Statistical aspects of the TNK-S2B trial of tenecteplase versus alteplase in
acute ischemic stroke: an efficient, dose-adaptive, seamless phase II/III design.
Author(s): Levin B, Thompson JL, Chakraborty B, Levy G, MacArthur R, Haley EC.
Affiliation(s): Department of Biostatistics, Mailman School of Public Health, Columbia
University, New York, NY 10025, USA.
Publication date & source: 2011, Clin Trials. , 8(4):398-407
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.
PURPOSE: (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
LIMITATIONS: 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.