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Phase 3 Trial of Desmoteplase in Stroke Fails to Show Clinical Improvement

NEW YORK, May 31 /PRNewswire-FirstCall/ -- Forest Laboratories, Inc. and PAION AG today announced topline results of the DIAS-2 (Desmoteplase In Acute Ischemic Stroke) study with the compound Desmoteplase. The Phase III study was designed to investigate the improvement of clinical outcome in patients with acute ischemic stroke treated with Desmoteplase within 3 to 9 hours after onset of stroke symptoms as compared to placebo. The primary efficacy endpoint (difference between active treatment and placebo in percentage of composite responders as defined below) was not met. The blinded, randomized, placebo-controlled, dose-ranging trial was jointly conducted by PAION and Forest Laboratories, Inc., and enrolled a total of 186 patients in Europe, USA, Canada, Australia, Hong Kong and Singapore. Forest Laboratories, Inc. is the partner of PAION for Desmoteplase for North America and H. Lundbeck A/S is PAION's partner for the rest of the world.

In this study, patients received either placebo (N=63), 90 mcg/kg (N=57), or 125 mcg/kg (N=66) of Desmoteplase as an intravenous bolus within 3-9 hours after the onset of stroke. Patients were eligible for treatment only in case of a distinct penumbra of at least 20% (insufficiently perfused but still salvageable tissue area around the primary location of stroke), which was confirmed by magnetic resonance imaging (MRI) or perfusion computed tomography (pCT).

The primary efficacy endpoint in the study was clinical improvement at Day 90 defined for each patient as achievement of all three of the following criteria; (1): Improvement of greater than or equal to 8 points from baseline on the National Institutes of Health Stroke Scale (NIHSS) or NIHSS score less than or equal to 1, (2): Modified Rankin Scale (MRS) score of 0-2, and (3): Barthel Index (BI) score of 75-100. Only patients who simultaneously met the criteria along all three scales were considered responders. Patients defined as responders by such criteria are in general able to function independently, having no or few deficits.

Improvement of clinical outcome was found with 47.4% of patients treated with 90 mcg/kg Desmoteplase and 36.4% of patients treated with 125 mcg/kg Desmoteplase, compared to 46.0% in the placebo group with neither dose of Desmoteplase statistically significantly different compared to placebo.

The rate of symptomatic intracranial bleeding within 72 hours after study drug administration was 0% in the placebo group, 3.5% in the 90 mcg/kg dose group and 4.5% in the 125 mcg/kg group. There were four patient deaths reported in the placebo group, three reported in the 90 mcg/kg dose group and 14 reported in the 125 mcg/kg dose group within the 90 day follow-up period. Ten of the 14 deaths in the 125 mcg/kg dose group were considered by the investigators as not related to the drug, 9 of which occurred 14 or more days after stroke and were from non-neurological causes.

These data are surprising and are not consistent with previously observed patterns in the DIAS/DEDAS trials and larger size, placebo-controlled acute stroke trials. The absence of consistency with previous findings is not easy to explain, but in-depth analyses are planned to better understand the data.

Forest will review the complete study database over the coming weeks to determine the appropriate next steps and its role regarding U.S. development of desmoteplase.

The headline results of the DIAS-2 study will be presented on 1 June 2007 at 10:45 a.m. BST within the "Large Clinical Trials II" session at the XVI European Stroke Conference in Glasgow, Scotland, U.K.

About Desmoteplase
Desmoteplase, the most fibrin-specific plasminogen activator known today, is a genetically engineered clot-dissolving protein found in the saliva of the vampire bat Desmodus rotundus. It has received fast-track designation from the U.S. Food and Drug Administration for the indication of acute ischemic stroke.

Source: Forest Laboratories

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