Efficacy of Probucol on cognitive function in Alzheimer’s disease: Study protocol for a double-blind, placebo-controlled, randomised phase II trial (PIA Study)

IntroductionPreclinical, clinical and epidemiological studies support the hypothesis that aberrant systemic metabolism of amyloid-beta (A{beta}) in the peripheral circulation is causally related to the development of Alzheimers disease (AD). Specifically, recent studies suggest that increased plasma concentrations of lipoprotein-A{beta} compromises the brain microvasculature, resulting in extravasation and retention of the lipoprotein-A{beta} 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-A{beta} 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 Alzheimers 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, 6th October 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 SUMMARYO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIThis 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 Alzheimers disease (AD). C_LIO_LIThe 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. C_LIO_LIProbucol 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. C_LI