IMpact of therapY using coleSevelam treatment reducing bile acids in patients with fonTan cIrCulation (MYSTIC): Rationale and Study Design

Patients with a Fontan circulation suffer from progressive multiorgan dysfunction, yet central biochemical drivers remain poorly defined. Our recent work exploring metabolomic analyses have identified markedly elevated circulating bile acids (BAs) in adult Fontan patients compared with healthy controls. Elevated BAs, especially secondary and hydrophobic ones produced by the gut microbiome were found to correlate with worse exercise capacity, greater frailty, and impaired hemodynamics. Bile acid accumulation may contribute to Fontan pathophysiology. Colesevelam, a non-absorbed bile acid sequestrant, offers a potential targeted therapy to reduce BA levels and interrupt this disease pathway. The MYSTIC trial is a prospective, randomized, double-blind, placebo-controlled cross-over pilot study in 25 adult Fontan patients (with 25 age- and sex-matched healthy controls for baseline comparisons) to evaluate the safety, tolerability, and efficacy of colesevelam in lowering plasma BA levels. Primary outcomes include safety/tolerability and change in total plasma BA levels. Secondary outcomes include changes in non-invasive hemodynamics, gut microbiome composition, fecal bile acid excretion, and biochemical profiles. Single center. Estimated enrollment: 25 patients and 25 healthy subjects. Enrollment dates: September 2025 - August 2027 Trial Registration: NCT06197763 This manuscript describes the rationale and design of the MYSTIC study, which to our knowledge is the first interventional trial targeting a Fontan-specific metabolic derangement. The results will inform the feasibility of BA sequestration therapy in Fontan patients and guide future larger studies aimed at improving outcomes in this growing high-risk population.