Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2).

Abstract

BACKGROUND:

Clazosentan, an endothelin receptor antagonist, significantly and dose-dependently reduced angiographic vasospasm after aneurysmal subarachnoid haemorrhage (aSAH). We investigated whether clazosentan reduced vasospasm-related morbidity and all-cause mortality.

METHODS:

In this randomised, double-blind, placebo-controlled, phase 3 study, we randomly assigned patients with aSAH secured by surgical clipping to clazosentan (5 mg/h, n=768) or placebo (n=389) for up to 14 days (27 countries, 102 sites, inpatient and outpatient settings) using an interactive web response system. The primary composite endpoint (week 6) included all-cause mortality, vasospasm-related new cerebral infarcts, delayed ischaemic neurological deficit due to vasospasm, and rescue therapy for vasospasm. The main secondary endpoint was dichotomised extended Glasgow outcome scale (GOSE; week 12). This trial is registered with ClinicalTrials.gov, number NCT00558311.

FINDINGS:

In the all-treated dataset, the primary endpoint was met in 161 (21%) of 764 clazosentan-treated patients and 97 (25%) of 383 placebo-treated patients (relative risk reduction 17%, 95% CI -4 to 33; p=0·10). Poor functional outcome (GOSE score ≤4) occurred in 224 (29%) clazosentan-treated patients and 95 (25%) placebo-treated patients (-18%, -45 to 4; p=0·10). Lung complications, anaemia, and hypotension were more common with clazosentan. Mortality (week 12) was 6% in both groups.

INTERPRETATION:

Clazosentan at 5 mg/h had no significant effect on mortality and vasospasm-related morbidity or functional outcome. Further investigation of patients undergoing endovascular coiling of ruptured aneurysms is needed to fully understand the potential usefulness of clazosentan in patients with aSAH.

FUNDING:

Actelion Pharmaceuticals.

• Authors: R Loch Macdonald, Randall T Higashida, Emanuela Keller, Stephan A Mayer, Andy Molyneux, Andreas Raabe, Peter Vajkoczy, Isabel Wanke, Doris Bach, Aline Frey, Angelina Marr, Sébastien Roux, Neal Kassell
• Journal: The Lancet. Neurology (Lancet Neurol) Vol. 10 Issue 7 Pg. 618-25 (Jul 2011) ISSN: 1474-4465 [Electronic] England
• PMID: 21640651 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Dioxanes
• Endothelin A Receptor Antagonists
• Pyridines
• Pyrimidines
• Sulfonamides
• Tetrazoles
• clazosentan

Topics

• Dioxanes (therapeutic use)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Endothelin A Receptor Antagonists
• Female
• Glasgow Outcome Scale
• Humans
• Male
• Pyridines (therapeutic use)
• Pyrimidines (therapeutic use)
• Subarachnoid Hemorrhage (complications, drug therapy, mortality, surgery)
• Sulfonamides (therapeutic use)
• Surgical Instruments
• Tetrazoles (therapeutic use)
• Treatment Outcome
• Vasospasm, Intracranial (drug therapy, etiology, mortality, prevention & control)