The detailed analysis of the dose-finding study CONSCIOUS-1 ( Clazosentan to Overcome Neurological iSChemia and Infarct OccUrring after Subarachnoid hemorrhage ) has shown a significant reduction of cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage ( SAH ) with administration of Clazosentan, an endothelin receptor antagonist.

The dose-finding study evaluated the efficacy of 3 dose levels of Clazosentan ( 15, 5 and 1mg/hour ) in preventing the occurrence of cerebral vasospasm following SAH who underwent either clipping or coiling to stop the initial aneurismal bleed, assessed by angiography. As a secondary endpoint, the study also evaluated the ability of Clazosentan to reduce the occurrence of early morbidity/mortality as well as overall safety and tolerability of the drug.

CONSCIOUS-1 recruited 413 patients in 52 centers in 11 countries worldwide and was initiated after promising pre-clinical and clinical data that was published in the Journal of Neurosurgery in July 2005.

All three doses of i.v. Clazosentan tested ( 1mg/h, 5mg/h and 15mg/h ) reached statistical significance versus placebo for the primary endpoint: the reduction in the occurrence of moderate or severe cerebral vasospasm, as measured by digital subtraction angiography ( DSA ) at day 9 ( plus/minus 2 days ) post-aneurysm rupture.

The effect was dose-related and most significantly seen with the dose of 15 mg/hour, a relative risk reduction compared to placebo of 65 percent ( p<0.0001 ). Effects were also statistically significant for the 5mg dose ( p=0.0003 ) and the 1mg dose ( p=0.0027 ).

Clazosentan showed a trend in favor of reducing morbidity/mortality related to vasospasm. The trend was more pronounced on 5mg/h ( relative risk reduction of 28 percent, p=ns ) and 15mg/h ( relative risk reduction of 26 percent; p=ns ) and mainly the result of substantial reductions in new cerebral infarcts and DIND ( delayed ischemic neurological deficit ).

Clazosentan showed a higher incidence versus placebo of adverse events such as fluid retention, also evidenced by excess cases of pulmonary complications, and hypotension, especially when used concomitantly with Nimodipine.

Source: Congress of Neurological Surgeons, 2006


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