An efficacy and safety study of the ETA/B receptor antagonist TAK-044 in subarachnoid hemorrhage

Malcolm D. M. Shaw M.A., F.R.C.S.1, Marinus Vermeulen M.D., Ph.D.1, Gordon D. Murray M.A., Ph.D., F.R.C.P.(Ed)1, John D. Pickard M.Chir., F.R.C.S., F.Med.Sci.1, B. Anthony Bell M.D., F.R.C.S.1, and Graham M. Teasdale F.R.C.S., F.Med.Sci.1
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  • 1 The Walton Centre for Neurology and Neurosurgery, Liverpool; Medical Statistics Unit, The University of Edinburgh Medical School, Edinburgh; Department of Neurosurgery, Addenbrooke's Hospital, Cambridge; Department of Neurosurgery, Atkinson Morleys Hospital, London; and Institute of Neurological Sciences, Glasgow, United Kingdom; and Department of Neurology, Academic Medical Center, Amsterdam, The Netherlands
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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 ETA/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.

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