Preliminary results of the Desmoteplase In Acute Ischemic Stroke 2 (DIAS-2) trial show no benefit of either of 2 doses of desmoteplase, a novel thrombolytic agent derived from vampire-bat saliva, over placebo. Mortality was actually increased with the 125-µg/kg dose vs both placebo and the 90-µg/kg dose, although the excess deaths occurred late after treatment and were predominantly nonneurological, and there was no excess in intracerebral hemorrhage (ICH) between groups. Werner Hacke, MD, from the University of Heidelberg, in Germany, cochair of the steering committee for the DIAS-2 trial, presented the disappointing findings at the 16th European Stroke Conference, in Glasgow, Scotland. "It simply does not make real sense, what we are seeing here," Dr. Hacke said. DIAS-2 DIAS-2 was a prospective, double-blind, single-bolus study investigating the efficacy and safety of 2 doses of desmoteplase, 90 and 125 µg/kg, given as an intravenous bolus. Two phase 2 trials of desmoteplase, DIAS and DEDAS, had been previously reported and provided encouraging data on both the safety and potential efficacy out to 9 hours after stroke onset with this agent. Patients were eligible for DIAS-2 if they could be treated within 3 and 9 hours after the onset of stroke symptoms, had a score on the National Institutes of Health Stroke Scale (NIHSS) of 4 to 20, and had a distinct ischemic penumbra of at least 20% established by magnetic resonance imaging (MRI) (perfusion-weighted imaging /diffusion-weighted imaging ) or perfusion computed tomography (CT). The primary outcome was clinical improvement at day 90, defined as having achieved all of the following: an improvement in NIHSS score of 8 points or more (or an NIHSS score of < 1), Barthel Index score of 75 to 100, and a modified Rankin Scale score of 0 to 2. On October 25, 2006, Paion AG, in Aachen, Germany, announced that the trial had been halted by the data monitoring committee (DMC) for apparent safety concerns, the precise nature of which the DMC did not disclose. However, on October 30, the trial was allowed to resume enrollment without modification of the protocol, and the data remained blinded. Now it is clear what had given the DMC pause. Using intention-to-treat analysis, investigators found no significant difference between the groups in clinical response rates, with numbers that contrasted sharply with their previous findings with this agent. "This is far from our expectations," Dr. Hacke said. "This pattern makes no sense, specifically when we look at what we had seen in the previous randomized trials — everything is turned upside down." When they considered clinical response rates without dropouts, he noted, "The picture changes slightly; now we have an equal response in all treatment arms, but not what we had expected."
Further review of data from the second Desmoteplase in Acute Ischemic Stroke (DIAS-2) trial has led both researchers and the company developing the novel thrombolytic to conclude that further studies of the drug are warranted. The company, PAION AG, in Aachen, Germany, issued a statement October 18 saying it plans to pursue investigation of desmoteplase for the treatment of acute ischemic stroke, despite the disappointing DIAS-2 results, which showed no benefit of either of 2 doses of desmoteplase, a novel thrombolytic agent derived from vampire-bat saliva, over placebo. Mortality was actually increased with the 125-µg/kg dose vs both placebo and the 90-µg/kg dose, although the excess deaths occurred late after treatment and were predominantly nonneurological. However, there was no excess in intracerebral hemorrhage (ICH) between groups. The results were presented at the 16th European Stroke Conference, in Glasgow, Scotland and reported by Medscape Neurology & Neurosurgery at that time. The decision to pursue further investigation of the drug is based on examination of imaging scans of these patients that show many of the patients had no discernible thrombus for the thrombolytic to address, despite the presence of a penumbra surrounding the infarct core on magnetic resonance imaging (MRI). It was on the basis of the presence of a distinct ischemic penumbra of at least 20% established either by perfusion-weighted/diffusion-weighted (PWI/DWI) MR imaging or perfusion computed tomography (CT) that patients were included in DIAS-2. It had been assumed that the presence of a penumbra indicated the presence of a clot that would be visible in larger arteries but invisible in smaller arteries, the statement noted. When they examined outcomes only for patients for whom a clot could be detected, there was some indication of efficacy, which seemed to increase with the size of the clot. The company plans to take these findings into account when designing new trials of desmoteplase. "We have identified probable reasons for the unexpectedly good outcome in the placebo arm as well as variables that will help optimize patient selection," Werner Hacke, MD, from the University of Heidelberg, in Germany, and Anthony Furlan, MD, from the Cleveland Clinic Foundation, in Ohio, chairs of the DIAS-2 steering committee, say in a statement from the company. "Therefore, we see a scientific rationale to move on to the next study." "The imaging subanalysis still suggests a treatment effect," Dr. Furlan told Medscape Neurology & Neurosurgery. "Placebo patients who have a big baseline [PWI/DWI] mismatch on MR do poorly," he added. "We are in the process of refining our imaging selection criteria; for example, we are seeing differences between patients selected with MR vs CT." Wolfgang Söhngen, chief executive officer of PAION, states that these new findings "provide a sound development rationale for desmoteplase. Following positive feedback from our investigators, the key issue to be addressed in the near future is to secure funding and to implement the latest findings into the design of future trials. This has to be based on an assessment of potential patient benefit and the commercial opportunity from a revised program with desmoteplase."
