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SOAR: Study Observing Antiarrhythmic Remodelling Using LGE-MRI

Sponsor
University of Utah (Other)
Overall Status
Completed
CT.gov ID
NCT01182376
Collaborator
Sanofi (Industry)
33
Enrollment
2
Arms
25
Duration (Months)

Study Details

Study Description

Brief Summary

The primary objective of this study is to demonstrate how dronedarone (Multaq®) may aid in the slowing of progression of left atrial and ventricular fibrosis in patients with atrial fibrillation as assessed by late gadolinium enhanced magnetic resonance imaging.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

BACKGROUND AND INTRODUCTION:

Atrial fibrillation (AF) arises as a result of a complex interaction between triggers, perpetuators and substrate. As early as 1995, Morillo et al have demonstrated that AF is associated with ultrastructural changes in myocytes. In animal models, alterations in myocytes after sustained AF resemble those of myocardial hybernation with a phenotypical adaptation towards a more fetal stage. Ultimately, these structural changes would lead to Calcium overload and metabolic stress, similar changes have been observed in humans. However, in humans, atrial dilatation and degenerative changes have been observed. Interstitial fibrosis (caused by deposits of collagen and fibronectin) is the prime cause of structural remodeling in left atrium (Boldt et al., 2004). It has been well established that fibrosis is a confounding clinical factor in causing AF (Kostin et al., 2002). But AF itself promotes fibrosis, which in turn leads to increased conduction heterogeneity within the atrial substrate resulting in further progression of AF (Everett,and Olgin, 2007).

The recent introduction of Late Gadolinium enhancement magnetic resonance imaging (LGE-MRI) sequence now allows for non-invasive assessment of the location and extent of arrhythmia related fibrosis.

Contrast enhancement occurs as a result of altered washout kinetics of gadolinium relative to normal surrounding tissue, which may reflect increased fibrosis or tissue remodeling of the myocardium. Our group has demonstrated the feasibility of a new LGE-MRI acquisition and processing protocol to detect fibrosis in the LA.

To date, no controlled trials evaluating the effect of antiarrhythmic drugs (AAD) and regression of left atrial fibrosis as assessed by LGE-MRI has been performed. We propose to use LGE-MRI to evaluate the effects of dronedarone vs. placebo on atrial and ventricular fibrosis. It has been shown that the success of catheter ablation procedure (which has been shown to be superior in terms of maintaining sinus rhythm in AF patients when compared to anti-arrhythmic drugs) is dependent upon the extent of fibrosis (Akoum et al., in prep). In AF patients with greater than 35% enhancement (percent left atrial fibrosis), the success of catheter ablation in reducing AF recurrence is greatly reduced. Hence for these patients, a drug that can control the progression of fibrosis and simultaneously provide respite from AF recurrence would be an extremely desirable prescription.

Multaq® is the chosen drug in this study because clinical trials (Hohnloser et al., 2009) have shown that it has the potential to reduce incidence of hospitalizations due to cardiovascular events by 25.5% and death in AF patients by 45%. We acknowledge the information that Dronedarone may be more prone to AF recurrence, however, it has a better safety profile with regards to thyroid and neurologic events and does not interfere with oral anticoagulants (Le Heuzey et al., 2010), which make dronedarone a more preferred antiarrhythmic drug to be used for this study. Furthermore, in patients who took dronedarone post cardioversion procedure to revert arrhythmia back to normal sinus rhythm (NSR), dronedarone has been shown to decrease AF recurrences (Le Heuzey et al., 2010).

OBJECTIVES:
Primary:

The primary objective of this study is to demonstrate how dronedarone may aid in the regression or slowing of progression of left atrial and ventricular fibrosis in patients with atrial fibrillation as assessed by LGE-MRI, using longitudinal data from a double-blinded, prospective study of patients diagnosed with atrial fibrillation over a twelve month follow up period.

Secondary:

  • To study the effects of dronedarone in global parameters of myocardial remodeling such as right and left atrial volumes and right and left ventricular volumes.

  • To study correlation between AF burden expressed as percentage of AF measured by an 8-day Holter Monitoring at three, six and twelve months post initiation.

Study Design

Study Type:
Interventional
Actual Enrollment :
33 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Outcomes Assessor)
Primary Purpose:
Prevention
Official Title:
SOAR: Study Observing Antiarrhythmic Remodelling Using LGE-MRI
Study Start Date :
Nov 1, 2010
Actual Primary Completion Date :
Dec 1, 2012
Actual Study Completion Date :
Dec 1, 2012

Arms and Interventions

Arm Intervention/Treatment
Placebo Comparator: Placebo

Half of the patients will be assigned placebo.

Drug: Placebo
Placebo will be administered by the patient's team according to established guidelines.
Experimental: Multaq® (dronedarone)

Half of the patients will be prescribed dronedarone.

Drug: dronedarone
Dronedarone will be prescribed by the patient's team according to established guidelines.
Other Names:
  • Multaq®

    		•

    Outcome Measures

    Primary Outcome Measures

    1. LA Fibrosis [baseline, 1 year]

      The change in left atrial fibrosis percentage, as measured on a scale, using MRI imaging, from baseline to the end of treatment.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Patients age 18 and older

    • Must carry a diagnosis of Paroxysmal Atrial Fibrillation for 1 months or longer prior to being enrolled.

    • AAD: Multaq® (dronedarone) candidate

    • Patients have given informed consent

    Exclusion Criteria:

    • Patients who are unavailable to continue follow-up at the University of Utah outpatient clinic.

