Clinical Trials

■■❚❙❘Chapter 25Adjustmentfor CovariatesClaudio Verzilli, Duolao Wang,Tim Clayton, and Wenyang ZhangThe main purpose of randomization is to avoid bias andconfounding by ensuring the characteristics of patients(measured and unmeasured) that might influence outcomeare randomly distributed between treatment groups so thatthe treatment groups are comparable (or balanced). As aresult of randomization, any difference in the primary outcomecan be explained by the effect of the treatment or by randomvariation. However, randomization does not guarantee perfectbalance across treatment arms with respect to one or morebaseline covariates, especially in small trials. The questionthen arises of whether it is more appropriate to adjust theanalysis for such baseline imbalances using statistical methods,or to report unadjusted results. In this chapter, we explain thecircumstances under which adjusted and unadjusted analyseswill lead to different results, discuss the rationale for baselinecovariate adjustment, and give some recommendations on howto mitigate this problem during the design and analysis of a trial.287