Sanofi stops phase IIIb of trial using dronedarone in patients with permanent AF

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Sanofi announced on 7 July 2011 that the company has discontinued the PALLAS (Permanent atrial fibrillation outcome study using dronedarone on top of standard therapy) phase IIIb trial in patients with permanent atrial fibrillation, a population different from the population with non-permanent AF for which Multaq (dronedarone) is currently approved.

The decision follows 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 with permanent AF and vascular risk factors are at high risk of major vascular events and no previous study has investigated whether any intervention can reduce major morbidity or mortality in these patients. PALLAS is the first trial to investigate whether an anti-arrhythmic drug can decrease outcomes in this important population of patients,” said Stuart Connolly, PALLAS trial’s co- principal investigator, Division of Cardiology, McMaster University, Hamilton, Canada. “The PALLAS Operations Committee is very disappointed to discover that the hypothesis that dronedarone would improve major outcomes for this high risk patient population has been refuted.”

“Patient safety is of highest priority for Sanofi. We are notifying regulatory authorities in all countries where the product is approved or under review on this matter,” said Jean-Pierre Lehner, chief medical officer, Sanofi. “We remain committed to Multaq as an essential treatment option for non-permanent AF patients.”

The patient population included in the PALLAS study is different from the population for which Multaq is currently approved. In the PALLAS population, 70% of the 3,149 patients enrolled had permanent AF for over 2 years; approximately 70% had New York Heart Association (NYHA) heart failure Class I to III at baseline.

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 to prevent recurrence of AF or to lower ventricular rate.

In the USA, Multaq is indicated to reduce the risk of cardiovascular hospitalisation in patients with paroxysmal or persistent atrial fibrillation 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 <40%, who are in sinus rhythm or who will be cardioverted.

Multaq is currently available in 32 countries and is recommended as a first line treatment option in the majority of AF patients by the ESC and ACC/AHA Guidelines. Approximately 400,000 patients have been treated with Multaq worldwide.

About PALLAS

PALLAS was a multinational, randomised, double-blind, parallel-group, placebo-controlled, multicentre 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 hospitalisation or death from any cause.