Efficacy and Safety of Intranasal MSP-2017 (Etripamil) for the Conversion of PSVT to Sinus Rhythm (NODE-1)

Multi-Center, Placebo-Controlled, Dose-Ranging Phase 2 Electrophysiological Study of Intranasal Administration of MSP-2017 for the Conversion of Induced Paroxysmal Supraventricular Tachycardia (PSVT) to Sinus Rhythm

The primary objective of this study is to demonstrate the superiority of at least 1 dose of intranasal (IN) MSP-2017 (Etripamil) over placebo in terminating PSVT induced in an electrophysiology (EP) laboratory.

Study Overview

• Status: Completed
• Conditions: Paroxysmal Supraventricular Tachycardia (PSVT)
• Intervention / Treatment: Drug: Etripamil; Drug: Placebo

Detailed Description

This is a multi-center, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the effects of 4 different doses of MSP-2017 (Etripamil) in subjects with paroxysmal supraventricular tachycardia. It includes an up to 21-day Screening Period, a 1-day Treatment Visit, and either a Follow-up Visit or Early Termination Visit occurring 12 hours to 5 days after the Treatment Visit. Subjects will be randomized to yield at least 100 evaluable subjects distributed into 5 groups of at least 20 subjects each.

• Study Type: Interventional
• Enrollment (Actual): 199
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Center
  • Quebec
    • Montreal, Quebec, Canada, H2W 1T8
      • CHUM Hôtel Dieu
    • Montreal, Quebec, Canada, H1T 1C8
      • The Montreal Heart Institute
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Arizona
    • Phoenix, Arizona, United States, 85013
      • Arizona Heart Rhythm Center
  • California
    • Sacramento, California, United States, 95819
      • Mercy General Hospital
  • Colorado
    • Littleton, Colorado, United States, 80120
      • South Denver Cardiology Associates
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Medstar Washington Hospital Center
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Jacksonville
    • Jacksonville, Florida, United States, 32216
      • Memorial Hospital Jacksonville
    • Saint Petersburg, Florida, United States, 33709
      • Northside Hospital
    • Tampa, Florida, United States, 33606
      • University of South Florida Health South Tampa Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital
    • Atlanta, Georgia, United States, 30309
      • Piedmont Atlanta Hospital
  • Iowa
    • West Des Moines, Iowa, United States, 50266
      • Iowa Heart Center
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21237
      • MedStar Health Research Institute
  • Minnesota
    • Rochester, Minnesota, United States, 55902
      • Mayo Clinic
  • Ohio
    • Canton, Ohio, United States, 44708
      • Aultman Hospital Cardiology Clinical Trials
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Medical Center Division of Cardiovascular Diseases
    • Toledo, Ohio, United States, 43606
      • ProMedica Toledo Hospital
    • Willoughby, Ohio, United States, 44094
      • Great Lakes Medical Research, LLC
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Black Hills Cardiovascular Research
  • Texas
    • Austin, Texas, United States, 78705
      • Texas Cardiac Arrhythmia Research Foundation
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital
    • Houston, Texas, United States, 77030
      • Baylor St. Luke's Hospital
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Medical Center
    • Lynchburg, Virginia, United States, 24501
      • Centra Stroobants Cardiovascular Center
    • Norfolk, Virginia, United States, 23507
      • Sentara Norfolk General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female, aged 18 years and older at Screening
• Has a history of PSVT
• Is scheduled for an electrophysiology study and catheter ablation
• Has provided written informed consent
• Agrees to use a medically accepted form of contraception or abstinence to prevent pregnancy. Males must agree to use an acceptable form of contraception or abstinence from the time of study drug administration through the Follow-up Visit. Females must agree to use an acceptable form of contraception or abstinence from Screening until 30 days following study drug administration. Post-menopausal female subjects must be amenorrheic for ≥ 12 months prior to Screening or ≥ 6 weeks post-surgical bilateral oophorectomy (with or without hysterectomy) prior to Screening, if they do not wish to use an acceptable form of contraception or abstinence. Acceptable forms of contraception include: A condom and an intrauterine device; A condom and hormonal contraception; A condom and a diaphragm; Sterilization of the subject or the subject's partner(s) (sterilization procedure must have been performed 3 or more months prior); Hysterectomy of the subject or the subject's partner(s)
• If a female of childbearing potential: Has a negative serum pregnancy test result at Screening (Screening must occur ≥7 days prior to randomization [ie, on or before Day -7]) and at the Treatment Visit (pre-PSVT induction); Has had a menstrual period within 28 days of the Treatment Visit.

