title: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Actelion Pharmaceuticals.
authors.affiliation: St Michael's Hospital, University of Toronto, Toronto, ON, Canada.
authors.forename: R Loch
authors.initials: RL
authors.lastname: Macdonald
authors.forename: Randall T
authors.initials: RT
authors.lastname: Higashida
authors.forename: Emanuela
authors.initials: E
authors.lastname: Keller
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Mayer
authors.forename: Andy
authors.initials: A
authors.lastname: Molyneux
authors.forename: Andreas
authors.initials: A
authors.lastname: Raabe
authors.forename: Peter
authors.initials: P
authors.lastname: Vajkoczy
authors.forename: Isabel
authors.initials: I
authors.lastname: Wanke
authors.forename: Doris
authors.initials: D
authors.lastname: Bach
authors.forename: Aline
authors.initials: A
authors.lastname: Frey
authors.forename: Angelina
authors.initials: A
authors.lastname: Marr
authors.forename: Sébastien
authors.initials: S
authors.lastname: Roux
authors.forename: Neal
authors.initials: N
authors.lastname: Kassell
mesh_terms: D004146:Dioxanes / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D065130:Endothelin A Receptor Antagonists; D005260:Female; D023261:Glasgow Outcome Scale; D006801:Humans; D008297:Male; D011725:Pyridines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D013449:Sulfonamides / Q000627:therapeutic use*; D013525:Surgical Instruments; D013777:Tetrazoles / Q000627:therapeutic use*; D016896:Treatment Outcome; D020301:Vasospasm, Intracranial / Q000188:drug therapy / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*
chemical_list: D004146:Dioxanes; D065130:Endothelin A Receptor Antagonists; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; D013777:Tetrazoles; C109641:clazosentan