The purpose of this study was to explore trends in safety and efficacy, and to find the optimal dose for the subsequent phase III trial. The decision to initiate the phase III trial will depend on both safety (incidence of symptomatic intracranial hemorrhage) and efficacy (reperfusion measured by MRI and correlating with clinical outcome) profiles. The safety (incidence of symptomatic intracranial haemorrhage) and efficacy (reperfusion measured by MRI and correlating with clinical outcome) profiles gained from this study were the basis of planning the phase III.
Desmoteplase is a novel, highly fibrin-specific and non-neurotoxic thrombolytic agent. Evidence of safety and efficacy was obtained in two phase II trials (DIAS and DEDAS). The DIAS-2 phase III trial did not replicate the positive phase II efficacy findings. Post-hoc analyses were performed with the aim of predicting treatment responders based on CT and MR angiography. The predictive value of infarct volume and TIMI grade at baseline with respect to drug response measured by clinical outcome at Day 90 was investigated using DIAS-2 data. Patients were grouped according to vessel status (TIMI grade) for logistic regression of clinical response, applying the data from DIAS-2 as well as the pooled data from DIAS, DEDAS, and DIAS-2. In DIAS-2, a substantial number of mismatch-selected patients (126/179, 70%) presented with a normal flow/low-grade stenosis (TIMI 2-3) at screening, the majority having a favorable outcome at Day 90. In contrast, favorable outcome rates in patients with vessel occlusion/high-grade stenosis (TIMI 0-1) were 18% with placebo versus 36% and 27% with desmoteplase 90 and 125 μg/kg, respectively. The clinical effect size based on the pooled data from DIAS, DEDAS, and DIAS-2 was borderline statistically significantly different (P=0.05) in the TIMI 0-1 and TIMI 2-3 subgroups. It was favorable for desmoteplase-treated patients presenting with TIMI 0-1 at baseline (odds ratio, 4.144; 95% CI, 1.40-12.23; P=0.010), while there was no desmoteplase treatment benefit in patients presenting with TIMI 2-3 (odds ratio, 1.109). In this sample of patients diagnosed with a mismatch, proximal vessel occlusion or severe stenosis was associated with clinically beneficial treatment effects of desmoteplase. Selecting patients using CT or MR angiography in clinical trials of thrombolytic therapy is justifiable.
The purpose of this study was to explore trends in safety and efficacy, and to find the optimal dose for the subsequent phase III trial. The decision to initiate the phase III trial will depend on both safety (incidence of symptomatic intracranial hemorrhage) and efficacy (reperfusion measured by MRI and correlating with clinical outcome) profiles. The safety (incidence of symptomatic intracranial haemorrhage) and efficacy (reperfusion measured by MRI and correlating with clinical outcome) profiles gained from this study were the basis of planning the phase III.
