Comparison of the Validity of Intention-To-Treat and Per-Protocol Approaches Using Monte-Carlo Simulation: Secondary Analysis of a Clinical Trial in the Treatment of Schizophrenic Patients in the Presence of Non-Compliance

The standard methods for the comparison of two drugs in a randomized controlled clinical trial in the presence of non-compliance are intention-to-treat or per-protocol approaches. Both approaches have problems with estimation of drug effects, and researchers are not still certain to adopt which one. In this study, the bias of intention-to-treat and per-protocol approaches was calculated using Monte-Carlo simulation. We tried to choose the best approach (based on the AIC index) for comparing Risperidone plus Celecoxib and Risperidone plus Placebo. This secondary study was conducted to compare the effect of Risperidone plus Celecoxib and Risperidone plus Placebo among 60 schizophrenic patients. To choose between the intention-to-treat and per-protocol approaches, Monte-Carlo simulation with Ackaike (AIC) and Baysian (BIC) indices was used. The results of Monte-Carlo simulation showed that when the sample size was small (n=30 or n=60) under fixed conditions of non-compliance equal to 5% and 10%, intention-to-treat had a better goodness of fit than per-protocol based on AIC and BIC. However, increasing the sample size in active and placebo groups (e.g., n=100) showed that per-protocol had a better goodness of fit than intention-to-treat. When the sample size is large, the per-protocol approach may have a better goodness of fit than intention-to-treat to address the effects of non-compliance in randomized clinical trials.