The expected toxicity rate at the maximum tolerated dose in bridging studies in Alzheimer's disease

A bridging study has been recommended to determine the maximum tolerated dose in Alzheimer's disease patients, because the maximum tolerated dose in the Alzheimer's disease patient population versus the normal population can vary greatly. Although bridging studies in Alzheimer's disease have often been conducted, it is surprising to note that very little is known about the statistical properties of the studies. For example, even how toxic the maximum tolerated dose is has not been examined. In addition, both the number of patients needed and the number of patients who will experience the toxicity cannot be predicted either. In this paper, we examine the exact statistical properties of a fixed-dose panel design which is frequently used in bridging studies in Alzheimer's disease. We introduce the formulas for the overall toxicity rate at the maximum tolerated dose, the expected number of patients who will experience the overall toxicity, and the expected number of patients in the bridging studies in Alzheimer's disease. The exact statistical properties of bridging studies depend on the unknown dose-toxicity curve. In this paper, we assume the logistic and the hyperbolic tangent functions as the true dose-toxicity curves, because the two families of functions seem to include most practical dose-toxicity curves. Based on the assumptions we investigate extensively the exact statistical properties of the bridging studies in Alzheimer clinical trials. The investigation shows that the expected toxicity rate at the maximum tolerated dose ranges from 18% to 30%. All rights reserved.