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Statistical aspects of the TNK-S2B trial of tenecteplase versus alteplase in acute ischemic stroke: an efficient, dose-adaptive, seamless phase II/III design.

Levin B, Thompson JL, Chakraborty B, Levy G, MacArthur R, Haley EC - Clin Trials (2011)

Bottom Line: Phase III incorporated two co-primary hypotheses, allowing for a treatment effect at either end of the trichotomized Rankin scale.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY 10025, USA.

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.

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 analysis.

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.

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Related in: MedlinePlus

Graphical representation of the                                win-lose-type situations for tenecteplase in the interim analyses as                                well as the terminal analysis, using barycentric                            coordinates
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Related In: Results  -  Collection

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fig1-1740774511410582: Graphical representation of the win-lose-type situations for tenecteplase in the interim analyses as well as the terminal analysis, using barycentric coordinates

Mentions: Figure 1 contains a graphical representation of the win-lose-type situations for tenecteplase in the interim analyses and the terminal analysis, using barycentric coordinates. Any point in the triangle represents a triplet consisting of the probabilities of poor, neither, and good outcome; the perpendicular distance of the point from any one of the three sides represents the probability of the outcome denoted by the vertex opposite that side. Figure 1


Statistical aspects of the TNK-S2B trial of tenecteplase versus alteplase in acute ischemic stroke: an efficient, dose-adaptive, seamless phase II/III design.

Levin B, Thompson JL, Chakraborty B, Levy G, MacArthur R, Haley EC - Clin Trials (2011)

Graphical representation of the                                win-lose-type situations for tenecteplase in the interim analyses as                                well as the terminal analysis, using barycentric                            coordinates
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198122&req=5

fig1-1740774511410582: Graphical representation of the win-lose-type situations for tenecteplase in the interim analyses as well as the terminal analysis, using barycentric coordinates
Mentions: Figure 1 contains a graphical representation of the win-lose-type situations for tenecteplase in the interim analyses and the terminal analysis, using barycentric coordinates. Any point in the triangle represents a triplet consisting of the probabilities of poor, neither, and good outcome; the perpendicular distance of the point from any one of the three sides represents the probability of the outcome denoted by the vertex opposite that side. Figure 1

Bottom Line: Phase III incorporated two co-primary hypotheses, allowing for a treatment effect at either end of the trichotomized Rankin scale.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY 10025, USA.

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.

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 analysis.

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.

Show MeSH
Related in: MedlinePlus