ReVeRA-201: Etripamil in Atrial Fibrillation, Phase 2

Multi-Centre, Placebo-Controlled, Phase 2 Study of Etripamil Nasal Spray (NS) for the Reduction of Ventricular Rate in Patients With Atrial Fibrillation.

Many patients with atrial fibrillation (AF) experience persistent tachycardia with episodes of rapid ventricular rate despite chronic treatment to reduce ventricular rate. The objectives of this study were to demonstrate the superiority of a nasal spray of etripamil over placebo in reducing ventricular rate in patients with AF; and to evaluate the safety and efficacy of etripamil nasal spray in participants with AF.

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: Placebo; Drug: Etripamil

Detailed Description

This was a multi-center, randomized, double-blind, placebo-controlled study to evaluate the effects of etripamil nasal spray in participants with AF. This study included Screening, the Treatment Period (Screening and Treatment Period occur on the same day) and safety follow-up procedures.

Each participant received placebo or 70 mg of etripamil intranasally; treatment were randomized in a 1:1 ratio, to yield 50 evaluable participants with AF in 2 groups of 25.

Participants with AF were selected by the Investigator. The screening procedures included obtaining informed consent, a review of inclusion/exclusion criteria, a complete physical examination, and recording of any concomitant medications.

After screening procedures were complete, eligible participants were randomized to receive etripamil or placebo. Heart rate was measured continuously via Holter Electrocardiogram (ECG) from at least 10 minutes prior to dosing to 6 hours after study drug administration. Participants had to exhibit a rapid ventricular rate (≥110 bpm measured during 1 minute) on the Holter report prior to drug administration in order to receive the study drug. Beyond 60 minutes after study drug administration, medical care was offered in accordance with the standard of care and the participant was discharged from the clinic, while still wearing the Holter device.

Participants underwent a safety follow-up assessment and return the Holter device approximately 24 hours post-dose. Participants were contacted by phone 7 days post-dosing for safety follow-up.

• Study Type: Interventional
• Enrollment (Actual): 69
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • QEII HSC - Nova Scotia Health Authority
  • Ontario
    • Hamilton, Ontario, Canada, L2L 2X2
      • Hamilton Health Science
    • Newmarket, Ontario, Canada, L3Y 2P6
      • PACE (Partners in Advanced Cardiac Evaluation)
    • Ottawa, Ontario, Canada, K1Y4E9
      • Ottawa Hospital General & Civic Campus Research Institute
  • Quebec
    • Montréal, Quebec, Canada, H1T 1C8
      • Institut de Cardiologie de Montreal
    • Montréal, Quebec, Canada, H2X 0A9
      • CHU Montreal
    • Montréal, Quebec, Canada, H4J 1C5
      • CIUSSS du Nord-de-l'Île-de-Montréal - Hôpital du Sacré-Cœur
    • Rimouski, Quebec, Canada, G5L 5T1
      • CISSS Bas-Saint-Laurent / Hôpital de Rimouski
    • Saint-Jérôme, Quebec, Canada, J7Z 5T3
      • CISSS des Laurentides / Unité de recherche clinique
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • CIUSSS de l'Estrie - CHU
    • Terrebonne, Quebec, Canada, J6V 2H2
      • CISSS de Lanaudière - Hôpital Pierre-Le Gardeur
• Netherlands
  • Arnhem, Netherlands, 6815 AD
    • Jeroen Bosch Ziekenhuis Rijnstate Ziekenhuis
  • Den Bosch, Netherlands, 5223 GZ
    • Jeroen Bosch Ziekenhuis
  • Doetinchem, Netherlands, 7009 BL
    • Slingeland Ziekenhuis
  • Emmen, Netherlands, 7824 AA
    • TREANT zorggroep
  • Helmond, Netherlands, 5707 HA
    • Elkerliek Ziekenhuis
  • Rotterdam, Netherlands, 3045 PM
    • Franciscus Gasthuis
  • Zutphen, Netherlands, 7207 AE
    • Gelre Ziekenhuizen

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

A participant was eligible for study participation if they met all of the following criteria:

1. Aged 18 years and over.
2. Provided written informed consent.
3. Participants with episodes of paroxysmal, persistent or permanent AF, presenting with AF and a ventricular rate ≥110 bpm, measured over 1 minute

4. Participants received appropriate antithrombotic therapy as per the applicable guidelines for atrial fibrillation management (e.g., Canadian Cardiovascular Society (CCS) guidelines / European Society of Cardiology (ESC) guidelines).

   1. Etripamil (a calcium channel blocker) was intended for acute rate control only. If rhythm control was desired (outside of the present protocol), anticoagulation as per guidelines could be started after the administration of study drug.

