Clinical trial NCT04467905: ReVeRA-201: Etripamil in Atrial Fibrillation, Phase 2
Official title: Multi-Centre, Placebo-Controlled, Phase 2 Study of Etripamil Nasal Spray (NS) for the Reduction of Ventricular Rate in Patients With Atrial Fibrillation.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Atrial Fibrillation
Keywords: atrial fibrillation
ventricular rate control
rapid ventricular rate
etripamil
Lead sponsor: Milestone Pharmaceuticals Inc.
Sponsor class: OTHER
Collaborators: name: The Montreal Health Innovations Coordinating Center (MHICC)
name: JSS Medical Research Inc.
First posted: 2020-07-13
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: The Maximum Reduction in Ventricular Rate, Measured on Holter Monitoring, Within 60 Minutes From Drug Administration.
timeFrame: 60 minutes post drug administration
Secondary outcomes:
Other outcomes:
Locations:
city: Halifax
country: Canada
facility: QEII HSC - Nova Scotia Health Authority
state: Nova Scotia
city: Hamilton
country: Canada
facility: Hamilton Health Science
state: Ontario
city: Newmarket
country: Canada
facility: PACE (Partners in Advanced Cardiac Evaluation)
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital General & Civic Campus Research Institute
state: Ontario
city: Montréal
country: Canada
facility: Institut de Cardiologie de Montreal
state: Quebec
city: Montréal
country: Canada
facility: CHU Montréal
state: Quebec
city: Montréal
country: Canada
facility: CIUSSS du Nord-de-l'Île-de-Montréal - Hôpital du Sacré-Cœur
state: Quebec
city: Rimouski
country: Canada
facility: CISSS Bas-Saint-Laurent / Hôpital de Rimouski
state: Quebec
city: Saint-Jérôme
country: Canada
facility: CISSS des Laurentides / Unité de recherche clinique
state: Quebec
city: Sherbrooke
country: Canada
facility: CIUSSS de l'Estrie - CHU
state: Quebec
city: Terrebonne
country: Canada
facility: CISSS de Lanaudière - Hôpital Pierre-Le Gardeur
state: Quebec
city: Arnhem
country: Netherlands
facility: Jeroen Bosch Ziekenhuis Rijnstate Ziekenhuis
city: Den Bosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
city: Doetinchem
country: Netherlands
facility: Slingeland Ziekenhuis
city: Emmen
country: Netherlands
facility: Treant Zorggroep
city: Helmond
country: Netherlands
facility: Elkerliek Ziekenhuis
city: Rotterdam
country: Netherlands
facility: Franciscus Gasthuis
city: Zutphen
country: Netherlands
facility: Gelre Ziekenhuizen
Study officials:
affiliation: Montreal Heart Institute (MHI)
name: Denis Roy, M.D
role: PRINCIPAL_INVESTIGATOR
References: