The Limb-Leaf Design

This dissertation proposes a method to explore a dose response curve adaptively, allowing new doses to be inserted into the trial after initial results have been observed. The context of our work is adaptive seamless Phase II/III trials and a systematic Limb-Leaf Design is developed. In a case of a nonmonotonic dose response curve where the desired level of effect exists in only a narrow dose range, a simulated comparison between a Limb-Leaf Design and a standard (Thall, Simon, and Ellenberg or TSE-type) adaptive seamless design shows a savings in risk adjusted expected sample size of up to 25%. Chapter 1 is a review of concepts and particular adaptive seamless designs of interest. Chapter 2 proposes dose addition in adaptive seamless designs and identifes ALS research as an area of application. Chapter 3 develops dose addition as an application of existing methodology. Chapter 4 identifies shortcomings of this approach and proposes a new Horizontal Test as the basis for the Limb-Leaf Design. Chapter 5 supports the development of the Limb-Leaf Design with several theoretical observations. The Limb-Leaf Design is developed in Chapters 6 and 7. Chapter 8 shows a comparison of the Limb-Leaf Design with a TSE-type adaptive seamless design by simulation. Future work is suggested in Chapter 9.