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The effect of missing data on design efficiency in repeated cross-sectional multi-period two-arm parallel cluster randomized trials.

ABSTRACT: The reduced efficiency of the cluster randomized trial design may be compensated by implementing a multi-period design. The trial then becomes longitudinal, with a risk of intermittently missing observations and dropout. This paper studies the effect of missing data on design efficiency in trials where the periods are the days of the week and clusters are followed for at least one week. The multilevel model with a decaying correlation structure is used to relate outcome to period and treatment condition. The variance of the treatment effect estimator is used to measure efficiency. When there is no data loss, efficiency increases with increasing number of subjects per day and number of weeks. Different weekly measurement schemes are used to evaluate the impact of planned missing data designs: the loss of efficiency due to measuring on fewer days is largest for few subjects per day and few weeks. Dropout is modeled by the Weibull survival function. The loss of efficiency due to dropout increases when more clusters drop out during the course of the trial, especially if the risk of dropout is largest at the beginning of the trial. The largest loss is observed for few subjects per day and a large number of weeks. An example of the effect of waiting room environments in reducing stress in dental care shows how different design options can be compared. An R Shiny app allows researchers to interactively explore various design options and to choose the best design for their trial.

SUBMITTER: Moerbeek M

PROVIDER: S-EPMC8367915 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundBayesian adaptive designs can be more efficient than traditional methods for multi-arm randomised controlled trials. The aim of this work was to demonstrate how Bayesian adaptive designs can be constructed for multi-arm phase III clinical trials and assess potential benefits that these designs offer.MethodsWe constructed several alternative Bayesian adaptive designs for the Collaborative Ankle Support Trial (CAST), which was a randomised controlled trial that compared four treatments for severe ankle sprain. These designs incorporated response adaptive randomisation (RAR), arm dropping, and early stopping for efficacy or futility. We studied the operating characteristics of the Bayesian designs via simulation. We then virtually re-executed the trial by implementing the Bayesian adaptive designs using patient data sampled from the CAST study to demonstrate the practical applicability of the designs.ResultsWe constructed five Bayesian adaptive designs, each of which had high power and recruited fewer patients on average than the original designs target sample size. The virtual executions showed that most of the Bayesian designs would have led to trials that declared superiority of one of the interventions over the control. Bayesian adaptive designs with RAR or arm dropping were more likely to allocate patients to better performing arms at each interim analysis. Similar estimates and conclusions were obtained from the Bayesian adaptive designs as from the original trial.ConclusionsUsing CAST as an example, this case study shows how Bayesian adaptive designs can be constructed for phase III multi-arm trials using clinically relevant decision criteria. These designs demonstrated that they can potentially generate earlier results and allocate more patients to better performing arms. We recommend the wider use of Bayesian adaptive approaches in phase III clinical trials.Trial registrationCAST study registration ISRCTN, ISRCTN37807450. Retrospectively registered on 25 April 2003.

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The effect of missing data on design efficiency in repeated cross-sectional multi-period two-arm parallel cluster randomized trials.

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