Bmc Med Res Methodol
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Bmc Med Res Methodol · Feb 2016
Augmenting the logrank test in the design of clinical trials in which non-proportional hazards of the treatment effect may be anticipated.
Most randomized controlled trials with a time-to-event outcome are designed assuming proportional hazards (PH) of the treatment effect. The sample size calculation is based on a logrank test. However, non-proportional hazards are increasingly common. At analysis, the estimated hazards ratio with a confidence interval is usually presented. The estimate is often obtained from a Cox PH model with treatment as a covariate. If non-proportional hazards are present, the logrank and equivalent Cox tests may lose power. To safeguard power, we previously suggested a 'joint test' combining the Cox test with a test of non-proportional hazards. Unfortunately, a larger sample size is needed to preserve power under PH. Here, we describe a novel test that unites the Cox test with a permutation test based on restricted mean survival time. ⋯ The combined test increases trial power under an early treatment effect and protects power under other scenarios. Use of restricted mean survival time facilitates testing and displaying a generalized treatment effect.