Clinical trial NCT02707458: Dosage and Efficacy of Probucol-induced apoE to Negate Cognitive Deterioration
Official title: Dose-finding and Proof-of-concept Trial of Probucol to Increase Availability of CSF Apolipoprotein-E
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Dementia of the Alzheimer Type
Age-related Cognitive Decline
Mild Cognitive Impairment Due to Alzheimer Disease
Keywords: apolipoprotein E
Alzheimer
pre-clinical
pre-symptomatic
dose-finding
prevention
Lead sponsor: Douglas Mental Health University Institute
Sponsor class: OTHER
Collaborators: name: Weston Brain Institute
name: McGill University
First posted: 2016-03-14
Enrollment: 23
Sex: ALL
Minimum age (years): 55
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief 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.

Eligibility criteria: Inclusion Criteria:

* Family history of one or more parents or multiple siblings who developed Alzheimer-like dementia, as established by review of history and/or medical records, and by responses to a brief questionnaire describing characteristics of the relatives' condition
* Aged 60+. May be aged 55-59 only if at least one parent or sibling experienced onset of Alzheimer's dementia at an age no more than 15 years beyond the prospective participant's current age
* At least six years of formal education
* Sufficient fluency in spoken and written English and/or French to participate in study visits and in psychometric testing
* A collateral respondent available to provide information on the cognitive and health status of the participant, and to assist with monitoring of study interventions, if needed
* Willingness to undergo four lumbar punctures for collection of CSF
* Affirmation of prior informed consent to undergo genetic testing for APOE and other known or suspected AD risk factors
* Ability and intention to participate in study visits per protocol, in the opinion of a study physician
* Willingness to limit use of over-the-counter or prescription medicines (e.g., tricyclic antidepressants, anti-histamines) known to prolong QTc interval, or to potentiate the tendency of probucol to prolong this interval, in the opinion of a study physician
* If on a statin or other lipid lowering drug that, in the opinion of a study physician, can safely be co-administered with probucol, willingness to remain on a stable dose of this medication during the entire trial period.
* Provision of informed consent for this trial.

Exclusion Criteria:

* Known or identified cognitive disorder diagnosed previously by a physician, psychologist, nurse-clinician, or other health care provider, or by StoP-AD staff
* Past or present use of a commercially available acetyl-cholinesterase inhibitor including tacrine, donepezil, rivastigmine, or galantamine
* Past or present use of memantine or other approved cognitive enhancement prescription agent
* History of heart disease, myocardial infarction or documented acute coronary syndrome, or arrhythmia (including atrial fibrillation)
* Corrected QT interval using Bazett's formula (QTcB) interval \> 450 msec for males or 470 msec for females as detected by EKG and confirmed by consultant cardiologist
* Clinically significant hypertension, anemia, liver disease, or kidney disease, in opinion of a study physician (participants with treated hypertension who are normotensive as a result of intervention may be enrolled.)
* Concurrent use of over-the-counter or prescription medicines (e.g., tricyclic antidepressants, anti-histamines) known to prolong QTc interval, or to potentiate the tendency of probucol to prolong this interval, in the opinion of a study physician
* Any inflammatory or chronic pain condition that necessitates regular use of opiates (e.g., oxycodone, hydrocodone, tramadol, meperidine, hydromorphone), or NSAIDs (more than 4 doses / week)
* Current plasma creatinine \> 132 mmol/l (1.5 mg/dl)
* Current alcohol, barbiturate or benzodiazepine abuse or dependence (in opinion of study physician)
* Any other medical condition that, in the opinion of a study physician, makes it inadvisable for the participant to be assigned to regular dosage of probucol
* Enrolment in any trial or experimental protocol that, in the opinion of a study physician, is likely to interfere with PREVENT-AD or any of its derivative protocols including this one
* Any other condition that, in the opinion of a study physician, makes it medically inappropriate for the participant to enroll in the program

Primary outcomes:
measure: Plasma concentration of probucol following test dose
timeFrame: three months
measure: Apolipoprotein concentration in CSF before and after treatment with probucol at individualized dose
timeFrame: One year on individualized dosing, as suggested by experimental observations above
Secondary outcomes:
Other outcomes:
Locations:
city: Montreal
country: Canada
facility: Douglas Hospital Research Centre
state: Quebec
Study officials:
affiliation: Douglas Hospital Research Centre & McGill University Faculty of Medicine
name: John C Breitner, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References: