Status:
Completed. Trial was halted October 25, 2006, due to a decision of the Steering Committee to analyze further data before continuing due to a possible safety hazard, but decision was rescinded and study continued as of October 30, 2006. Results presented at the 2007 European Stroke Conference. Results published in Lancet Neurology December 2008.
Purpose:
To further investigate the clinical efficacy and safety of two different dosages of recombinant desmoteplase (90 µg/kg and 125 µg/kg) in acute ischemic stroke.
Interventions:
Desmoteplase
An effective plasminogen activator but, in contrast to tPA, is nearly inactive in the absence of a fibrin cofactor.
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Location(s):
U.S., Canada, Europe, Asia, Australia.
Year Started:
2005
Year Finished:
2007
Year Presented:
2007
Design:
Prospective, randomized, double-blind, placebo-controlled, single bolus, multinational, multicenter, parallel group, dose ranging trial.
Inclusion Criteria
Treatment onset within 3-9 hours after onset of stroke symptoms; score of 4-24 on the NIHSS; distinct penumbra (at least 20%).
Exclusion Criteria
Early infarction involving >1/3 MCA or ACA territory; imaging evidence of ICH or SAH, AV malformation, cerebral aneurysm or cerebral neoplasm; well-developed parenchymal hyperintensity on FLAIR, T2 or EPI-T2 images, or marked hypodensity on CT, indicative of subacute infarction or enhancement, with morphologic features suggesting a lesion is >9 hrs old; internal carotid artery occlusion on the side of the stroke lesion; any contraindications to imaging technique.
Patient Involvement:
Patients will be randomized to receive either placebo, or one of two doses of desmoteplase (90 µ/kg or 125 µ/kg).
Primary Outcome:
Primary Efficacy: Clinical improvement at day 90 measured by NIHSS, BI and mRS, and infarct volume (as measured by MRI).
Secondary Outcome:
Change from baseline infarct volume at day 30 (measured by MRI or perfusion CT).
Results:
At 90-day follow up, 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 were responders (patients who improved by >/=8 NIHSS points, had a modified Rankin score of 0 to 2, and a Barthel index score of 75-100).
Mortality rate 90-day follow up was 4 in the placebo group, 3 in the 90 mcg/kg dose group and 14 in the 125 mcg/kg dose group (10 of the 14 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).
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.
Between June, 2005, and March, 2007, 193 patients were randomised, and 186 patients received treatment: 57 received 90 μg/kg desmoteplase; 66 received 125 μg/kg desmoteplase; and 63 received placebo. 158 patients completed the study. The median baseline NIHSS score was 9 (IQR 6—14) points, and 30% (53 of 179) of the patients had a visible occlusion of a vessel at presentation. The core lesion and the mismatch volumes were small (median volumes were 10·6 cm3 and 52·5 cm3, respectively). The clinical response rates at day 90 were 47% (27 of 57) for 90 μg/kg desmoteplase, 36% (24 of 66) for 125 μg/kg desmoteplase, and 46% (29 of 63) for placebo. The median changes in lesion volume were: 90 μg/kg desmoteplase 14·0% (0·5 cm3); 125 μg/kg desmoteplase 10·8% (0·3 cm3); placebo −10·0% (−0·9 cm3). The rates of symptomatic intracranial haemorrhage were 3·5% (2 of 57) for 90 μg/kg desmoteplase, 4·5% (3 of 66) for 125 μg/kg desmoteplase, and 0% for placebo. The overall mortality rate was 11% (5% [3 of 57] for 90 μg/kg desmoteplase; 21% [14 of 66] for 125 μg/kg desmoteplase; and 6% [4 of 63] for placebo).
The DIAS-2 study did not show a benefit of desmoteplase given 3—9 h after the onset of stroke. The high response rate in the placebo group could be explained by the mild strokes recorded (low baseline NIHSS scores, small core lesions, and small mismatch volumes that were associated with no vessel occlusions), which possibly reduced the potential to detect any effect of desmoteplase.
Source of Information:
Paion press release.
Correspondence with trial coordinators.
Presented at the 2007 International Stroke Conference [February 2007].
Presented at the 2007 European Stroke Conference [June 2007].
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