BACKGROUND: Long-chain fatty acid oxidation disorders (LC-FAOD) are inherited metabolic conditions caused by impaired mitochondrial β-oxidation of long-chain fatty acids, leading to rhabdomyolysis, cardiomyopathy, and hypoglycemia. Triheptanoin, a medium odd-chain triglyceride, provides anaplerotic substrates that replenish tricarboxylic acid cycle intermediates, offering alternative energy sources and potential therapeutic benefit. METHODS: This open-label, single-center phase II study evaluated the safety and efficacy of triheptanoin in 10 Korean patients with genetically confirmed LC-FAOD who experienced recurrent rhabdomyolysis despite conventional treatment. Triheptanoin was titrated to 35% of total daily caloric intake, and all patients completed 3 years of treatment. The primary outcome was safety, assessed by adverse events. Secondary outcomes included changes in the major clinical event (MCE) rate and duration, functional capacity, health-related quality of life (HRQoL), and organ function. RESULTS: The mean study duration was 3.5 ± 0.3 years. Serious adverse events occurred in nine patients (90%), most commonly rhabdomyolysis (100%), and were considered unrelated to triheptanoin. Mild gastrointestinal symptoms during titration were the most frequent treatment-related adverse events (80%). The median annualized MCE rate and duration decreased by 42.4% and 43.6%, respectively (P = 0.114 and P = 0.059). The duration per MCE was significantly reduced by 3.5 days, as assessed by a linear mixed-effects model (P = 0.022), with a significant reduction observed in the child subgroup (P < 0.001). In eight patients, the 12-minute walk test distance increased by 12.4% at 6 months and was maintained over 3 years (P = 0.385). HRQoL improved to within the normative range in adults, whereas child self-reported and parent proxy-reported scores showed an initial increase but remained suboptimal at 3 years. Progressive neuropathy and newly developed retinopathy and attention-deficit/hyperactivity disorder were observed during treatment. CONCLUSION: Triheptanoin significantly reduced hospitalization burden in Korean patients with LC-FAOD and was well-tolerated, with potential benefits in physical function. TRIAL REGISTRATION: Clinical Research Information Service (CRIS), Republic of Korea, KCT0006756, 15 November 2021.
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