The DIAS study: results of a phase II, MRI-based dose finding study of desmoteplase in acute stroke

BACKGROUND:

Thrombolytic therapy with i.v. rt-PA in a 3h time window is so far the only approved therapy of acute ischemic stroke. However, the majority of patients arrive after 3h of stroke onset in the hospital representing a clear unmet medical need. Desmoteplase (DSPA) is a highly fibrin specific plasminogen activator with a long terminal half-life, lack of neurotoxicity, and due to some distinct pharmacological properties may have a good safety profile especially in the elderly.

METHODS:

The DIAS (Desmoteplase In Acute ischaemic Stroke) trial, a placebo controlled, double blind, international, dose finding phase II study, randomized 104 acute ischemic stroke patients. Patients scoring 4-20 on NIHSS, presenting a PWI/DWI mismatch on MRI and eligible to be treated 3-9h after stroke onset were selected. DSPA or placebo was administered as i.v. bolus. Safety endpoints included the rate of symptomatic intracerebral hemorrhage (sICH). Efficacy endpoints were the rate of reperfusion (measured by a reduction of the PWI deficit >/= 30% or a reopening of the affected vessel 4-8h after treatment) and clinical outcome (reduction by >/= 8 points or scoring 0-1 on NIHSS, mRS 0-2 and BI 100-75). The first part of the DIAS trial investigated fixed doses (25, 37.5 and 50 mg) of DSPA vs placebo in 47 patients. In the second part (n=57), DSPA doses were adjusted to body weight and lowered: 62.5, 90 and 125 µg/kg BW.

RESULTS:

All treatment groups were generally balanced with regard to their baseline parameters. The first part of the study was terminated prematurely, because the predefined threshold for sICH was exceeded. In the second part, sICH rates were 0% in the 62.5 µg/kg group, 6.7% in the 90 µg/kg group and 0% in the 125 µg/kg group (overall sICH rate of 2.2%). Reperfusion rates were: Placebo 19.2%, DSPA 62.5 µg/kg 23.1%, 90 µg/kg 46.7%, 125 µg/kg 71.4%, resulting in a linear dose response curve. Clinical outcome at day 30 (day 90 data still blinded) was: Placebo 22.2%, DSPA 62.5 µg/kg 20.0%, 90 µg/kg 20.0% and 125 µg/kg 46.7%. The 125 µg/kg dose group was selected as the target dose for phase III having the best benefit-to-risk ratio.