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

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

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.

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: Vernakalant Injection; Drug: Amiodarone Injection:

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 254
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • Royal Hobart Hospital Cardiology Research
    • Launceston, Tasmania, Australia
      • Launceston General Hospital Cardiac Research Unit
  • Western Australia
    • Perth, Western Australia, Australia, 6000
      • Royal Perth Hospital Emergency Research
• Canada
  • Ontario
    • Kingston, Ontario, Canada, K7L 2V7
      • Kingston General Hospital
    • Ottawa, Ontario, Canada, K1Y 4E9
      • The Ottawa Hospital
  • Quebec
    • Laval, Quebec, Canada, H7M 3L9
      • Hopital de la Cite-de-la-Sante
    • Montreal, Quebec, Canada, H1T 1C8
      • Institut de Cardiologie de Montreal
    • Montreal, Quebec, Canada, H2W 1T8
      • Centre Hopitalier de L'Universite de Montreal - Hotel Dieu
    • Montreal, Quebec, Canada, H3G 1A4
      • McGill University Health Center The Montreal General Hospital
    • Terrebonne, Quebec, Canada, J6V 2H2
      • Centre de santé et de services sociaux du Sud de Lanaudière - Hôpital Pierre-Le Gardeur
• Czech Republic
  • Caslav, Czech Republic, 286 01
    • Mestrska nemocnice Caslav
  • Kroměříž, Czech Republic, 767 55
    • Nemocnice Kroměříž
  • Kutna Hora, Czech Republic
    • Nemocnice Kutna Hora s.r.o. Interni Oddeleni
  • Nove Město, Czech Republic, 405 02
    • Nemocnice Decin Internal Medicine
  • Praha, Czech Republic, 150 00
    • Fakultní nemocnice v Motole, KAR
  • Praha, Czech Republic, 162 00
    • Ustredni vojenska nemocnice Koronarni jednotka
  • Praha, Czech Republic
    • VFN - III. Interni Klinika
  • Pribram, Czech Republic
    • Oblastni nemocnice Pribram Interni Oddeleni
  • Semily, Czech Republic
    • Nemocnice v Semilech Interní oddělení
  • Slaný, Czech Republic
    • Nemocnice Slaný Interní oddělení
  • Tabor, Czech Republic, 390 03
    • Nemocnice Tábor
  • Uherské Hradiste, Czech Republic, 686 08
    • Uherskohradistska nemocnice
• Denmark
  • Hellerup, Denmark
    • Gentofte Amtssygehus Kardiologisk afdeling
  • Herlev, Denmark, 2730
    • Herlev Amtssygehus, Kardiologisk
  • Hjorring, Denmark
    • Sygehus Vendsyssel Hjorring
  • Koge, Denmark
    • Roskilde Amts Sygehus Køge
  • Silkeborg, Denmark
    • Regionshospitalet Silkeborg
• Estonia
  • Haabneeme, Estonia, 74001
    • Viimsi Hospital, Heart Clinic
  • Parnu, Estonia
    • Pärnu Hospital Department of Cardiology
  • Tallinn, Estonia
    • East Tallinn Central Hospital-Clinic of Cardiology
  • Tartu, Estonia
    • Tartu University Hospital Heart Clinic
• Finland
  • Oulu, Finland, 90014
    • Oulu University Hospital - Dept of Internal Medicine
• France
  • Chambray-les-Tours, France
    • Hopital Trousseau - Service de Cardiologie
  • Nancy, France
    • CHU de Nancy - Hopital Brabois - Service de Cardiologie
  • Paris, France
    • Hopital Lariboisiere
  • Strasbourg, France
    • CHU de Strasbourg - Hopital Hautepierre - Service de Cardiologie
• Germany
  • Berlin, Germany, 10117
    • Charite Campus Mitte, Med. Klinik und Poliklinik mit Schwerpunkt Kardiologie und Angiologie
  • Berlin, Germany
    • Campus Virchow-Klinikum, Charite - Universitaetsmedizin Berlin
  • Bernau, Germany, 16321
    • Herzzentrum Brandenburg in Bernau Innere Medizin
  • Bonn, Germany, 53105
    • Universitätsklinikum Bonn, Med. Klinik und Poliklinik II
  • Frankfurt, Germany
    • Johann Wolfgang Goethe Universitaet Med Klinik III - Kardiologie
  • Gottingen, Germany, 37075
    • Universitatsklinikum Gottingen, Herzzentrum
  • Halle, Germany
    • Martin-Luther Universitat Halle, Med. Klinik und Poliklinik III- Fachrichtung Kardiologie
  • Hamburg, Germany, 22291
    • Klinik Hamburg Bambek Kardiologie
  • Hamburg, Germany, 22527
    • Medizinisches Versorgungszentrum Prof. Mathey, Prof. Schofer GmbH
  • Hannover, Germany
    • Medizinische Klinik, Klinikum Hannover Nordstadt
  • Kassel, Germany, 34121
    • Ambulantes Herzzentrum Kassel Innere Medizin
  • Köln, Germany, 50924
    • Klinikum der Universität Köln, Medizinische Klinik III
  • Ludwigshafen, Germany, 67063
