SOAR: Study Observing Antiarrhythmic Remodelling Using LGE-MRI

Phase 3

Completed

• Conditions: Atrial Fibrillation
• Interventions: Drug: Placebo; Drug: dronedarone

• Registration Number: NCT01182376
• Lead Sponsor: University of Utah

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.

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 Timeline

• Study First Submitted: 2010-08-11
• Study First Submitted QC: 2010-08-11
• Study First Posted: 2010-08-16
• Study Start: 2010-11
• Primary Completion: 2012-12
• Study Completion: 2012-12
• Results First Submitted: 2015-09-10
• Status Verified: 2016-01
• Results First Submitted QC: 2016-01-22
• Last Update Submitted: 2016-01-22
• Results First Posted: 2016-02-19
• Last Update Posted: 2016-02-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 33

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Half of the patients will be assigned placebo.
Multaq® (dronedarone)	dronedarone	Half of the patients will be prescribed dronedarone.

Primary Outcome Measures

Name	Time	Method
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.