A placebo-controlled Bayesian dose finding design based on continuous reassessment method with application to stroke research.

Traditional dose-finding designs do not require assignment of patients to a control group. Motivated by SHRINC (Safety of Pioglitazone for hematoma resolution in intracerebral hemorrhage), we developed a placebo-controlled dose-finding study to identify the maximum tolerated dose for pioglitazone in stroke patients with spontaneous intracerebral hemorrhage. We designed an extension of the continuous reassessment method that allowed to incorporate information from the control group (i.e., the standard of care), and utilized it to determine the maximum tolerated dose in the SHRINC trial. We evaluated the operating characteristics of our design by conducting extensive simulation studies. Our findings from the simulation studies demonstrate that our proposed design is robust and performs well. By estimating the toxicity rate in the control group, we were able to obtain more accurate information about the natural history of the disease and identify appropriate dose for the next phase of this study. The proposed design provides a tool to incorporate the information from the control group into the dose-finding framework for trials with similar objectives.