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 > or = 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.
RCT Entities:
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 > or = 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 aneurysmalSAH with the incidence and severity of adverse events comparable to that of placebo.
Authors: Jared M Pisapia; Xiangsheng Xu; Jane Kelly; Jamie Yeung; Geneive Carrion; Huaiyu Tong; Sudha Meghan; Omar M El-Falaky; M Sean Grady; Douglas H Smith; Sergei Zaitsev; Vladimir R Muzykantov; Michael F Stiefel; Sherman C Stein Journal: Exp Neurol Date: 2011-11-04 Impact factor: 5.330
Authors: Bhavani P Thampatty; Paula R Sherwood; Matthew J Gallek; Elizabeth A Crago; Dianxu Ren; Allison J Hricik; Chien-Wen J Kuo; Megan M Klamerus; Sheila A Alexander; Catherine M Bender; Leslie A Hoffman; Michael B Horowitz; Amin B Kassam; Samuel M Poloyac Journal: Neurocrit Care Date: 2011-08 Impact factor: 3.210
Authors: Khalid A Hanafy; R Morgan Stuart; Luis Fernandez; J Michael Schmidt; Jan Claassen; Kiwon Lee; E Sander Connolly; Stephan A Mayer; Neeraj Badjatia Journal: J Clin Neurosci Date: 2009-12-08 Impact factor: 1.961
Authors: Ryszard M Pluta; Jacob Hansen-Schwartz; Jens Dreier; Peter Vajkoczy; R Loch Macdonald; Shigeru Nishizawa; Hideotoshi Kasuya; George Wellman; Emanuela Keller; Alois Zauner; Nicholas Dorsch; Joseph Clark; Shigeki Ono; Talat Kiris; Peter Leroux; John H Zhang Journal: Neurol Res Date: 2009-03 Impact factor: 2.448