen, Germany, 81379
      • Peter Osypka Herzzentrum München
• Hungary
  • Budapest, Hungary, 1134
    • Magyar Honvedseg Egeszsegugyi Kozpont
  • Budapest, Hungary, 1097
    • Dél-Pesti Centrumkórház
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem Klinikai
  • Encs, Hungary, H-3860
    • CRU Hungary Kft.
  • Zalaegerszeg, Hungary, 8900
    • Belvárosi Egészségház
  • Bekescaba
    • Bekescsaba, Bekescaba, Hungary, 5600
      • Dr Lakatos Ferenc Belgyogyaszati-Kardiologiai Maganrendelo
  • Debrecon
    • Debrecen, Debrecon, Hungary, 4026
      • Nehezlegzes Ambulancia
• Netherlands
  • Amersfoort, Netherlands, 3813 TZ
    • Meander Medisch Centrum - Locatie Amersfoort
  • Arnhem, Netherlands, 6815 AD
    • Ziekenhuis Rijnstate - Locatie Arnhem
  • Beverwijk, Netherlands, 1942 LE
    • Rode Kruis Ziekenhuis
  • Blaricum, Netherlands, 1261 AN
    • Tergooiziekenhuizen Blaricum
  • Breda, Netherlands, 4818 CK
    • Amphia Ziekenhuis - Locatie Breda Molengracht
  • Capelle Aan Den IJssel, Netherlands, 2906 ZC
    • IJsselland Ziekenhuis
  • Delft, Netherlands, 2625 AD
    • Reinier de Graaf Gasthuis
  • Deventer, Netherlands, 7416 SE
    • Deventer Ziekenhuis
  • Doetinchem, Netherlands, 7009 BL
    • Slingeland Ziekenhuis
  • Ede, Netherlands, 6716 RP
    • Ziekenhuis Gelderse Vallei
  • Hardenberg, Netherlands, 7772 SE
    • Ropcke-Zweers Ziekenhuis
  • Hoogeveen, Netherlands, 7909
    • Treant Zorggroep
  • Leiderdorp, Netherlands, 2353 GA
    • Alrijne Ziekenhuis
  • Maastricht, Netherlands, 6229 HX
    • Maastricht University Medical Center
  • Schiedam, Netherlands, 3118 JH
    • Franciscus Gasthuis & Vlietland - Locatie Vlietland
  • Utrecht, Netherlands, 3582 KE
    • Diakonessenhuis - Locatie Utrecht
  • Utrecht, Netherlands, 3584 CX
    • Jeroen Bosch Ziekenhuis
• Poland
  • Bydgoszcz, Poland, 85-065
    • MICS Centrum Medyczne Torun
  • Bydgoszcz, Poland, 85-231
    • Centrum Medyczne Kermed
  • Katowice, Poland, 40-530
    • Specjalistyczna Praktyka Lekarska
  • Libiąż, Poland, 32-590
    • Prywatny Specjalistyczny Gabinet Internistyczny
  • Oswiecim, Poland, 32-600
    • Medicome Sp. Z O.O.
  • Puławy, Poland, 24-100
    • SP ZOZ Szpital Specjalistyczny w Pulawach
  • Sopot, Poland, 81-717
    • NZOZ PRO CORDIS Sopockie Centrum Badan Kardiologicznych
  • Toruń, Poland, 87-100
    • Osrodek Badan Klinicznych CLINSANTE S.C.
  • Tychy, Poland, 43-100
    • X Oddzial Kardiologii Inwazyjnej, Elektrofizjologii i Elektrostymulacji
  • Warsaw, Poland, 04-628
    • Kardiosystem
  • Kedzierzyn Kozle
    • Kędzierzyn-Koźle, Kedzierzyn Kozle, Poland, 43-450
      • American Heart of Poland S.A., IV Oddzial Kardiologii Inwazyjnej, Elektrostymulacji i Angiologii
  • Krakov
    • Kraków, Krakov, Poland, 31-534
      • Gabinety Daszmed
  • Lodz
    • Łódź, Lodz, Poland, 92-213
      • Samodzielny Publiczny Zaklad Opieki Zdrowotnej Centralny Szpital Kliniczny, Uniwersytetu Medycznego w Lodzi
    • Łódź, Lodz, Poland, 93-338
      • Instytut Centrum Zdrowia Matki Polki
  • Rzeszow
    • Rzeszów, Rzeszow, Poland, 35-301
      • Kliniczny Szpital Wojewódzki nr 2, Rzeszów
• Spain
  • Alicante, Spain, 03010
    • Hospital General Universitario de Alicante
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Barcelona, Spain, 8025
    • Hospital de la Santa Creu i Sant Pau
  • Barcelona, Spain, 08907
    • Hospital Universitari de Bellvitge
  • Granada, Spain, 18014
    • Complejo Hospitalario Universitario de Granada - Hospital Universitario Virgen de las Nieves
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañon
  • Majadahonda, Spain, 28222
    • Hospital Universitario Puerta de Hierro
  • Oviedo, Spain, 33011
    • Hospital Universitario Central de Asturias
  • Pamplona, Spain, 31008
    • Complejo Hospitalario de Navarra
  • Reus, Spain, 43204
    • Hospital Universitari Sant Joan de Reus
  • Santiago De Compostela, Spain, 15706
    • Hospital Universitario la Paz Rua Choupana
  • Sevilla, Spain, 41009
    • Hospital Universitario Virgen Macarena
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocio
  • Valencia, Spain, 46010
    • Hospital Clínico Universitario de Valencia
  • Zaragoza, Spain, 50009
    • Hospital Universitario Clínico Lozano Blesa
  • Andalucia
    • Granada, Andalucia, Spain, 18002
      • Martínez Hervás Cardiólogos
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Hospital Germans Trias i Pujol
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46014
      • Hospital General Universitario de Valencia (HGUV)
  • Cordoba
    • Córdoba, Cordoba, Spain, 14004
      • Hospital Universitario Reina Sofia
  • Malaga
    • Málaga, Malaga, Spain, 29010
      • Hospital Universitario Virgen de la Victoria
  • Murcia
    • El Palmar, Murcia, Spain, 30120
      • Hospital Clinico Universitario Virgen de la Arrixaca
  • Pontevedra
    • Vigo, Pontevedra, Spain, 36213
      • Hospital Alvaro Cunqueiro
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Arizona Arrhythmia Research Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
    • Little Rock, Arkansas, United States, 72205
      • Arkansas Cardiology
  • California
    • Cerritos, California, United States, 91722
      • Medvin Clinical Research
    • Encinitas, California, United States, 92024
      • North Coast Cardiolog
    • Encinitas, California, United States, 92024
      • Titan Medical Research - Oceanside
    • Los Alamitos, California, United States, 90720
      • Los Alamitos Cardiovascular
    • Northridge, California, United States, 91324
      • Amicis Research Center - Northridge
    • Palm Springs, California, United States, 92262
      • RESPIRE Research
  • Colorado
    • Littleton, Colorado, United States, 80120
      • South Denver Cardiology Associates, P.C
  • Connecticut
    • Norwalk, Connecticut, United States, 06905
      • Cardiology Associates of Fairfield County
