Permanent Atrial fibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS)

A Randomized, Double Blind, Placebo Controlled, Parallel Group Trial for Assessing the Clinical Benefit of Dronedarone 400mg BID on Top of Standard Therapy in Patients With Permanent Atrial Fibrillation and Additional Risk Factors

Primary Objective:

• Demonstrate the efficacy of Dronedarone in preventing major cardiovascular events (stroke, systemic arterial embolism, myocardial infarction or cardiovascular death) or unplanned cardiovascular hospitalization or death from any cause in patients with permanent Atrial Fibrillation [AF] and additional risk factors

Secondary Objective:

• Demonstrate the efficacy of Dronedarone in preventing cardiovascular death

This was an event-driven study where a common study end date [CSED] was to be determined by Steering Committee based on the number of events (stroke, systemic arterial embolism, myocardial infarction or cardiovascular death).

Study Overview

• Status: Terminated
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: Dronedarone; Drug: Placebo (for Dronedarone)

Detailed Description

The study period per participant was variable depending on the enrollment in the study.

A final follow-up visit had to occur within 1 month after the CSED.

• Study Type: Interventional
• Enrollment (Actual): 3236
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Sanofi-Aventis Administrative Office
• Australia
  • Macquarie Park, Australia
    • Sanofi-Aventis Administrative Office
• Austria
  • Vienna, Austria
    • Sanofi-Aventis Administrative Office
• Belgium
  • Diegem, Belgium
    • Sanofi-Aventis Administrative Office
• Brazil
  • Sao Paulo, Brazil
    • Sanofi-Aventis Administrative Office
• Bulgaria
  • Sofia, Bulgaria
    • Sanofi-Aventis Administrative Office
• Canada
  • Laval, Canada
    • Sanofi-Aventis Administrative Office
• Chile
  • Providencia Santiago, Chile
    • Sanofi-Aventis Administrative Office
• Czech Republic
  • Praha, Czech Republic
    • Sanofi-Aventis Administrative Office
• Denmark
  • Horsholm, Denmark
    • Sanofi-Aventis Administrative Office
• Finland
  • Helsinki, Finland
    • Sanofi-Aventis Administrative Office
• France
  • Paris, France
    • Sanofi-Aventis Administrative Office
• Germany
  • Frankfurt, Germany
    • Sanofi-Aventis Administrative Office
• Greece
  • Kallithea, Greece
    • Sanofi-Aventis Administrative Office
• Hong Kong
  • Hong Kong, Hong Kong
    • Sanofi-Aventis Administrative Office
• Hungary
  • Budapest, Hungary
    • Sanofi-Aventis Administrative Office
• Israel
  • Natanya, Israel
    • Sanofi-Aventis Administrative Office
• Italy
  • Milan, Italy
    • Sanofi-Aventis Administrative Office
• Korea, Republic of
  • Seoul, Korea, Republic of
    • Sanofi-Aventis Administrative Office
• Malaysia
  • Kuala Lumpur, Malaysia
    • Sanofi-Aventis Administrative Office
• Mexico
  • Col. Coyoacan, Mexico
    • Sanofi-Aventis Administrative Office
• Netherlands
  • Gouda, Netherlands
    • Sanofi-Aventis Administrative Office
• New Zealand
  • Auckland, New Zealand
    • Sanofi-Aventis Administrative Office
• Norway
  • Lysaker, Norway
    • Sanofi-Aventis Administrative Office
• Poland
  • Warsaw, Poland
    • Sanofi-Aventis Administrative Office
• Romania
  • Bucuresti, Romania
    • Sanofi-Aventis Administrative Office
• Russian Federation
  • Moscow, Russian Federation
    • Sanofi-Aventis Administrative Office
• Singapore
  • Singapore, Singapore
    • Sanofi-Aventis Administrative Office
• Slovakia
  • Bratislava, Slovakia
    • Sanofi-Aventis Administrative Office
• South Africa
  • Gauteng, South Africa
    • Sanofi-Aventis Administrative Office
• Spain
  • Barcelona, Spain
    • Sanofi-Aventis Administrative Office
• Sweden
  • Bromma, Sweden
    • Sanofi-Aventis Administrative Office
• Switzerland
  • Geneva, Switzerland
    • Sanofi-Aventis Administrative Office
• Taiwan
  • Taipei, Taiwan
    • Sanofi-Aventis Administrative Office
• Ukraine
  • Kiev, Ukraine
    • Sanofi-Aventis Administrative Office
• United Kingdom
  • Guildford Surrey, United Kingdom
    • Sanofi-Aventis Administrative Office
• United States
  • New Jersey
    • Bridgewater, New Jersey, United States, 08807
      • Sanofi-Aventis Administrative Office

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Permanent AF defined by the presence of all of the following criteria:

  • Availability of one 12-lead ECG not more than 14 days prior to randomization showing that the patient is in AF or atrial flutter;
  • Availability of documentation (including either rhythm strips or medical report of the rhythm) showing that the patient was in AF or atrial flutter at least 6 months prior to randomization;
  • No evidence of sinus rhythm in the period between these two documentations of AF;
  • Decision of the patient and physician to allow AF to continue without further efforts to restore sinus rhythm.