    • Klinikum der Stadt Ludwigshafen am Rhein gGmbH
  • Merseburg, Germany, 06217
    • Carl-von Basedow-Klinikum Merseburg
  • Pirna, Germany
    • Klinikum Pirna GmbH, Innere Medizin II, Kardiologie
  • Reinbek, Germany
    • Krankenhaus Reinbek, St. Adolf-Stift
  • Stuttgart, Germany, 70376
    • Robert-Bosch-Krankenhaus, Abt. Kardiologie / Pulmologie
• Latvia
  • Riga, Latvia, LV1002
    • Latvian Center of Cardiology, P. Stradins Clinical University Hospital
• Lithuania
  • Kaunas, Lithuania
    • Kaunas Medical University Hospital - Department of Cardiology
  • Klaipeda, Lithuania
    • Klaipeda Seamen's Hospital
  • Vilnius, Lithuania
    • Vilnius University Hospital Santariskiu Clinic - Center of Cardiology and Angiology
• Netherlands
  • Arnhem, Netherlands, 6-800 TA
    • WCN - Department of Cardiology Rijnstate Ziekenhuls
  • Eindhoven, Netherlands, 5623EJ
    • Catharina Ziekenhuis Eindhoven
  • Gouda, Netherlands, 2800BB
    • Groene Hart Zeikenhhaus
  • Hoogeveen, Netherlands, 7909 AA
    • WCN - Bethesda ziekenhuis
  • Maastricht, Netherlands, 6229 HX
    • Academisch Ziekenhuis Maastricht
  • Nijmegen, Netherlands, 6532 SZ
    • WCN - Canisius-Wilhelmina Ziekenhuis
  • Rotterdam, Netherlands, 3045 PM
    • WCN - St. Franciscus Gasthuis
• Poland
  • Bydgoszcz, Poland
    • Oddzial Kardiologiczny Wielospecjalityczny Szpital Miejski im.
  • Gdynia, Poland
    • Szpital Miejski im. J. Brudzinskiego Oddzial Kardiologii
  • Lodz, Poland
    • Klinika Chorob Wewnetrznych z Oddzialem Farmakologii Klinicznej i Terapii Monitorowanej
  • Lublin, Poland, 20-089
    • Oddział Internistyczno-Kardiologiczny Samodzielny Publiczny Szpital Wojewódzki im. Jana Bożego w Lublinie
  • Lublin, Poland
    • Okregowy Szpital Kolejowy w Lublinie Samodzielny
  • Tarnow, Poland, 33-100
    • Oddzial Kardiologii Inwazyjnej Szpital Specjalistyczny im. E.Szczeklika w Tarnowie
  • Toruń, Poland, 87-100
    • Oddział Kardiologiczno-Internistyczny Specjalistyczny Szpital Miejski im. Mikołaja Kopernika
  • Toruń, Poland, 87-100
    • Specjalistyczny Szpital Miejski im. Mikołaja Kopernika
  • Warszawa, Poland, 00-382
    • III Klinika Chorob Wewnetrznych i Kardiologii
  • Warszawa, Poland, 00-909
    • Wojskowy Instytut Medyczny, CSK MON
  • Warszawa, Poland, 02-507
    • Klinika Kardiologii Zachowawczej Centralny Szpital Kliniczny Ministerstwa Spraw Wewnętrznych i Administracji w Warszawie
  • Wroclaw, Poland
    • Osrodek Chorob Serca, Klinika Kardiologii, 4 Wojskowy Szpital Kliniczny z Poliklinika Samodzielny
• Serbia
  • Belgrade, Serbia, 11000
    • Clinical Center of Serbia, Institute of CV Diseases
  • Belgrade, Serbia, 11040
    • "Dedinje" Cardiovascular Institute
  • Niska Banja, Serbia, 18205
    • Institute of Treatment and Reahabilitation 'Niska Banja'
  • Zemun, Serbia, 11080
    • Clinical Center Zemun, Dept. of Cardiology
• Slovakia
  • Banska Bysterica, Slovakia, 97401
    • Middle Slovak Institute of Cardiovascular Diseases (SUSCCH)
  • Bojnice, Slovakia, 97201
    • NsP Prievidza so sidlom v Bojniciah
  • Bratislava, Slovakia, 83348
    • Slovensky ustav srdcovych a cevnych chorob
  • Liptovsky Mikulas, Slovakia, 03101
    • ICU, Hospital Lipt. Mikulas
  • Nitra, Slovakia, 950 01
    • FN - I. interna klinika
  • Ruzomberok, Slovakia, 03401
    • Liva - Central Military Hospital
  • Trnava, Slovakia, 91701
    • Interna klinika FN Trnava, Fakultna nemocnica Trnava
  • Žilina, Slovakia, 012 07
    • Internal Dep. Hospital Žilina
• Sweden
  • Malmo, Sweden
    • Universitetssjukhuset MAS
  • Orebro, Sweden
    • Universityetssjukhuset, Orebro
  • Uppsala, Sweden
    • Akademiska sjukhuset, Uppsala
• Ukraine
  • Donetsk, Ukraine
    • Donetsk Regional Clinical Hospital
  • Kharkiv, Ukraine
    • City Clinical Hospital #8
  • Kiev, Ukraine
    • Kiev City Clinical Hospital No 5, Coronary Care Unit
  • Kiev, Ukraine
    • City Clinical Hospital #1 Intensive Care Unit
  • Kiev, Ukraine
    • N.D. Strazhesko Institute of Cardiology Intensive Care Unit
  • Lugansk, Ukraine
    • Lugansk First Clinical Multiprofile Hospital #1, Cardiology
  • Lviv, Ukraine
    • Lviv Reg St Clinical Treat-and-Diagn Cardio. Centre Dept of Myocardial Infarction
  • Odessa, Ukraine
    • City Clinical Hospital #9 Dept of Arrhythmia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

