Introduction: IFALD ,defined as steatosis and cholestasis, is associated with significant morbidity in patients dependent on parenteral nutrition(PN).Choline is an essential nutrient that is a fundamental component of cell membranes, VLDL for triglyceride export from the liver, and normal bile.PN products do not contain sufficient choline.Buchman et al(2001) determined that IFALD may be reversible in choline-deficient patients.The current study wreviewed, transformed and analyzed data from Buchman et al 2001 using state of the art methods to inform a confirmatory phase 3 trial.

Methods: Data were imported from original source documents into an electronic eCTD format. Because MRI-Proton Density Fat Fraction(PDFF)has become the gold standard method for non-invasive quantification of hepatic steatosis, CT data were transformed to MRI-PDFF using an established linear equation (Kramer et al, 2017).The trial was then re-analyzed using MMRM statistical approach, and in two subgroups of patients meeting contemporary definitions of IFALD.Missing data were reasonably assumed to be missing at random.

Results: This was a study of adults dependent on PN for many years(11.8 years(6.47).IV Choline Chloride was safe and well-tolerated. Baseline MRI-PDFF values(mean 19.6%, range [9.8-38.3%])demonstrate moderate to severe fatty liver in the study population.The benefit of IV Choline Chloride vs PBO achieves significance or trend-significance from Weeks 4-24 despite small sample size.Comparing groups on the relative (%) change of MRI-PDFF, drug-PBO differences from Weeks 4-24 are large and clinically meaningful(range 31%-54%).The benefit of IV Choline Chloride vs PBO achieves trend-to or statistical significance from Weeks 4-24 despite small sample size. In the sub-group analyses, improvement in ALP is consistent and substantial, with 20-30% improvement over 12-24 weeks of treatment.

Conclusion: Using MRI-PDFF, a contemporary definition of IFALD, modern analytic approaches, and source-verified data, the original findings from Buchman et al 2001 are replicated and extended. These robust results in a rare, but serious condition affecting PN patients can inform future trials attempting to replicate these promising results in a larger cohort to support the development of a safe, choline PN product.