ReVeRA-201: Etripamil in Atrial Fibrillation, Phase 2

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.

• Etripamil (Drug), also known as MSP-2017: 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.
• Placebo (Drug): 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.

Primary outcomes

• The Maximum Reduction in Ventricular Rate, Measured on Holter Monitoring, Within 60 Minutes From Drug Administration. [60 minutes post 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.

Sex: All, ages: 18 Years to any

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.

Participant flow

Outcome results

• The Maximum Reduction in Ventricular Rate, Measured on Holter Monitoring, Within 60 Minutes From Drug Administration. (Primary), Mean, bpm: Placebo 135.5 +/- 13.9; Etripamil 130.3 +/- 15.3 (p <0.0001)

Adverse events

Time frame: 7 days. Adverse events were monitored from Screening until study participation was complete after the final Follow-Up.

Serious adverse events by term

Other adverse events by term

• Results publication: Camm AJ, Piccini JP, Alings M, Dorian P, Gosselin G, Guertin MC, Ip JE, Kowey PR, Mondesert B, Prins FJ, Roux JF, Stambler BS, van Eck J, Al Windy N, Thermil N, Shardonofsky S, Bharucha DB, Roy D. Multicenter, Phase 2, Randomized Controlled Study of the Efficacy and Safety of Etripamil Nasal Spray for the Acute Reduction of Rapid Ventricular Rate in Patients With Symptomatic Atrial Fibrillation (ReVeRA-201). Circ Arrhythm Electrophysiol. 2023 Dec;16(12):639-650. doi: 10.1161/CIRCEP.123.012567. Epub 2023 Nov 11. PMID 37950726

• Study Protocol (PDF, 2022-07-06)
• Statistical Analysis Plan (PDF, 2023-07-27)

• Denis Roy, M.D, Principal investigator, Montreal Heart Institute (MHI)