  • Florida
    • Boca Raton, Florida, United States, 33486
      • FWD Clinical Research
    • Jacksonville, Florida, United States, 32207
      • Baptist Health Ambulatory Services d/b/a
    • Miami, Florida, United States, 33144
      • United Health Research, LLC
  • Georgia
    • Columbus, Georgia, United States, 31904
      • IACT Health
    • Fayetteville, Georgia, United States, 30214
      • Piedmont Heart Institute- Fayetteville
    • Fayetteville, Georgia, United States, 30309
      • Piedmont Heart Institute-Fayetteville
    • Macon, Georgia, United States, 31201
      • Georgia Arrythmia Consultants&Research Institute
  • Idaho
    • Boise, Idaho, United States, 83702
      • St. Luke's Idaho Cardiology Associates
    • Idaho Falls, Idaho, United States, 83404
      • Idaho Catalyst Clinical Research
  • Illinois
    • Elk Grove Village, Illinois, United States, 60007
      • AMITA Health Medical Group Heart & Vascular Elk Grpve Village
  • Indiana
    • Fort Wayne, Indiana, United States, 46845
      • Parkview Physicians Group - Cardiology
  • Iowa
    • West Des Moines, Iowa, United States, 50266
      • Mercy One Iowa Heart Center
  • Louisiana
    • West Monroe, Louisiana, United States, 71291
      • Clinical Trials of America, LLC - Monroe, LA
  • Maryland
    • Baltimore, Maryland, United States, 21237
      • MedStar Health Research Institute - Chesapeake Cardiovascular Associates
  • Michigan
    • Lansing, Michigan, United States, 48912
      • Sparrow Clinical Research Institute
    • Southgate, Michigan, United States, 48195
      • Revival Research Institute, LLC - Southgate, MI
  • Missouri
    • Saint Louis, Missouri, United States, 65804
      • Mercy Research
  • New Jersey
    • Elmer, New Jersey, United States, 08318
      • Cardiovascular Associates of the Delaware Valley - Elmer
    • Haddon Heights, New Jersey, United States, 08035
      • Cardiovascular Associates of the Delaware Valley
    • Morristown, New Jersey, United States, 07962
      • Atlantic Health System - Morristown Medical Center
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • New York, New York, United States, 10032
      • Columbia University
    • New York, New York, United States, 10065
      • New York Presbyterian Hospital/Weill Cornell Medical Center
  • North Carolina
    • Cary, North Carolina, United States, 27518
      • Cary Research Group, LLC
    • Charlotte, North Carolina, United States, 28204
      • The Presbyterian Hospital DBA Novant Health Heart and Vascular Institute
    • Charlotte, North Carolina, United States, 28204
      • Sanger Heart and Vascular Institute
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Hatton Institute for Research & Education, Trihealth, Inc. - Cardiology
    • Columbus, Ohio, United States, 43210
      • The Ohio State University (OSU) Wexner Medical Center
    • Marion, Ohio, United States, 43302
      • Rama Research LLC
    • Springfield, Ohio, United States, 45505
      • Heart House Research Foundation, LLC
    • Toledo, Ohio, United States, 43615
      • ProMedica Toledo Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina (MUSC)
    • Columbia, South Carolina, United States, 29203
      • Prisma Health Midlands
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Monument Health Clinical Research, A Department of Monument Health Rapid City Hospital, Inc
  • Texas
    • Allen, Texas, United States, 75013
      • North Texas Research Associates
    • Denton, Texas, United States, 76201
      • Cardiovascular Clinic of North Texas
    • Denton, Texas, United States, 76201
      • Revival Research Institute, LLC
    • Fort Worth, Texas, United States, 76104
      • Apex Trials Group
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Houston, Texas, United States, 77025
      • Angiocardiac Care of Texas
    • Temple, Texas, United States, 76508
      • Scott & White Memorial Hospital: Baylor Scott & White Research Institute
    • Webster, Texas, United States, 77598
      • Bay Area Heart
  • Utah
    • Murray, Utah, United States, 84157-7000
      • Intermountain Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Etripamil 70 mg Single Dose; Self-administration of a single dose etripamil 70 mg for a perceived episode of PSVT.	Drug: Etripamil; 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.; Other Names: MSP-2017
Placebo Comparator: Part 1: Placebo Single Dose; Self-administration of a single dose of placebo for a perceived episode of PSVT.	Drug: Placebo; 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.
Other: Part 1: Test dose only (etripamil 70 mg); Single test dose of etripamil 70 mg in sinus rhythm	Drug: Etripamil 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.; Other Names: MSP-2017 Test Dose
Experimental: Part 2 & Part 3: Etripamil 70 mg with Optional Second Dose; Self-administration of 70 mg etripamil for a perceived episode of PSVT followed 10 minutes later by an optional second dose of 70 mg etripamil, if symptoms persisted. Participants could be enrolled in the open-label period to treat an additional PSVT episode with etripamil.	Drug: Etripamil; 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.; Other Names: MSP-2017
Placebo Comparator: Part 2 & Part 3: Placebo with Optional Second Dose; Self-administration of placebo for a perceived episode of PSVT followed 10 minutes later by an optional second dose of placebo, if symptoms persisted. Participants could be enrolled in the open-label period to treat an additional PSVT episode with etripamil.	Drug: Placebo; 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.
Other: Part 2 & Part 3: Test dose only (etripamil 70 mg + 70 mg); Repeat Test Dose of etripamil 70 mg (2X 70mg) 10 minutes apart in sinus rhythm	Drug: Etripamil 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.; Other Names: MSP-2017 Test Dose

