title: Sample size estimates for clinical trials of vasospasm in subarachnoid hemorrhage.
abstract: OBJECTIVE
  Clinical trials for prevention of vasospasm after aneurysmal subarachnoid hemorrhage (SAH) seldom have improved overall outcome; one reason may be inadequate sample size. We used data from the tirilizad trials and the Columbia University subarachnoid hemorrhage outcomes project to estimate sample sizes for clinical trials for reduction of vasospasm after SAH, assuming trials must show effect on 90-day patient-centered outcome.
  
  
  METHODS
  Sample size calculations were based on different definitions of vasospasm, enrichment strategies, sensitivity of short- and long-term outcome instruments for reflecting vasospasm-related morbidity, different event rates of vasospasm, calculation of effect size of vasospasm on outcome instruments, and different treatment effect sizes. Sensitivity analysis was performed for variable event rates of vasospasm for a given treatment effect size. Sample size tables were constructed for different rates of vasospasm and outcome instruments for a given treatment effect size.
  
  
  RESULTS
  Vasospasm occurred in 12% to 30% of patients. Symptomatic deterioration and infarction from vasospasm exhibited the strongest relationship to mortality and morbidity after SAH. Enriching for vasospasm by selection of patients with thick SAH slightly decreased sample sizes. Assuming beta=0.80, alpha=0.05 (2-tailed) and treatment effect size of 50%, total sample size exceeds 5000 patients to demonstrate efficacy on 3-month patient-centered outcome (modified Rankin Scale).
  
  
  CONCLUSIONS
  Clinical trials targeting vasospasm and using traditional patient-centered outcome require very high sample sizes and will therefore be costly, time-consuming, and impractical. This will hinder development of new treatment strategies.
authors.affiliation: Biogen Idec, Wellesley, MA, USA.
authors.forename: Kurt T
authors.initials: KT
authors.lastname: Kreiter
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Mayer
authors.forename: George
authors.initials: G
authors.lastname: Howard
authors.forename: Volker
authors.initials: V
authors.lastname: Knappertz
authors.forename: Don
authors.initials: D
authors.lastname: Ilodigwe
authors.forename: Michael A
authors.initials: MA
authors.lastname: Sloan
authors.forename: R Loch
authors.initials: RL
authors.lastname: Macdonald
mesh_terms: D000328:Adult; D000368:Aged; D002986:Clinical Trials as Topic / Q000379:methods*; D006801:Humans; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000627:therapeutic use; D017063:Outcome Assessment, Health Care; D011281:Pregnatrienes / Q000627:therapeutic use; D018401:Sample Size; D012680:Sensitivity and Specificity; D013345:Subarachnoid Hemorrhage / Q000150:complications*; D020301:Vasospasm, Intracranial / Q000517:prevention & control*
chemical_list: D018696:Neuroprotective Agents; D011281:Pregnatrienes; C053355:tirilazad