PALLAS trial

The following information is drawn from a Sanofi Aventis press release.

On July 7th 2011, Sanofi Aventis discontinued the PALLAS Phase IIIb trial in patients with permanent Atrial Fibrillation (AF), a population different from the population with non-permanent (paroxysmal) AF for which Multaq® (dronedarone) is currently approved. The decision followed recommendations from the study’s Operations Committee and the Data Monitoring Committee (DMC) which observed a significant increase in cardiovascular events in the dronedarone arm. The decision to terminate the study was not related to any hepatic adverse event. Sanofi has informed regulatory authorities of this decision. The company also has asked all PALLAS clinical investigators to inform their patients included in the trial to stop taking the study medication and consult their clinical trial center. This direction applies to the PALLAS study patients only. The benefit-risk of Multaq remains unchanged in its approved indication in non-permanent AF. Patients currently taking Multaq should not stop their therapy and should consult their treating physician should they have any questions.

In the PALLAS population, 70% of the 3,149 patients enrolled had permanent AF for over 2 years; approximately 70% had NYHA heart failure Class I to III at baseline. 2/3 In contrast, in the study supporting the current indication (ATHENA), no patients enrolled had permanent AF and less than 30% of patients had NYHA heart failure Class I to III. PALLAS patients were also older than ATHENA patients. Multaq is currently approved in the EU in adult clinically stable patients with a history of, or current non-permanent atrial fibrillation (AF) to prevent recurrence of AF or to lower ventricular rate. In the U.S., Multaq is indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≥50 mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted.

About PALLAS PALLAS (Permanent Atrial fibriLLAtion outcome Study using Dronedarone on top of standard therapy) was a multinational, randomized, double-blind, parallel-group, placebo-controlled, multicenter Phase IIIb trial comparing the efficacy of dronedarone 400mg twice-daily to placebo in permanent AF patients. Patients were required to have an age above 65 years with co-morbid conditions, such as systemic arterial embolism, myocardial infarction, documented coronary artery disease, prior stroke, symptomatic heart failure, or the combination of age above 75 years, hypertension and diabetes mellitus. Exclusion criteria included New York Heart Association (NYHA) Class IV heart failure or unstable NYHA Class III heart failure. The trial had two composite co-primary endpoints: 1. Major cardiovascular events (stroke, systemic arterial embolism, myocardial infarction or cardiovascular death). 2. Cardiovascular hospitalization or death from any cause. About Permanent Atrial Fibrillation According to ACC/AHA/ESC guidelines, permanent AF is the designation given when sinus rhythm cannot be sustained after cardioversion of AF (medical intervention designed to restore sinus rhythm) or when the patient and physician have decided to allow AF to continue without further efforts to restore sinus rhythm. In the Euro Heart Survey one year follow-up, one year mortality in patients suffering from AF was high and the risk continuously present. Mortality (5.3%) was comparable with results of previous studies, which is also the case for the observed higher mortality in permanent AF than in other AF types.