title: Sequential Multiple Assignment Randomized Trials: An Opportunity for Improved Design of Stroke Reperfusion Trials.
abstract: BACKGROUND
  Modern clinical trials in stroke reperfusion fall into 2 categories: alternative systemic pharmacological regimens to alteplase and "rescue" endovascular approaches using targeted thrombectomy devices and/or medications delivered directly for persistently occluded vessels. Clinical trials in stroke have not evaluated how initial pharmacological thrombolytic management might influence subsequent rescue strategy. A sequential multiple assignment randomized trial (SMART) is a novel trial design that can test these dynamic treatment regimens and lead to treatment guidelines that more closely mimic practice.
  
  
  OBJECTIVE
  To characterize a SMART design in comparison to traditional approaches for stroke reperfusion trials.
  
  
  METHODS
  We conducted a numerical simulation study that evaluated the performance of contrasting acute stroke clinical trial designs of both initial reperfusion and rescue therapy. We compare a SMART design where the same patients are followed through initial reperfusion and rescue therapy within 1 trial to a standard phase III design comparing 2 reperfusion treatments and a separate phase II futility design of rescue therapy in terms of sample size, power, and ability to address particular research questions.
  
  
  RESULTS
  Traditional trial designs can be well powered and have optimal design characteristics for independent treatment effects. When treatments, such as the reperfusion and rescue therapies, may interact, commonly used designs fail to detect this. A SMART design, with similar sample size to standard designs, can detect treatment interactions.
  
  
  CONCLUSIONS
  The use of SMART designs to investigate effective and realistic dynamic treatment regimens is a promising way to accelerate the discovery of new, effective treatments for stroke.
authors.affiliation: Department of Emergency Medicine, University of Michigan, Ann Arbor, Michigan; Department of Neurology, University of Michigan, Ann Arbor, Michigan; Stroke Program, University of Michigan, Ann Arbor, Michigan. Electronic address: wmeurer@umich.edu.
authors.forename: William J
authors.initials: WJ
authors.lastname: Meurer
authors.affiliation: Department of Statistics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Seewald
authors.affiliation: Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan.
authors.forename: Kelley
authors.initials: K
authors.lastname: Kidwell
mesh_terms: D003198:Computer Simulation; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D015424:Reperfusion; D020521:Stroke / Q000628:therapy*; D015912:Thrombolytic Therapy / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator
keywords: Ischemic stroke; clinical trials; reperfusion; simulation; thrombectomy; thrombolysis