Covariate adjustment in clinical trials with non‐ignorable missing data and non‐compliance

Estimating causal effects in psychiatric clinical trials is often complicated by treatment non‐compliance and missing outcomes. While new estimators have recently been proposed to address these problems, they do not allow for inclusion of continuous covariates. We propose estimators that adjust for continuous covariates in addition to non‐compliance and missing data. Using simulations, we compare mean squared errors for the new estimators with those of previously established estimators. We then illustrate our findings in a study examining the efficacy of clozapine versus haloperidol in the treatment of refractory schizophrenia. For data with continuous or binary outcomes in the presence of non‐compliance, non‐ignorable missing data, and a covariate effect, the new estimators generally performed better than the previously established estimators. In the clozapine trial, the new estimators gave point and interval estimates similar to established estimators. We recommend the new estimators as they are unbiased even when outcomes are not missing at random and they are more efficient than established estimators in the presence of covariate effects under the widest variety of circumstances. Copyright © 2004 John Wiley & Sons, Ltd.