What is the study measuring?

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 5 hours (NODE-301 Part 1), or 30 minutes (NODE-301 Parts 2 and 3) of start of study drug dosing.	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.

Secondary Outcome Measures

Outcome Measure	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
Time to conversion at time points prior to, and later than, 30 minutes.	From 10 minutes to 300 minutes after start of study drug dosing.
Rating of Treatment Satisfaction Questionnaire for Medication (TSQM-9).	Completed as soon as possible after termination of the treated PSVT episode

Other Outcome Measures

Outcome Measure	Time Frame
The percentage of patients requiring additional medical intervention to terminate an episode of PSVT.	Within 5 hours after administration of study drug
The repeat of key efficacy endpoints in various subgroups of interest (e.g., concomitant medications).	Within 5 hours after administration of study drug

Collaborators and Investigators

• Sponsor: Milestone Pharmaceuticals Inc.
• Collaborators: Medpace, Inc.; IQVIA Biotech
• Investigators: Study Director: David Bharucha, MD, Milestone Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): June 18, 2018
• Primary Completion (Actual): January 20, 2023
• Study Completion (Actual): January 20, 2023

Study Registration Dates

• First Submitted: March 7, 2018
• First Submitted That Met QC Criteria: March 7, 2018
• First Posted (Actual): March 13, 2018

Study Record Updates

• Last Update Posted (Actual): July 12, 2024
• Last Update Submitted That Met QC Criteria: June 18, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: cardiac monitoring; Paroxysmal supraventricular tachycardia; atrioventricular nodal reentrant tachycardia; atrioventricular reciprocating tachycardia; conversion rate; calcium channel blocker administered at home
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Cardiac Conduction System Disease; Tachycardia; Tachycardia, Ventricular; Tachycardia, Supraventricular; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Etripamil
• Other Study ID Numbers: MSP-2017-1138; 2018-000308-41 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No