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A logrank test-based method for sizing clinical trials with two co-primary time-to-event endpoints.

ABSTRACT: We discuss sample size determination for clinical trials evaluating the joint effects of an intervention on two potentially correlated co-primary time-to-event endpoints. For illustration, we consider the most common case, a comparison of two randomized groups, and use typical copula families to model the bivariate endpoints. A correlation structure of the bivariate logrank statistic is specified to account for the correlation among the endpoints, although the between-group comparison is performed using the univariate logrank statistic. We propose methods to calculate the required sample size to compare the two groups and evaluate the performance of the methods and the behavior of required sample sizes via simulation.

SUBMITTER: Sugimoto T

PROVIDER: S-EPMC4148615 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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A logrank test-based method for sizing clinical trials with two co-primary time-to-event endpoints.

Sugimoto Tomoyuki T Sozu Takashi T Hamasaki Toshimitsu T Evans Scott R SR

Biostatistics (Oxford, England) 20130110 3

We discuss sample size determination for clinical trials evaluating the joint effects of an intervention on two potentially correlated co-primary time-to-event endpoints. For illustration, we consider the most common case, a comparison of two randomized groups, and use typical copula families to model the bivariate endpoints. A correlation structure of the bivariate logrank statistic is specified to account for the correlation among the endpoints, although the between-group comparison is perform ...[more]

PMID: 23307913

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Project description:BackgroundComposite time-to-event endpoints are beneficial for assessing related outcomes jointly in clinical trials, but components of the endpoint may have different censoring mechanisms. For example, in the PRagmatic EValuation of evENTs And Benefits of Lipid-lowering in oldEr adults (PREVENTABLE) trial, the composite outcome contains one endpoint that is right censored (all-cause mortality) and two endpoints that are interval censored (dementia and persistent disability). Although Cox regression is an established method for time-to-event outcomes, it is unclear how models perform under differing component-wise censoring schemes for large clinical trial data. The goal of this article is to conduct a simulation study to investigate the performance of Cox models under different scenarios for composite endpoints with component-wise censoring.MethodsWe simulated data by varying the strength and direction of the association between treatment and outcome for the two component types, the proportion of events arising from the components of the outcome (right censored and interval censored), and the method for including the interval-censored component in the Cox model (upper value and midpoint of the interval). Under these scenarios, we compared the treatment effect estimate bias, confidence interval coverage, and power.ResultsBased on the simulation study, Cox models generally have adequate power to achieve statistical significance for comparing treatments for composite outcomes with component-wise censoring. In our simulation study, we did not observe substantive bias for scenarios under the null hypothesis or when the treatment has a similar relative effect on each component outcome. Performance was similar regardless of if the upper value or midpoint of the interval-censored part of the composite outcome was used.ConclusionCox regression is a suitable method for analysis of clinical trial data with composite time-to-event endpoints subject to different component-wise censoring mechanisms.

Dataset Information

A logrank test-based method for sizing clinical trials with two co-primary time-to-event endpoints.

Publications

A logrank test-based method for sizing clinical trials with two co-primary time-to-event endpoints.

Similar Datasets

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