title: Statistical aspects of the TNK-S2B trial of tenecteplase versus alteplase in acute ischemic stroke: an efficient, dose-adaptive, seamless phase II/III design.
abstract: BACKGROUND
  TNK-S2B, an innovative, randomized, seamless phase II/III trial of tenecteplase versus rt-PA for acute ischemic stroke, terminated for slow enrollment before regulatory approval of use of phase II patients in phase III.
  
  
  OBJECTIVE
  (1) To review the trial design and comprehensive type I error rate simulations and (2) to discuss issues raised during regulatory review, to facilitate future approval of similar designs.
  
  
  METHODS
  In phase II, an early (24-h) outcome and adaptive sequential procedure selected one of three tenecteplase doses for phase III comparison with rt-PA. Decision rules comparing this dose to rt-PA would cause stopping for futility at phase II end, or continuation to phase III. Phase III incorporated two co-primary hypotheses, allowing for a treatment effect at either end of the trichotomized Rankin scale. Assuming no early termination, four interim analyses and one final analysis of 1908 patients provided an experiment-wise type I error rate of <0.05.
  
  
  RESULTS
  Over 1,000 distribution scenarios, each involving 40,000 replications, the maximum type I error in phase III was 0.038. Inflation from the dose selection was more than offset by the one-half continuity correction in the test statistics. Inflation from repeated interim analyses was more than offset by the reduction from the clinical stopping rules for futility at the first interim analysis.
  
  
  CONCLUSIONS
  Design complexity and evolving regulatory requirements lengthened the review process.
  
  
  CONCLUSIONS
  (1) The design was innovative and efficient. Per protocol, type I error was well controlled for the co-primary phase III hypothesis tests, and experiment-wise. (2a) Time must be allowed for communications with regulatory reviewers from first design stages. (2b) Adequate type I error control must be demonstrated. (2c) Greater clarity is needed on (i) whether this includes demonstration of type I error control if the protocol is violated and (ii) whether simulations of type I error control are acceptable. (2d) Regulatory agency concerns that protocols for futility stopping may not be followed may be allayed by submitting interim analysis results to them as these analyses occur.
authors: Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY 10025, USA.
authors: Bruce
authors: B
authors: Levin
authors: John L P
authors: JL
authors: Thompson
authors: Bibhas
authors: B
authors: Chakraborty
authors: Gilberto
authors: G
authors: Levy
authors: Robert
authors: R
authors: MacArthur
authors: E Clarke
authors: EC
authors: Haley
mesh_terms: D000208:Acute Disease; D017322:Clinical Trials, Phase II as Topic / Q000379:methods / Q000706:statistics & numerical data*; D017326:Clinical Trials, Phase III as Topic / Q000379:methods / Q000706:statistics & numerical data*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D017277:Drug Approval; D057239:Early Termination of Clinical Trials; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D015337:Multicenter Studies as Topic / Q000379:methods / Q000706:statistics & numerical data; D018579:Patient Selection; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000706:statistics & numerical data; D012107:Research Design; D015983:Selection Bias; D020521:Stroke / Q000188:drug therapy*; D000077785:Tenecteplase; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator; D000077785:Tenecteplase