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

Age-related Cognitive Decline Clinical Trial

— DEPEND  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02707458
• Other study ID #: DEPEND
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: February 23, 2016
• Last updated: January 30, 2018
• Start date: April 2016
• Est. completion date: March 2017

Study information

• Verified date: January 2018
• Source: Douglas Mental Health University Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 23
• Est. completion date: March 2017
• Est. primary completion date: March 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 55 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

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

Intervention

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.

Locations

Country	Name	City	State
Canada	Douglas Hospital Research Centre	Montreal	Quebec

Sponsors (3)

Lead Sponsor	Collaborator
Douglas Mental Health University Institute	McGill University, Weston Brain Institute

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Plasma concentration of probucol following test dose	Participants are given a test dose of probucol 600 mg q.d. Plasma concentration of probucol and cerebrospinal fluid (CSF) concentrations of probucol and apolipoprotein E (apoE) are measured at baseline and after 3 months. Results should suggest a range of plasma concentrations associated with an increase in CSF apoE by at least 50%. Relying on dose-proportionality of plasma concentration achieved, an estimated optimum individual dose for target levels of apolipoprotein E induction is then calculated.	three months
Primary	Apolipoprotein concentration in CSF before and after treatment with probucol at individualized dose	After a washout period => 2 months, participants will initiate treatment with probucol at individualized dosage determined in Outcome 1. Results after 1 year will establish whether such individualized dosage of probucol achieves 'target engagement' of specified increase in CSF apoE, to be tested subsequently for its ability to prevent progression of pre-symptomatic Alzheimer disease.	One year on individualized dosing, as suggested by experimental observations above

External Links

•   main website describing activities of Centre for Studies on Prevention of Alzheimer's Disease at the Douglas Hospital Research Centre