Atrial Fibrillation
Conditions
Keywords
atrial fibrillation, ventricular rate control, rapid ventricular rate, etripamil
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.
Interventions
DRUGEtripamil
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.
DRUGPlacebo
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.
Sponsors
The Montreal Health Innovations Coordinating Center (MHICC)
JSS Medical Research Inc.
Milestone Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Canada, Netherlands
Participant flow
Recruitment details
Participants with atrial fibrillation and ventricular rate =\>110bpm over 1 minute were screened to participate in the study (first participant enrolled on 19-Nov-2020, last participant completed 10-Aug-2023). Overall, 87 participants were screened and from those, 69 participants were randomized. From those participants, 56 participants received etripamil or placebo.
Pre-assignment details
Of the 69 participants randomized, 13 (18.8%) did not receive etripamil/placebo because of the following reasons: baseline heart rate \<110bpm (n=5), converted to sinus rhythm (n=3), technical issue with Holter and ECGs were missing (n=3), hemodynamic instability (n=1), site misinterpretation of protocol (n=1).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Administration of placebo at the emergency department for an episode of atrial fibrillation
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. | 29 |
| Etripamil Administration of 70 mg etripamil at the emergency department for an episode of atrial fibrillation
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. | 27 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Baseline heart rate <110 bpm | 0 | 0 | 5 |
| Overall Study | Conversion to SR | 0 | 0 | 3 |
| Overall Study | Hemodynamic instability | 0 | 0 | 1 |
| Overall Study | Site misinterpretation of protocol | 0 | 0 | 1 |
| Overall Study | Technical issue with Holter ECG | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | Placebo | Total | Etripamil |
|---|---|---|---|
| AF diagnosis confirmed by ECG No | 0 Participants | 0 Participants | 0 Participants |
| AF diagnosis confirmed by ECG Yes | 29 Participants | 56 Participants | 27 Participants |
| Age, Customized Age at Informed Consent | 64.6 years STANDARD_DEVIATION 10.5 | 64.6 years STANDARD_DEVIATION 10.5 | 64.6 years STANDARD_DEVIATION 10.6 |
| Diastolic blood pressure (mmHg) | 85 mmHg STANDARD_DEVIATION 15.5 | 85.3 mmHg STANDARD_DEVIATION 16.9 | 85.6 mmHg STANDARD_DEVIATION 18.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 55 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Heart rate (bpm) | 134.9 bpm STANDARD_DEVIATION 22.9 | 132.1 bpm STANDARD_DEVIATION 18.8 | 129.2 bpm STANDARD_DEVIATION 13 |
| Participant had pacemaker No | 28 Participants | 55 Participants | 27 Participants |
| Participant had pacemaker Yes | 1 Participants | 1 Participants | 0 Participants |
| Participant symptomatic during AF episode No | 8 Participants | 13 Participants | 5 Participants |
| Participant symptomatic during AF episode Yes | 21 Participants | 43 Participants | 22 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 29 Participants | 53 Participants | 24 Participants |
| Sex: Female, Male Female | 11 Participants | 22 Participants | 11 Participants |
| Sex: Female, Male Male | 18 Participants | 34 Participants | 16 Participants |
| Systolic blood pressure (mmHg) | 125.6 mmHg STANDARD_DEVIATION 17.3 | 127.7 mmHg STANDARD_DEVIATION 18.5 | 130.0 mmHg STANDARD_DEVIATION 19.8 |
| Type of AF Paroxysmal | 22 Participants | 42 Participants | 20 Participants |
| Type of AF Permanent | 2 Participants | 4 Participants | 2 Participants |
| Type of AF Persistent | 5 Participants | 10 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 27 |
| other Total, other adverse events | 18 / 29 | 23 / 27 |
| serious Total, serious adverse events | 4 / 29 | 1 / 27 |
Outcome results
Primary
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.
Time frame: 60 minutes post drug administration
Population: The primary efficacy analysis was performed on the 49 participants in the Efficacy Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | The Maximum Reduction in Ventricular Rate, Measured on Holter Monitoring, Within 60 Minutes From Drug Administration. | Baseline Ventricular Rate (bpm) | 135.5 bpm | Standard Deviation 13.9 |
| Placebo | The Maximum Reduction in Ventricular Rate, Measured on Holter Monitoring, Within 60 Minutes From Drug Administration. | Nadir (bpm) | 130.7 bpm | Standard Deviation 16.4 |
| Etripamil | The Maximum Reduction in Ventricular Rate, Measured on Holter Monitoring, Within 60 Minutes From Drug Administration. | Baseline Ventricular Rate (bpm) | 130.3 bpm | Standard Deviation 15.3 |
| Etripamil | The Maximum Reduction in Ventricular Rate, Measured on Holter Monitoring, Within 60 Minutes From Drug Administration. | Nadir (bpm) | 95.2 bpm | Standard Deviation 23.7 |
p-value: <0.000195% CI: [-40.3, -19.3]ANCOVA