Dementia of the Alzheimer TypePhase 1/2DEPENDNCT02707458
Dosage and Efficacy of Probucol-induced apoE to Negate Cognitive Deterioration
A Phase 1/2 study testing Probucol in people with Dementia of the Alzheimer Type and Age-related Cognitive Decline, run by Douglas Mental Health University Institute at 1 site in Canada.
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. Read more about this study
- Who is it for?
- Ages 55 to 80 yearsHealthy volunteers can take part
- Conditions the study is for
- Dementia of the Alzheimer Type, Age-related Cognitive Decline, Mild Cognitive Impairment Due to Alzheimer Disease
- What is being tested?
- Probucol
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 23 participants
- Where
- 1 siteCanada
- Study dates
- Apr 2016to Mar 2017
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 55 to 80 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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
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- 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.
Who cannot join
- 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.)
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- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Dose-finding and Proof-of-concept Trial of Probucol to Increase Availability of CSF Apolipoprotein-E
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.
Read the 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
- Being tested
- Probucol
- Keywords
- apolipoprotein E, Alzheimer, pre-clinical, pre-symptomatic, dose-finding, prevention
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ProbucolDrug
Also called Lorelco (trade name in Japan)
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Probucol |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: One year on individualized dosing, as suggested by experimental observations above
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Mar 2016 (estimated)
- Study startApr 2016
- Primary completionMar 2017
- Study completionMar 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Dementia of the Alzheimer TypeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 23 participants (actual)
Sponsor and investigators
- Lead sponsor
- Douglas Mental Health University Institute
- Sponsor type
- University, hospital or other
- Collaborators
- Weston Brain Institute, McGill University
- Responsible party
- Principal investigator, John C. S. Breitner, Douglas Mental Health University Institute
- Investigators
- John C Breitner, MD, MPH, Principal investigator, Douglas Hospital Research Centre & McGill University Faculty of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02707458
- Sponsor's protocol ID
- DEPEND
- Acronym
- DEPEND
- Status last verified
- Jan 2018
- First submitted
- 23 Feb 2016
- Last updated
- 31 Jan 2018
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: Will share de-identified data upon completion and publication of trial
Study at a glance
From the registry record, last updated by the sponsor on 31 Jan 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Dose-finding and Proof-of-concept Trial of Probucol to Increase Availability of CSF Apolipoprotein-E
- ClinicalTrials.gov ID
- NCT02707458
- Acronym / sponsor ID
- DEPEND / DEPEND
- 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
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 23 participants (actual)
- Lead sponsor
- Douglas Mental Health University InstituteUniversity, hospital or other
- Collaborators
- Weston Brain Institute, McGill University
- Study start
- Apr 2016
- Primary completion
- Mar 2017 (actual)
- Study completion
- Mar 2017 (actual)
- First posted
- 14 Mar 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Single arm | Experimental | Drug: ProbucolAll 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. |
Who may qualify
- Ages
- 55 to 80 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- 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
Key exclusion criteria (13 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ProbucolAlso: Lorelco (trade name in Japan)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. | Drug | Single arm |
Primary outcome
Plasma concentration of probucol following test dose
Time frame: three months
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.
Apolipoprotein concentration in CSF before and after treatment with probucol at individualized dose
Time frame: One year on individualized dosing, as suggested by experimental observations above
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.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Jan 2018.
- Individual participant dataSharing planned: Yes. Will share de-identified data upon completion and publication of trial
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
John C Breitner, MD, MPH principal investigator
Douglas Hospital Research Centre & McGill University Faculty of Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Probucol in people with Dementia of the Alzheimer Type and Age-related Cognitive Decline, run by Douglas Mental Health University Institute at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 31 Jan 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Plasma concentration of probucol following test dose (time frame: three months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Jan 2018.