• At least one of the following risk criteria:

  • Coronary artery disease;
  • Prior stroke or Transient Ischemic Attack [TIA];
  • Symptomatic heart failure;
  • Left ventricular ejection fraction [LVEF] less or equal to 0.40;
  • Peripheral arterial occlusive disease;
  • Aged 75 years or older with both hypertension and diabetes mellitus.

Exclusion criteria:

• Paroxysmal AF;
• Persistent AF without a decision to allow AF to continue without further efforts to restore sinus rhythm;
• Heart failure of New-York Heart Association [NYHA] class IV or recent unstable NYHA class III.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dronedarone; Dronedarone 400 mg twice a day until the CSED	Drug: Dronedarone; Film-coated tablet Oral administration under fed conditions (during breakfast and dinner); Other Names: SR33589; MULTAQ
Placebo Comparator: placebo; Placebo (for Dronedarone) twice a day until the CSED	Drug: Placebo (for Dronedarone); film-coated tablet strictly identical in appearance Oral administration under fed conditions (during breakfast and dinner)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overview of the Two Co-primary Outcomes	First co-primary outcome was defined as the first event among stroke, systemic arterial embolism, Myocardial Infarctions [MI], or cardiovascular death. Second co-primary outcome was defined as the first event among unscheduled cardiovascular hospitalization or death from any cause. Both co-primary outcomes were determined based on the central review and adjudication by a blinded Adjudication Committee of all reported deaths (from any cause), MI, systemic arterial embolisms, strokes, Transient Ischemic Attacks [TIA], Heart Failure hospitalization and unplanned hospitalisations for cardiovascular cause.	From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)
Time to First Co-primary Outcome (Cumulative Incidence Function)	Time to first co-primary outcome was defined as the time from randomization to the first event among stroke, systemic arterial embolism, MI or cardiovascular death. Cumulative incidence function in each treatment group was calculated using non-parametric Kaplan-Meier estimate. 95% confidence interval was computed at each time-point using Greenwood's variance estimation.	From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)
Time to Second Co-primary Outcome (Cumulative Incidence Function)	Time to second co-primary outcome was defined as the time from randomization to the first event among unscheduled cardiovascular hospitalization or death from any cause. Cumulative incidence function in each treatment group was calculated using non-parametric Kaplan-Meier estimate. 95% confidence interval was computed at each time-point using Greenwood's variance estimation.	From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Deaths	Deaths were classified according to the primary cause of death.	From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)
Time to Cardiovascular Death (Cumulative Incidence Function)	Time to cardiovascular death was defined as the time from randomization to the death. Cumulative incidence function in each treatment group was calculated using non-parametric Kaplan-Meier estimate. 95% confidence interval was computed at each time-point using Greenwood's variance estimation.	From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overview of Cardiovascular Events		From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)
Overview of Adverse Events [AE]	AE are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.	from first study drug intake up to 10 days after the last study drug intake

Collaborators and Investigators

• Sponsor: Sanofi

Publications and helpful links

General Publications

• Connolly SJ, Camm AJ, Halperin JL, Joyner C, Alings M, Amerena J, Atar D, Avezum A, Blomstrom P, Borggrefe M, Budaj A, Chen SA, Ching CK, Commerford P, Dans A, Davy JM, Delacretaz E, Di Pasquale G, Diaz R, Dorian P, Flaker G, Golitsyn S, Gonzalez-Hermosillo A, Granger CB, Heidbuchel H, Kautzner J, Kim JS, Lanas F, Lewis BS, Merino JL, Morillo C, Murin J, Narasimhan C, Paolasso E, Parkhomenko A, Peters NS, Sim KH, Stiles MK, Tanomsup S, Toivonen L, Tomcsanyi J, Torp-Pedersen C, Tse HF, Vardas P, Vinereanu D, Xavier D, Zhu J, Zhu JR, Baret-Cormel L, Weinling E, Staiger C, Yusuf S, Chrolavicius S, Afzal R, Hohnloser SH; PALLAS Investigators. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med. 2011 Dec 15;365(24):2268-76. doi: 10.1056/NEJMoa1109867. Epub 2011 Nov 14. Erratum In: N Engl J Med. 2012 Feb 16;366(7):672.
• Hohnloser SH, Halperin JL, Camm AJ, Gao P, Radzik D, Connolly SJ; PALLAS investigators. Interaction between digoxin and dronedarone in the PALLAS trial. Circ Arrhythm Electrophysiol. 2014 Dec;7(6):1019-25. doi: 10.1161/CIRCEP.114.002046. Epub 2014 Nov 6.

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): September 1, 2011
• Study Completion (Actual): September 1, 2011

Study Registration Dates

• First Submitted: June 22, 2010
• First Submitted That Met QC Criteria: June 24, 2010
• First Posted (Estimate): June 25, 2010

Study Record Updates

• Last Update Posted (Estimate): October 26, 2012
• Last Update Submitted That Met QC Criteria: October 23, 2012
• Last Verified: October 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Anti-Arrhythmia Agents; Dronedarone
• Other Study ID Numbers: EFC11405; 2010-019791-73 (EudraCT Number); U1111-1116-5566 (Other Identifier: UTN)