    • Patients weighing >200 lbs (MR image efficacy decreases due to density)

    • Prior RF Ablation treatment for atrial fibrillation

    • Severe renal failure manifested by a chronic GFR of < 30 mL/min, or acute renal failure regardless of the GFR, until the renal function has stabilized. (Gadolinium contraindication)

    • Enrollment in any other investigational trial for anti-arrhythmic therapy

    • Any health related Gadolinium/MRI contraindications: Pacemaker devices, etc.

    • Pregnant women

    • Individuals with cognitive impairments who are unable to give informed consent

    • Multaq® (dronedarone) contraindications:

    • NYHA Class IV heart failure or NYHA Class II - III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic

    • Second- or third-degree atrioventricular (AV) block or sick sinus syndrome

    • Bradycardia < 50 bpm

    • Concomitant use of strong CYP 3A inhibitors, such as ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, and ritonavir

    • Concomitant use of drugs or herbal products that prolong the QT interval and might increase the risk of Torsade de Pointes, such as phenothiazine anti-psychotics, tricyclic antidepressants, certain oral macrolide antibiotics, and Class I and III antiarrhythmics

    • QTc Bazett interval ≥ 500 ms or PR interval > 280 ms

    • Severe hepatic impairment

    • Pregnant women

    • Nursing mothers

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • University of Utah
    • Sanofi

    Investigators

    • Principal Investigator: Nassir F Marrouche, MD, University of Utah

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Nassir F. Marrouche, MD, Associate Professor of cardiology, University of Utah
    ClinicalTrials.gov Identifier:
    NCT01182376
    Other Study ID Numbers:
    • IRB_00040931
    First Posted:
    Aug 16, 2010
    Last Update Posted:
    Feb 19, 2016
    Last Verified:
    Jan 1, 2016
    Keywords provided by Nassir F. Marrouche, MD, Associate Professor of cardiology, University of Utah
    Multaq
    dronedarone
    Atrial Fibrillation
    Additional relevant MeSH terms:
    Atrial Fibrillation
    Dronedarone

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Placebo Multaq® (Dronedarone)
    Arm/Group Description Half of the patients will be assigned placebo. dronedarone: Dronedarone will be prescribed by the patient's team according to established guidelines. Half of the patients will be prescribed dronedarone. dronedarone: Dronedarone will be prescribed by the patient's team according to established guidelines.
    Period Title: Overall Study
    STARTED 15 18
    COMPLETED 4 13
    NOT COMPLETED 11 5

    Baseline Characteristics

    Arm/Group Title Placebo Multaq® (Dronedarone) Total
    Arm/Group Description Half of the patients will be assigned placebo. dronedarone: Dronedarone will be prescribed by the patient's team according to established guidelines. Half of the patients will be prescribed dronedarone. dronedarone: Dronedarone will be prescribed by the patient's team according to established guidelines. Total of all reporting groups
    Overall Participants 15 18 33
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    3
    20%
    11
    61.1%
    14
    42.4%
    >=65 years
    12
    80%
    7
    38.9%
    19
    57.6%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    71
    (8)
    64
    (11)
    68
    (10)
    Sex: Female, Male (Count of Participants)
    Female
    5
    33.3%
    7
    38.9%
    12
    36.4%
    Male
    10
    66.7%
    11
    61.1%
    21
    63.6%
    Pre-treatment left atrial fibrosis percentage (percentage) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [percentage]
    19.9
    (.10)
    15.5
    (.05)
    17.7
    (.08)

    Outcome Measures

    1. Primary Outcome
    Title LA Fibrosis
    Description The change in left atrial fibrosis percentage, as measured on a scale, using MRI imaging, from baseline to the end of treatment.
    Time Frame baseline, 1 year

    Outcome Measure Data

    Analysis Population Description
    The number of participants analyzed for both groups is less than the number enrolled due to patient attrition or poor MRI scans.
    Arm/Group Title Placebo Multaq® (Dronedarone)
    Arm/Group Description Half of the patients will be assigned placebo. dronedarone: Dronedarone will be prescribed by the patient's team according to established guidelines. Half of the patients will be prescribed dronedarone. dronedarone: Dronedarone will be prescribed by the patient's team according to established guidelines.
    Measure Participants 4 12
    Mean (Standard Deviation) [percentage of fibrosis]
    24.6
    (.07)
    16.8
    (.05)

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Placebo Multaq® (Dronedarone)
    Arm/Group Description Half of the patients will be assigned placebo. dronedarone: Dronedarone will be prescribed by the patient's team according to established guidelines. Half of the patients will be prescribed dronedarone. dronedarone: Dronedarone will be prescribed by the patient's team according to established guidelines.
    All Cause Mortality
    Placebo Multaq® (Dronedarone)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Placebo Multaq® (Dronedarone)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/15 (0%) 0/18 (0%)
    Other (Not Including Serious) Adverse Events
    Placebo Multaq® (Dronedarone)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 11/15 (73.3%) 6/18 (33.3%)
    Cardiac disorders
    arrhythmias 1/15 (6.7%) 0/18 (0%)
    Gastrointestinal disorders
    Nausea 3/15 (20%) 0/18 (0%)
    General disorders
    drug interactions 0/15 (0%) 1/18 (5.6%)
    Social circumstances
    non compliance 5/15 (33.3%) 2/18 (11.1%)
    Surgical and medical procedures
    other surgeries 2/15 (13.3%) 3/18 (16.7%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Clinical Research Manager
    Organization University of Utah
    Phone 8015873889
    Email christina.pacchia@hsc.utah.edu
    Responsible Party:
    Nassir F. Marrouche, MD, Associate Professor of cardiology, University of Utah
    ClinicalTrials.gov Identifier:
    NCT01182376
    Other Study ID Numbers:
    • IRB_00040931
    First Posted:
    Aug 16, 2010
    Last Update Posted:
    Feb 19, 2016
    Last Verified:
    Jan 1, 2016