Clazosentan (AXV-034343), a selective endothelin A receptor antagonist, in the prevention of cerebral vasospasm following severe aneurysmal subarachnoid hemorrhage: Results of a randomized, double-blind, placebo-controlled, multicenter Phase IIa study

Peter Vajkoczy, Bernhard Meyer, Stefan Weidauer, Andreas Raabe, Claudius Thome, Florian Ringel, Volker Breu, Peter Schmiedek

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249 Scopus citations

Abstract

Objective. The goal of this study was to investigate the safety and tolerability of the novel endothelin A (ETA) receptor antagonist clazosentan in patients with subarachnoid hemorrhage (SAH) and its potential to reduce the incidence and severity of cerebral vasospasm following surgical clipping of the aneurysm. Methods. This Phase IIa multicenter study had two parts: a double-blind, randomized Part A (some patients given clazosentan [0.2 mg/kg/hr] and others given placebo), in which statistical inference was performed, and an open-label Part B (patients with established vasospasm given clazosentan [0.4 mg/kg/hr for 12 hours followed by 0.2 mg/kg/hr]) for exploratory purposes only. Primary end points were the incidence and severity of angiographic vasospasm on Day 8 after SAH and the safety and tolerability of the drug. Thirty-four patients (Hunt and Hess Grades III and IV and Fisher Grade ≥ 3) were recruited and 32 (15 in the clazosentan group and 17 in the placebo group) were retained in the intent-to-treat population; 19 patients entered Part B. In Part A, treatment with clazosentan resulted in a reduced incidence of angiographically evident cerebral vasospasm (40% compared with 88% of patients, p = 0.008). In addition, the severity of vasospasm was reduced in the clazosentan group (p = 0.012). In Part B of the study, in 50% of assessable patients who were initially treated with placebo reversal of vasospasm was observed following the initiation of clazosentan therapy. The incidence of new infarctions was 15% in the clazosentan group and 44% in the placebo group (p = 0.130). There was no adverse event pattern indicating a specific organ toxicity of clazosentan. Conclusions. This study indicates that clazosentan reduces the frequency and severity of cerebral vasospasm following severe aneurysmal SAH with the incidence and severity of adverse events comparable to that of placebo.

Original languageEnglish
Pages (from-to)9-17
Number of pages9
JournalJournal of Neurosurgery
Volume103
Issue number1
DOIs
StatePublished - Jul 2005

Keywords

  • Aneurysm
  • Clazosentan
  • Clinical trial
  • Endothelin
  • Subarachnoid hemorrhage
  • Vasospasm

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