Efficacy of Probucol on cognitive function in Alzheimer’s disease: Study protocol for a double-blind, placebo-controlled, randomised phase II trial (PIA Study)
Authors: Lam Virginie , Clarnette Roger , Francis Roslyn , Bynevelt Michael , Watts Gerald F , Flicker Leon , Orr Carolyn , Loh Poh , Lautenschlager Nicola T , Reid Christopher M , Foster Jonathan K , Dhaliwal Satvinder , Robinson Suzanne , Corti Emily , Vaccarezza Mauro , Horgan Ben , Takechi Ryusuke , Mamo John C.L 
Published: November 2021

AbstractIntroductionPreclinical, clinical and epidemiological studies support the hypothesis that aberrant systemic metabolism of amyloid-beta (Aβ) in the peripheral circulation is causally related to the development of Alzheimer’s disease (AD). Specifically, recent studies suggest that increased plasma concentrations of lipoprotein-Aβ compromises the brain microvasculature, resulting in extravasation and retention of the lipoprotein-Aβ moiety. The latter results in an inflammatory response and neurodegeneration ensues.Probucol, a historic cholesterol-lowering drug, has been shown in murine models to suppress lipoprotein-Aβ secretion, concomitant with maintaining blood-brain-barrier function and suppressing neurovascular inflammation. Probucol has also been shown to protect cognitive function in dietary-induced amyloidogenic mice.This protocol details the Probucol in Alzheimer’s Study (PIA-study), a double-blind, randomised, placebo-controlled drug intervention trial investigating if Probucol attenuates cognitive decline in patients with mild-to-moderate AD.ObjectivesThe primary objective of the 104-week study is to assess whether Probucol supports cognitive function and delays brain atrophy in AD patients. A secondary objective is to determine whether Probucol treatment will reduce cerebral amyloid burden.Methods & AnalysisThe study is a phase II single-site, randomised, placebo-controlled, double-blind clinical trial assessing the efficacy of Probucol in AD. A total of 300 participants with mild-to-moderate AD will be recruited and randomised 1:1 (active: placebo). Cognitive function, regional volumetric changes in brain and cerebral amyloid load will be evaluated via the cognitive subscale test, AD assessment scales (ADAS-Cog), magnetic resonance imaging (MRI) and positron emission tomography (PET) scans, respectively, after a 104-week intervention.Ethics & DisseminationThe study has been approved by the Bellberry Limited Human Research Ethics Committee (Approval number: HREC2019-11-1063; Version 4, 6thOctober 2021). The investigator group will disseminate study findings through peer-reviewed publications, key conferences and local stakeholder events.Trial registrationThis trial has been registered with the Australian New Zealand Clinical Trial Registry (ACTRN12621000726853).ARTICLE SUMMARYStrengths and limitations of this studyThis is the first-in-human (FIH) randomised double-blind placebo-controlled study to assess the efficacy of Probucol in delaying cognitive decline in individuals with mild cognitive impairment (MCI) and mild-to-moderate dementia due to Alzheimer’s disease (AD).The 24-month intervention study will be the first to investigate whether treatment with Probucol will stabilise structural/functional changes in brain and if cerebral amyloid load will decrease in individuals with AD, following treatment with Probucol.Probucol is clinically used to treat cardiovascular disease with well-characterised efficacy and safety profiles, thus reducing risk of the study, and if applicable, accelerate clinical translation of the study findings.