Refining an Innovative Phase III Trial of Adjunctive Therapy in Acute Kawasaki Disease with Coronary Artery Aneurysms

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ABTRACT Despite appropriate IVIG therapy, one in four children with Kawasaki disease (KD) develops coronary artery aneurysms (CAA) and 1% develop giant CAA which are at risk for adverse cardiac events including myocardial infarction and sudden death. To decrease CAA incidence and associated morbidity, the 2017 American Heart Association KD guidelines recommend consideration of primary adjunctive anti-inflammatory therapy for patients at high risk for CAA. However, no clinical trials have compared the efficacy of adjunctive anti-inflammatory regimens, leading to wide practice variation. Infliximab and corticosteroids are the strongest candidates for adjunctive therapy in high-risk KD, as they have both physiological rationale for their efficacy and the greatest amount of data supporting a beneficial effect on outcomes. The rationale for the proposed clinical trial is that clinical trial data are needed to compare the safety and efficacy of infliximab to steroids for primary adjunctive KD therapy. Given the morbidity and mortality of KD-associated CAA, closing this knowledge gap is a critical unmet need. Kawasaki disease is a rare disease, making it impossible to attain sufficient sample size for an adequately powered, traditional, controlled Phase III trial with a single primary outcome measure. Moreover, if the two therapies are similarly effective for reducing CAA, other outcomes such as fever duration, hospital length of stay, and need for additional therapies, may guide the choice of agent. Thus the overall objective of this proposal and the rationale to apply for this specific U34 is to refine the design of a feasible, innovative clinical trial to determine the optimal acute adjunctive therapy for high risk KD patients in consultation with the Innovative Clinical Trials Resource (ICTR). Specifically, we propose a prospective, randomized, Phase III trial utilizing a global rank endpoint that incorporates multiple clinically relevant outcome measures into a single primary endpoint. The expected outcome of the clinical trial is that the novel primary endpoint will provide sufficient statistical power to detect a clinically important difference between adjunctive primary therapy with infliximab or steroids. The specific objectives of the planning period are: 1) in consultation with ICTR, to develop best practices for combining individual patient outcomes to create a novel, hierarchical global rank endpoint; 2) to convene an advisory panel of KD experts to guide selection of the endpoints for inclusion, and their relative clinical importance to allow weighting of the variables. Our expected outcome of the planning period is to have a finalized design of the Phase III trial of adjunctive therapy with infliximab versus steroids for acute, high risk KD patients. This will have a positive impact on the care of children with KD and CAA as it will be the foundation for an adequately powered Phase III KD trial that will address the urgent clinical need of defining the best adjunctive therapy to prevent progression of CAA.