A phase 1B multiple ascending dose study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of a medium chain triglyceride supplement in Alzheimer’s disease

Abstract

AbstractBackgroundImpaired brain glucose metabolism is a prominent and early feature across neurodegenerative disorders, including Alzheimer’s disease (AD). Elevating brain ketones to bypass this metabolic failure is an emerging therapeutic strategy, with promising results in AD and Mild Cognitive Impairment (MCI). The Medium Chain Triglyceride Intervention in AD (MINT‐AD) is a randomized, placebo‐controlled Phase 1b trial investigating the pharmacokinetics and pharmacodynamics of a ketogenic supplement in Alzheimer’s disease (AD). It also explores outcome measures to support the development of larger ketogenic trials for this disorder.MethodPatients (n=32) with a clinical diagnosis of with mild‐moderate AD (MMSE 16‐26) were randomized at 4:1 to twice daily medium chain triglyceride drink (MCT – 60% C8, 40% C10) prepared as a 12% emulsion in lactose‐free milk, or placebo. A total of four dose groups were recruited, with doses ranging from 5 grams twice daily up to 25 grams twice daily, for a total of 18 days (including 8‐day drug titration). Primary outcome measures were safety, tolerability and pharmacodynamics effects of MCT supplementation on plasma ketones, and the pharmacokinetics of the MCT supplement. Exploratory outcome measures included N‐acetyl aspartate and glutamine/glutamate MR spectroscopy, functional resting brain connectivity, brain blood flow (arterial spin labeling), continuous actigraphy, ambulatory sleep EEG, and cognitive measures.ResultA total of 30 participants (94%) completed the study, with 2 subjects discontinuing early. MCT supplement up to 25 grams twice daily was safe and well tolerated in patients with mild‐moderate AD. Peak plasma ketones was seen around 4 hours post MCT ingestion. Exploratory cognitive and imaging measures are currently being analyzed and will be presented.ConclusionKetogenic MCT supplementation is safe and well tolerated in AD, with reasonably predictable pharmacokinetic and ketogenic properties. These data exploring a larger dose range should inform dose selection in future trials with MCT supplementation.