Protein-losing enteropathy (PLE) is a serious complication after the Fontan operation with limited treatment options. This phase 2, multi-center, open-label trial evaluated the efficacy and safety of Camostat Mesylate (CM), a serine protease inhibitor, as adjunctive therapy for PLE. Nineteen patients aged 4 years and older with PLE after the Fontan operation were enrolled. CM was administered for six months in addition to their individualized conventional treatments. Assessments were made at 1, 3, and 6 months of CM administration, and at one month after CM discontinuation. Outcomes evaluated were the changes in serum albumin level, stool alpha-1 antitrypsin, and clinical symptoms such as, diarrhea, edema, weight change, and ascites. Of the 19 patients enrolled, 4 voluntarily withdrew consent, and the data from the 15 patients who completed the study were analyzed. Their median age was 15.0 years (interquartile range, 12.0–21.5) and the median time between the Fontan surgery and PLE diagnosis was 2.4 years. Serum albumin levels increased from 2.2 to 2.5 g/dL (p = 0.183), while stool alpha-1 antitrypsin levels significantly decreased from 215.6 to 75.5 mg/dL (p = 0.016) over six months. Patients with baseline diarrhea showed notable improvements: serum albumin increased from 1.8 to 2.4 g/dL (p = 0.138) and stool alpha-1 antitrypsin decreased from 220.3 to 75.5 mg/dL (p = 0.075) over 6 months. No serious adverse events occurred. CM demonstrated significant reductions in gastrointestinal protein losses, particularly in patients with baseline diarrhea. Trial registration NCT05474664.
