OBJECT: Delayed cerebral ischemia remains an important cause of death and disability in patients who have suffered subarachnoid hemorrhage (SAH). Endothelin (ET) has a potent contractile effect on cerebral arteries and arterioles and has been implicated in vasospasm. The authors administered ET(A/B) receptor antagonist (TAK-044) to patients suffering from aneurysmal SAH. They then assessed whether this agent reduced the occurrence of delayed cerebral ischemic events and examined its safety profile in this group of patients. METHODS:Four hundred twenty patients who had suffered an SAH were recruited into a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II trial. The primary end point was whether a delayed ischemic event occurred within 3 months after the first dose of the study drug and the secondary end points included determining whether a delayed ischemic event occurred by 10 days after the first dose of the study drug, whether a new cerebral infarct was demonstrated on a computerized tomography scan or at postmortem examination by 3 months after administration of the initial dose, the patient's Glasgow Outcome Scale scores at 3 months after the initial dose, and adverse events. There was a lower incidence of delayed ischemic events at 3 months in the TAK-044-treated group: 29.5% compared with 36.6% in a group of patients receiving placebo. The estimated relative risk was 0.8 with a 95% confidence interval of 0.61 to 1.06. There were no significant differences in the secondary end points, including clinical outcomes in the placebo-treated and TAK-044-treated groups. CONCLUSIONS: The TAK-044 was well tolerated by patients who had suffered an SAH, even though hypotension and headache--side effects compatible with the drug's vasodilatory properties--occurred. It would be valuable to proceed to a fully powered phase III trial of an ET receptor antagonist in treating aneurysmal SAH.
RCT Entities:
OBJECT: Delayed cerebral ischemia remains an important cause of death and disability in patients who have suffered subarachnoid hemorrhage (SAH). Endothelin (ET) has a potent contractile effect on cerebral arteries and arterioles and has been implicated in vasospasm. The authors administered ET(A/B) receptor antagonist (TAK-044) to patients suffering from aneurysmalSAH. They then assessed whether this agent reduced the occurrence of delayed cerebral ischemic events and examined its safety profile in this group of patients. METHODS: Four hundred twenty patients who had suffered an SAH were recruited into a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II trial. The primary end point was whether a delayed ischemic event occurred within 3 months after the first dose of the study drug and the secondary end points included determining whether a delayed ischemic event occurred by 10 days after the first dose of the study drug, whether a new cerebral infarct was demonstrated on a computerized tomography scan or at postmortem examination by 3 months after administration of the initial dose, the patient's Glasgow Outcome Scale scores at 3 months after the initial dose, and adverse events. There was a lower incidence of delayed ischemic events at 3 months in the TAK-044-treated group: 29.5% compared with 36.6% in a group of patients receiving placebo. The estimated relative risk was 0.8 with a 95% confidence interval of 0.61 to 1.06. There were no significant differences in the secondary end points, including clinical outcomes in the placebo-treated and TAK-044-treated groups. CONCLUSIONS: The TAK-044 was well tolerated by patients who had suffered an SAH, even though hypotension and headache--side effects compatible with the drug's vasodilatory properties--occurred. It would be valuable to proceed to a fully powered phase III trial of an ET receptor antagonist in treating aneurysmalSAH.
Authors: Raul G Nogueira; Michael J Bodock; Walter J Koroshetz; Mehmet A Topcuoglu; Bob S Carter; Christopher S Ogilvy; Johnny C Pryor; Ferdinando S Buonanno Journal: Neurocrit Care Date: 2007 Impact factor: 3.210
Authors: Anthony P Davenport; Kelly A Hyndman; Neeraj Dhaun; Christopher Southan; Donald E Kohan; Jennifer S Pollock; David M Pollock; David J Webb; Janet J Maguire Journal: Pharmacol Rev Date: 2016-04 Impact factor: 25.468