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

NCT02707458 | Completed Phase 1 DMC

• 1 other identifier: DEPEND
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (2)

• 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

• 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

Study Arms (1)

Single arm

EXPERIMENTAL

All subjects will receive probucol, starting with a fixed dose of 600 mg daily following the evening meal. The variable plasma concentrations achieved and the resulting modification in concentration of CSF apoE will suggest an ideal range of plasma concentrations for use of the drug as an inducer of increased availability of apoE in the CSF. The known dose-proportionality of the drug in plasma will then be used to estimate an ideal individualized dose for each participant. The effects of such individualized dosage will be tested over 1 year of follow-up observations, searching for treatment effects on CSF apoE and for evidence of other treatment effects, particularly including adverse effects.

Drug: Probucol

Interventions

Probucol DRUG

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.

Also known as: Lorelco (trade name in Japan)

Single arm

Eligibility Criteria

• Age: 55 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Douglas Mental Health University Institute: lead
• Weston Brain Institute: collaborator
• McGill University: collaborator

Study Sites (1)

Douglas Hospital Research Centre

Montreal, Quebec, H4H1R3, Canada

Location

MeSH Terms

Interventions

Probucol

Intervention Hierarchy (Ancestors)

Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• John C Breitner, MD, MPH

  Douglas Hospital Research Centre & McGill University Faculty of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Centre for Studies on Prevention of Alzheimer's Disease (StoP-AD)

Study Record Dates

• First Submitted: February 23, 2016
• First Posted: March 14, 2016
• Study Start: April 1, 2016
• Primary Completion: March 1, 2017
• Study Completion: March 1, 2017
• Last Updated: January 31, 2018

Record last verified: 2018-01

Data Sharing

• IPD Sharing: Will share

Locations

CA (1)