title: Using historical lesion volume data in the design of a new phase II clinical trial in acute stroke.
abstract: OBJECTIVE
  Clinical research into the treatment of acute stroke is complicated, is costly, and has often been unsuccessful. Developments in imaging technology based on computed tomography and magnetic resonance imaging scans offer opportunities for screening experimental therapies during phase II testing so as to deliver only the most promising interventions to phase III. We discuss the design and the appropriate sample size for phase II studies in stroke based on lesion volume.
  
  
  METHODS
  Determination of the relation between analyses of lesion volumes and of neurologic outcomes is illustrated using data from placebo trial patients from the Virtual International Stroke Trials Archive. The size of an effect on lesion volume that would lead to a clinically relevant treatment effect in terms of a measure, such as modified Rankin score (mRS), is found. The sample size to detect that magnitude of effect on lesion volume is then calculated. Simulation is used to evaluate different criteria for proceeding from phase II to phase III.
  
  
  RESULTS
  The odds ratios for mRS correspond roughly to the square root of odds ratios for lesion volume, implying that for equivalent power specifications, sample sizes based on lesion volumes should be about one fourth of those based on mRS. Relaxation of power requirements, appropriate for phase II, lead to further sample size reductions. For example, a phase III trial comparing a novel treatment with placebo with a total sample size of 1518 patients might be motivated from a phase II trial of 126 patients comparing the same 2 treatment arms. Discussion- Definitive phase III trials in stroke should aim to demonstrate significant effects of treatment on clinical outcomes. However, more direct outcomes such as lesion volume can be useful in phase II for determining whether such phase III trials should be undertaken in the first place.
authors.affiliation: Department of Mathematics and Statistics, Medical and Pharmaceutical Statistics Research Unit, Lancaster University, Lancaster, UK. j.whitehead@lancaster.ac.uk
authors.forename: John
authors.initials: J
authors.lastname: Whitehead
authors.forename: Kim
authors.initials: K
authors.lastname: Bolland
authors.forename: Elsa
authors.initials: E
authors.lastname: Valdès-Márquez
authors.forename: Anela
authors.initials: A
authors.lastname: Lihic
authors.forename: Myzoon
authors.initials: M
authors.lastname: Ali
authors.forename: Kennedy
authors.initials: K
authors.lastname: Lees
mesh_terms: D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D017322:Clinical Trials, Phase II as Topic / Q000379:methods* / Q000592:standards; D003198:Computer Simulation; D016208:Databases, Factual; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D016017:Odds Ratio; D016032:Randomized Controlled Trials as Topic / Q000379:methods* / Q000592:standards; D018401:Sample Size; D020521:Stroke / Q000175:diagnosis* / Q000628:therapy*; D014057:Tomography, X-Ray Computed