01490nas a2200157   4500000000100000008004100001100002200042700001400064700001000078245012000088250001500208300001200223490000700235520104400242020004601286       2011                            d1 aHeritier Stephane1 aMorgan C.1 aLo S.00aAn adaptive confirmatory trial with interim treatment selection: practical experiences and unbalanced randomization  a2011/03/25  a1541-540 v303 a<p>
This article has been motivated by an ongoing international adaptive confirmatory trial. At the interim analysis of this two-stage trial, none, one or two active treatment regimens are selected for further study in the second stage. A combination test approach is used in this practical setting with an extension of the theory to unbalanced randomization. We show that a combination test with suitable weights can still preserve the overall Type I error rate provided that the test statistic is chosen appropriately and the unpooled Z-test for proportions is not used. The accuracy of stagewise p-values is also discussed in a more general framework. Monte Carlo simulations confirm the validity of the approach retained and evaluate the necessary sample size. Additional issues addressed during the design of the trial are also examined such as multiplicity due to testing hypotheses on key secondary endpoints, a non-inferiority comparison to an active treatment and covariate adjusted analyses for various types of outcome.
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