Clazosentan, a selective Endothelin A ( ETA ) receptor antagonist, can reduce the number and severity of cases of vasospasm following aneurysmal subarachnoid haemorrhage ( SAH ).

Vasospasm occurs 5-14 days following SAH and leads to strokes and neurological deficits that cause significant disability to patients and is a major cause of death. As many as 70% of people who have aneurysmal SAH may have arterial narrowing and even with the most advanced surgical and endovascular advances in securing the aneurysm, the outcomes remain poor with up to 30% developing neurological deficits or dying.

This Phase IIa study with 34 patients demonstrated that patients given the i.v. Clazosentan continuously for up to 14 days suffered from significantly fewer and less severe cases of vasospasm compared to placebo. Only 40% of patients treated with Clazosentan developed cerebral vasospasm, as diagnosed on angiography, compared to 88% of patients treated with placebo ( p=0.008 ).

Furthermore, there were fewer patients with new cerebral infarcts in the Clazosentan group – 15% versus 44% in the placebo group. Overall the nature and severity of adverse events were comparable between the two treatment groups. Infusions of Clazosentan were generally well tolerated, with no clinically relevant effects on blood pressure or other vital signs.

Peter Vajkoczy, at the Department of Neurosurgery, University Hospital, Mannheim, and the main author of the study comments: " While our understanding of cerebral vasospasm has continued to improve, a solution to this challenge is yet to be found. However, these results are certainly promising and it is important that these findings are assessed and confirmed in a larger population to identify how Clazosentan may have an impact in clinical practice."

Neal Kassell, at the University of Virginia comments: " It is encouraging to finally, after nearly one-half century of futile investigations, be able to introduce into clinical trials an agent that, based on experimental studies, has a real potential for preventing vasospasm and, based on preliminary clinical studies, appears to be without significant side effects ( including hypotension ), as well as exhibiting a suggestion of efficacy."

The findings of this study have already led to the initiation of a comprehensive Phase IIb/III development programme for Clazosentan.

A multi-centre, international, double-blind, randomized, placebo-controlled, parallel group, dose-finding study CONSCIOUS-1 ( Clazosentan to Overcome Neurological iSChemia and Infarct OccUrring after Subarachnoid hemorrhage ) will analyse the efficacy of 3 dose levels of Clazosentan in preventing the occurrence of cerebral vasospasm following SAH, assessed by angiography. As a secondary endpoint, the study will also assess the ability of Clazosentan to reduce the occurrence of early morbidity/mortality as well as overall safety and tolerability of the drug.

CONSCIOUS-1 is expected to recruit 400 patients in approximately 70 centers in 13 countries worldwide. Study results are expected in the first half of 2006. These results will determine the need, size and duration of a Phase III study.

Source: Journal of Neurosurgery, 2005


XagenaMedicine2005