Leveraging existing registry resources to facilitate clinical trials

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The central objectives of this proposal are to: 1) design and conduct a “trial within a registry” of perioperative steroids to improve outcomes after neonatal cardiopulmonary bypass (CPB) surgery; 2) develop the infrastructure for a registry-based pediatric heart surgery trials network; and 3) define a new model for cost- effective clinical trials that may be used to study understudied diseases and conditions. The proposed work will be accomplished through collaboration between three CTSA hubs, Duke University, Johns Hopkins University and Vanderbilt University, as well as the Society of Thoracic Surgeons and its analytic center, the Duke Clinical Research Institute. Clinical trials are resource-intensive and costly. Consequently many patient populations remain understudied with limited evidence to guide clinical practice. One mechanism to improve the evidence base is to leverage existing registry resources to conduct simple, efficient and low cost trials. This “trial within a registry” concept can: 1) optimize trial design by using registry data to inform clinical trial simulations; 2) improve access to study subjects and centers; 3) provide quality control mechanisms ensuring efficient, accurate, and cost-effective data collection; and 4) provide mature and tested infrastructure to compile, analyze and disseminate trial data. The proposed work will demonstrate the benefits of the “trial within a registry” approach in an understudied and vulnerable patient population, neonates undergoing heart surgery with CPB. Mortality after neonatal heart surgery occurs in 10% with major complications in 23%. These poor outcomes are related to the severe neonatal systemic inflammatory response to CPB. For decades high-dose systemic steroids have been used to reduce post-CPB inflammation after neonatal heart surgery. However there are limited data to support this practice; prior trials have all been small and have relied upon surrogate outcome measures. Recent data from adults undergoing CPB suggest that steroids contribute to worse outcomes. There is an urgent and unmet need for a large scale, conclusive trial of steroids after neonatal CPB focused on clinically meaningful endpoints. This trial can be readily conducted at a fraction of the cost of a typical clinical trial by leveraging the existing infrastructure of the Society of Thoracic Surgeons Congenital Heart Surgery Database.