NCT02707458

Dosage and Efficacy of Probucol-induced apoE to Negate Cognitive Deterioration

Dose-finding and Proof-of-concept Trial of Probucol to Increase Availability of CSF Apolipoprotein-E

• Status: Completed
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 23 (actual)
• Sponsor: Douglas Mental Health University Institute · Academic / Other
• Sex: All
• Age: 55 Years – 80 Years
• Healthy volunteers: Accepted

Summary

DEPEND is an open-label but dosage-masked trial of the retired cholesterol-lowering drug probucol as an agent to increase availability of apolipoprotein E (apoE) in the cerebrospinal fluid (CSF) of cognitively intact older persons at risk of Alzheimer's dementia. Absorption of oral probucol is variable. In a sample of 23 cognitively intact persons over age 55, DEPEND will therefore develop an algorithm to prescribe individualized dosing to achieve plasma concentration that will likely increase availability of CSF apoE. These persons will then use their individualized dosage for 12 months to assess longer-term effects of the drug on CSF apoE concentration, while monitoring closely for evidence of adverse consequences of use.

Detailed description

Probucol is a cholesterol-lowering drug that has been removed from the market in Canada and the US, but remains in clinical use in Asia. In rodents, probucol increases synthesis and availability of apolipoprotein E (apoE) in the cerebrospinal fluid (CSF). ApoE is the protein product of the polymorphic gene APOE, allelic variation in which remains the strongest known risk factor (other than age itself) for Alzheimer's dementia. Oral Probucol is absorbed variably. Administration of a single, fixed dose therefore results in a wide range of plasma concentrations when the drug is given to various individuals in a fixed dosage. Limited human data suggest that higher plasma and CSF concentrations of probucol result in stronger increases in CSF apoE concentration. The dual aims of DEPEND are therefore 1) to develop an individualized dosing regimen that will result in plasma concentrations that are likely to increase CSF apoE concentration by 50%; and 2) to treat 20 persons at elevated risk of Alzheimer's dementia, each at his/her ideal individual dosage, for 12 months, observing the resulting change in CSF concentrations of apoE. Simultaneously, subjects will be observed carefully for evidence of any treatment effects on cognition or other probable markers of progression in pre-clinical Alzheimer's disease, as well as safety risks that might deter further human experimentation with the drug.

Conditions

• Dementia of the Alzheimer Type
• Age-related Cognitive Decline
• Mild Cognitive Impairment Due to Alzheimer Disease

Interventions

Type	Name	Description
DRUG	Probucol	Probucol was used with good effect for more than a decade in Canada and the US to reduce plasma cholesterol. Although withdrawn from the Canadian and US markets by its manufacturer for commercial reasons, it is still widely used for this purpose in Japan and Korea. Over the past decade, long-term follow-up studies in Asian populations at high risk of cardiovascular events have shown that the drug reduces the incidence of these events in a manner not unlike "statin" drugs used widely in Canada and the US.

Timeline

• Start date: 2016-04-01
• Primary completion: 2017-03-01
• Completion: 2017-03-01
• First posted: 2016-03-14
• Last updated: 2018-01-31

Locations

1 site across 1 country: Canada