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
Experimental: 1; 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; 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).; Other Names: Kynapid; RSD1235
Active Comparator: 2; 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: 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).; Other Names: Cordarone; Amiodarone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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.

Collaborators and Investigators

• Sponsor: Advanz Pharma
• Investigators: Principal Investigator: Tomas Janota, MD, VFN III. interní klinika; Principal Investigator: Christian Torp-Pedersen, MD, Gentofte Amtssygehus - Kardiologisk afdeling; Principal Investigator: Rein Kolk, MD, Tartu University Hospital Heart Clinic; Principal Investigator: Etienne Aliot, MD, CHU de Nancy - Hopital Brabois, Service de Cardiologie; Principal Investigator: Stefan Hohnloser, MD, Johann Wolfgang Goethe Universitaet Med Klinik III - Kardiologie; Principal Investigator: Heikki Huikuri, MD, Oulu University Hospital - Dept of Internal Medicine; Principal Investigator: Piotr Ponikowski, MD, Osrodek Chorob Serca, Klinika Kardiologii, IV Wojskowy Szpital Kliniczny z Poliklinika Samodzielny Publiczny Zaklad Opieki Zdrowotnej we Wroclawiu; Principal Investigator: Steen Juul-Moller, MD, Universitetssjukhuset MAS

Publications and helpful links

General Publications

• Camm AJ, Capucci A, Hohnloser SH, Torp-Pedersen C, Van Gelder IC, Mangal B, Beatch G; AVRO Investigators. A randomized active-controlled study comparing the efficacy and safety of vernakalant to amiodarone in recent-onset atrial fibrillation. J Am Coll Cardiol. 2011 Jan 18;57(3):313-21. doi: 10.1016/j.jacc.2010.07.046.

Study record dates

Study Major Dates

• Study Start: April 1, 2008
• Primary Completion (Actual): October 1, 2009
• Study Completion (Actual): November 1, 2009

Study Registration Dates

• First Submitted: April 25, 2008
• First Submitted That Met QC Criteria: April 28, 2008
• First Posted (Estimate): April 29, 2008

Study Record Updates

• Last Update Posted (Estimate): December 15, 2009
• Last Update Submitted That Met QC Criteria: December 12, 2009
• Last Verified: December 1, 2009

More Information

Terms related to this study

• Keywords: atrial fibrillation; AF; atrial fib
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Vasodilator Agents; Enzyme Inhibitors; Membrane Transport Modulators; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Sodium Channel Blockers; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Potassium Channel Blockers; Amiodarone
• Other Study ID Numbers: VERI-305-AMIO