A Phase III Superiority Study of Vernakalant vs Amiodarone in Subjects With Recent Onset Atrial Fibrillation

Study Overview
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Brief Summary
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The primary objective of the study is to demonstrate the superiority of vernakalant injection over amiodarone injection in the conversion of atrial fibrillation (AF) to sinus rhythm (SR) within 90 minutes of the start of drug administration. The secondary objective is to compare the safety of vernakalant to amiodarone.

Detailed Description
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This is a double-blind, active-controlled, double-dummy, multi-center, randomized trial in subjects with symptomatic AF of 3 to 48 hours duration. Subjects will be randomized to receive vernakalant injection or amiodarone injection in a 1:1 ratio. Safety will be assessed through the monitoring of adverse events, vital signs, continuous telemetry monitoring, 12-lead Holter monitoring, 12-lead ECGs, and laboratory tests. At 2 hours after the start of infusion, electrical cardioversion may be performed or rate control medication may be administered. Class I and Class III antiarrhythmics are not to be administered for 24 hours after the start of infusion. Subjects are to remain in the clinic for at least 6 hours after the start of infusion. Subjects will attend a follow-up visit at 7 (±2) days after treatment and will receive a follow-up telephone call at 30 (±3) days for assessment of serious adverse events, concomitant medications related to serious adverse events, and recurrence of AF. All roles were blinded with the exception of each site's designated unblinded personnel who were responsible for randomization and preparation, dispensation and accountability of the study medication. Expanded Access was not available through this protocol.

Official Title
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A Phase III Prospective, Randomized, Double-Blind, Active-Controlled, Multi-Center, Superiority Study of Vernakalant Injection Versus Amiodarone in Subjects With Recent Onset Atrial Fibrillation

Conditions
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Atrial Fibrillation

Intervention / Treatment
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* Drug: Vernakalant Injection
* Drug: Amiodarone Injection:


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Have symptomatic AF of 3 to 48 hours duration at baseline. Be eligible for cardioversion. Have adequate anticoagulation therapy for cardioversion in accordance with standard of practice as recommended by ACC/AHA/ESC guidelines [1]. Be hemodynamically stable and have systolic blood pressure (BP) above 100 mmHg and less than 160 mmHg and diastolic BP less than 95 mmHg at screening and baseline. Key Exclusion Criteria: Known or suspected prolonged QT or uncorrected QT interval of >440 msec as measured at screening on a 12 lead ECG, familial long QT syndrome, or previous torsades de pointes, ventricular fibrillation; or sustained ventricular tachycardia (VT). Symptomatic bradycardia, sick sinus syndrome, or ventricular rate less than 50 beats per minute (bpm) as documented by 12-lead ECG at screening. A QRS interval >140 msec. Atrial flutter. Significant valvular stenosis, hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy or constrictive pericarditis. Documented previous episodes of second or third degree atrioventricular (AV) block. Had a myocardial infarction (MI), acute coronary syndrome or cardiac surgery within 30 days prior to entry into the study. Uncorrected electrolyte imbalance of serum potassium or magnesium. Both K+ and Mg2+ must be corrected prior to dosing.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Vernakalant Injection: In one infusion line, subjects will receive a 10-minute infusion of vernakalant followed by a 15-minute observation period, followed by an additional 10-minute infusion of vernakalant if required (if the subject is still in AF). To maintain blinding, a 60-minute infusion of placebo (D5W) will be administered in a second infusion line, followed by a maintenance infusion of placebo for a minimum of an additional 60 minutes. | Drug: Vernakalant Injection<br>* 10-minute infusion of 3 mg/kg vernakalant injection followed by a 15-minute observation period, followed by an additional 10-minute infusion of 2 mg/kg of vernakalant if required (if the subject is still in AF).<br>* Other names: Kynapid;|
| Active Comparator: 2<br>Amiodarone Injection: In one infusion line subjects will receive a 60-minute infusion of amiodarone followed by a maintenance infusion of amiodarone over an additional 60 minutes. To maintain blinding, a 10-minute infusion of placebo (normal saline) will be administered in a second infusion line, followed by a 15 minute observation period, followed by a 10 minute infusion of placebo if the subject is still in AF. | Drug: Amiodarone Injection:<br>* 60-minute infusion of 5 mg/kg amiodarone followed by a maintenance infusion of 50 mg amiodarone over an additional 60 minutes (equivalent to approximately 15 mg/kg over 24 hrs).<br>* Other names: Cordarone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects with conversion of atrial fibrillation to sinus rhythm within 90 minutes after the start of infusion. |  | Conversion of AF to SR for a minimum duration of one minute within 90 minutes after start of infusion. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to conversion within 90 minutes after the start of infusion. |  | Time to conversion of AF to SR within 90 minutes after start of infusion. | 
| Proportion of subjects with symptom relief at 90 minutes after the start of infusion. |  | Relief of AF symptoms 90 minutes after start of infusion. | 
| EQ-5D quality of life assessment. |  | Assessment of quality of life 2 hours after start of infusion. | 
| Monitoring of adverse events, vital signs, continuous telemetry monitoring, 12-lead Holter monitoring, 12-lead ECGs, and laboratory tests. |  | Specified safety assessments completed at specified time points throughout the study from Screening to Discharge, at the Day 7 visit, and at the Day 30 follow-up call. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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atrial fibrillation, atrial fib, AF