Exclusion Criteria:

• Has a history of serious allergic reaction to verapamil (especially when administered intravenously) including rash, itching or swelling (especially of the face, tongue, or throat), severe dizziness, or trouble breathing
• Is currently participating in another drug or device study, or has received an investigational drug or device within 30 days of Screening
• Has evidence of clinically significant cardiovascular, endocrine, gastrointestinal, hematologic, hepatic, immunologic, neurologic, oncologic, pulmonary, psychiatric, or renal disease or any other condition which, in the opinion of the Investigator, would jeopardize the safety of the subject or impact the validity of study results
• Is a female who is breast feeding, pregnant, or planning to become pregnant during the study period
• Has evidence of any clinically significant acute or chronic condition of the nasal cavity (e.g., rhinitis or deviated septum) which could interfere with IN administration of the study drug in either or both nasal cavities
• Has any of the following at screening or at the Treatment Visit: Systolic blood pressure <100 mmHg, Diastolic blood pressure <50 mmHg
• Has evidence of hepatic impairment, defined as: Alanine aminotransferase or aspartate aminotransferase levels that are greater than or equal to 3× upper limit of normal (ULN) or Bilirubin levels that are greater than or equal to 2× ULN, unless due to Gilbert's syndrome
• Has evidence of renal impairment, defined as an estimated glomerular filtration rate <30 mL/min (Modification of Diet in Renal Disease method)
• Has taken digoxin, verapamil, diltiazem, or any Class I, II (e.g., beta blockers), or III antiarrhythmic drug less than the equivalent of 5 half-lives of this drug prior to the Treatment Visit
• Has taken amiodarone within 30 days of the Treatment Visit
• Has taken drugs of abuse which, in the opinion of the Investigator, would impact the validity of study results
• Has had myocardial infarction, percutaneous coronary intervention, cerebrovascular accident, transient ischemic attack, unstable angina, or acute decompensation of heart failure within 6 months of Screening
• Has a history or evidence of second- or third-degree atrioventricular block
• Has an implanted device (e.g., pacemaker, or implantable cardioverter defibrillator) that precludes study participation in the opinion of the Investigator and Study Medical Monitor
• Has a history or evidence of preexcitation syndrome (e.g., Wolff-Parkinson- White syndrome, short PR, etc.)
• Has evidence of a QT interval (Bazett's correction) (QTcB) >455 milliseconds at Screening or at the Treatment Visit
• Has a history or evidence of familial long QT syndrome, torsades de pointes, ventricular fibrillation, sustained ventricular tachycardia, Brugada syndrome, or sudden cardiac death
• Has evidence of recurrent or chronic atrial tachycardia, atrial flutter, or atrial fibrillation; that could interfere with the current investigation; or
• Has a history or evidence of congestive heart failure (except New York Heart Association Class I) or pulmonary edema

In addition, randomized subjects who meet any of the following criteria at the Treatment Visit (Day 1) prior to study drug administration, will be excluded from participation in the study:

• PSVT cannot be induced or the mechanism of PSVT is neither Atrioventricular reentrant tachycardia (AVRT) nor Atrioventricular nodal reentry tachycardia (AVNRT)
• It is not possible to sustain an episode of PSVT for 5 minutes
• The subject requires a continuous sedative (e.g., propofol), continuous analgesic, or inhaled anesthetic at any point until time 30. Minimally necessary dose(s) of benzodiazepine(s) (e.g., midazolam) and/or narcotic(s) (e.g., fentanyl) (given via single or multiple administration[s]) may be used at the Investigator's discretion. The identity(-ies) and actual administered dose(s) of any benzodiazepine(s) and/or narcotic(s) should be recorded in the study documentation. Local anesthetic(s) may be used at the Investigator's discretion; any use should be recorded in the study documentation
• The subject has undergone prior ablation, and the subject's atrioventricular node function is abnormal in the opinion of the Investigator

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Etripamil; 1 dose of Etripamil via 4 intranasal applications at time 0 (140 mg, 105 mg, 70 mg, or 35 mg)	Drug: Etripamil; intranasal administration via 4 prefilled Aptar Pharma Unit-Dose Spray devices; Other Names: MSP-2017
Placebo Comparator: Placebo; 1 dose of placebo via 4 intranasal applications at time 0	Drug: Placebo; intranasal administration via 4 prefilled Aptar Pharma Unit-Dose Spray devices

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Percentage of Subjects Successfully Converted From PSVT to Sinus Rhythm Within 15 Minutes of Study Drug Administration	The primary efficacy endpoint was the rate of successful PSVT conversion to sinus rhythm lasting at least 30 seconds within 15 minutes of study drug administration after a minimum of 5 minutes in sustained PSVT.	Within 15 minutes of study drug administration

Collaborators and Investigators

• Sponsor: Milestone Pharmaceuticals Inc.
• Collaborators: Medpace, Inc.
• Investigators: Study Director: Francis Plat, Chief Medical Officer

Publications and helpful links

General Publications

• Stambler BS, Dorian P, Sager PT, Wight D, Douville P, Potvin D, Shamszad P, Haberman RJ, Kuk RS, Lakkireddy DR, Teixeira JM, Bilchick KC, Damle RS, Bernstein RC, Lam WW, O'Neill G, Noseworthy PA, Venkatachalam KL, Coutu B, Mondesert B, Plat F. Etripamil Nasal Spray for Rapid Conversion of Supraventricular Tachycardia to Sinus Rhythm. J Am Coll Cardiol. 2018 Jul 31;72(5):489-497. doi: 10.1016/j.jacc.2018.04.082.

Study record dates

Study Major Dates

• Study Start: March 27, 2015
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: November 18, 2014
• First Submitted That Met QC Criteria: November 19, 2014
• First Posted (Estimate): November 20, 2014

Study Record Updates

• Last Update Posted (Actual): December 30, 2020
• Last Update Submitted That Met QC Criteria: December 4, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• 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-2017-1109

Plan for Individual participant data (IPD)

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