Exclusion Criteria:

A participant was excluded from the study if they met any of the following criteria:

1. Had evidence of atrial flutter (ECG) at presentation.
2. Had a history of stroke, transient ischemic attack (TIA) or peripheral embolism within the last 3 months.
3. Had received by IV route any of the following within one hour before study drug administration: flecainide, procainamide, digoxin, beta-blocker, or calcium channel blocker.
4. Had signs and symptoms of severe congestive heart failure at presentation (e.g. tachypnea, oxygen desaturation <90% unless due to known pulmonary disease, pulmonary rales, sign of peripheral hypoperfusion).
5. Hemodynamic instability, with systolic blood pressure <90 mmHg or diastolic blood pressure <60 mmHg.
6. Known uncorrected severe aortic or mitral stenosis.
7. Hypertrophic cardiomyopathy with outflow tract obstruction.
8. Had a history of second- or third-degree atrioventricular block.
9. Regular rhythm suggesting a complete atrioventricular block.
10. Had a history or evidence of torsades de pointes, sick sinus syndrome, or Brugada syndrome.
11. Evidence of acute coronary syndrome within the last 12 months except if participant was successfully revascularized.
12. Positive pregnancy test result at screening, and females of childbearing potential who did not agree to use adequate method of contraception for the duration of the study.
13. Had evidence of any clinically significant acute or chronic condition of the nasal cavity (e.g., rhinitis or deviated septum) which could have interfered with administration of the study drug in either or both nasal cavities.
14. Had a history of sensitivity to verapamil.
15. Had previously participated in a clinical study for etripamil.
16. Had a history of sensitivity to any components of the investigational product.
17. Had signs of alcohol or drug intoxication at the time of presentation which, in the opinion of the Investigator, would have impacted the validity of study results.
18. Was participating in another drug or device study, or had received an investigational drug or device within 30 days of Screening.
19. Had 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 have jeopardized the safety of the participant or impacted the validity of study results.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Administration of placebo at the emergency department for an episode of atrial fibrillation	Drug: Placebo; The formulation of placebo nasal spray consists of water, sodium acetate, disodium, disodium ethylene-diamine-tetra-acetic acid (EDTA), and sulfuric acid to reproduce the same pH as the etripamil formulation.
Experimental: Etripamil; Administration of 70 mg etripamil at the emergency department for an episode of atrial fibrillation	Drug: Etripamil; The formulation of etripamil nasal spray consists of MSP-2017 (etripamil), water, acetic acid, disodium ethylene-diamine-tetra-acetic acid (EDTA), and sulfuric acid. The dose of etripamil to be evaluated in this study is 70 mg.; Other Names: MSP-2017

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Maximum Reduction in Ventricular Rate, Measured on Holter Monitoring, Within 60 Minutes From Drug Administration.	Baseline ventricular rate is defined as the average heart rate over 5 minutes immediately prior to drug administration. Nadir is defined as the lowest moving average heart rate over 5 minutes recorded in the 60 minutes post drug administration.	60 minutes post drug administration

Secondary Outcome Measures

Outcome Measure	Time Frame
The elapsed time from drug administration to nadir (lowest average heart rate) in the 60 minutes post drug administration.	60 minutes post drug administration
The percentage of patients achieving ventricular rate of <100 bpm in the 60 minutes post drug administration.	60 minutes post drug administration
The percentage of patients with 10% reduction from baseline ventricular rate in the 60 minutes post drug administration.	60 minutes post drug administration
The percentage of patients with 20% reduction from baseline ventricular rate in the 60 minutes post drug administration.	60 minutes post drug administration
The percentage of patients cardioverting into sinus rhythm in the 60 minutes post drug administration.	60 minutes post drug administration
Rating of Treatment Satisfaction Questionnaire for Medication (TSQM-9).	60 minutes post drug administration

Collaborators and Investigators

• Sponsor: Milestone Pharmaceuticals Inc.
• Collaborators: The Montreal Health Innovations Coordinating Center (MHICC); JSS Medical Research Inc.
• Investigators: Principal Investigator: Denis Roy, M.D, Montreal Heart Institute (MHI)

Study record dates

Study Major Dates

• Study Start (Actual): November 19, 2020
• Primary Completion (Actual): August 3, 2023
• Study Completion (Actual): August 10, 2023

Study Registration Dates

• First Submitted: July 8, 2020
• First Submitted That Met QC Criteria: July 8, 2020
• First Posted (Actual): July 13, 2020

Study Record Updates

• Last Update Posted (Actual): September 19, 2024
• Last Update Submitted That Met QC Criteria: September 16, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: atrial fibrillation; ventricular rate control; rapid ventricular rate; etripamil
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; 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-2017-5001

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
• product manufactured in and exported from the U.S.: Yes