Statistical Methods and Adaptive Trial Designs for Cardiovascular Outcomes with Information Sharing

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Project Summary/Abstract. This application for a K01 award describes the research & mentoring plans and coursework for Dr. Alexander Kaizer, an Assistant Professor of Biostatistics and Informatics at the University of Colorado-Anschutz Medical Campus (CU-AMC), to achieve advancement towards independent research in the use of adaptive designs for cardiovascular outcome clinical trials that facilitate information sharing across different sources of data to improve the statistical efficiency of evaluating new therapies. The process to develop effective novel treatments traditionally proceeds through a series of studies and phases. Conventionally, each phase is treated independently from previous phases, which are traditionally only used in the design stage of a new trial. This represents a potentially inefficient use of all available data that could be incorporated beyond the design stage and represents an important limitation for newer trial designs that may include multiple treatments within the context of a single protocol, but where comparisons only use concurrently collected data. The statistical methodologies and trial designs proposed in this application address this limitation by developing new methods to facilitate information sharing along with applications to platform trial designs. In this award, the development of statistical methods will be coupled with formal training in the biology of the cardiovascular system to assure that these new methods have seamless application in the design of cardiovascular outcomes research. To achieve the training goals and research aims laid out in this K01, a research team of three mentors has been assembled. Dr. John Kittelson, Professor of Biostatistics and Informatics at CU-AMC, is an expert in clinical trial design and has extensive experience with cardiovascular trial implementation and analysis. Dr. Gregory Schwartz, Professor of Medicine at CU-AMC and Chief of the Cardiology Section at the VA Medical Center, is a leader in proposing, implementing, and disseminating cardiovascular outcome clinical trials. Dr. Robert Eckel, Professor of Medicine at CU-AMC, past President of the American Heart Association, and President-elect of the American Diabetes Association, is an expert in lipid and lipoprotein metabolism and diabetes. In Aim 1, we will develop statistical methods for incorporating data from supplemental sources, such as past trials, into the analysis of a current study based on their exchangeability (i.e., equivalence) after adjusting for covariates (also known as information sharing). In Aim 2, we will develop adaptive platform trial designs that consider new treatment arms compared to a shared control arm. To improve the accessibility of the new methods, user-friendly software will be developed (Aim 3). The methods and designs from these aims will be evaluated via rigorous simulation study to understand their small sample properties under various scenarios. Methods will be illustrated through application to previously conducted cardiovascular trial data available from the NHLBI BioLINCC. Together, these methods for information sharing and adaptive trial designs will improve the efficiency of the research process and take fuller advantage of available information for statistical inference.