Mild Cognitive ImpairmentPhase 2MCINCT00620191
Metformin in Amnestic Mild Cognitive Impairment
A Phase 2 study testing Metformin in people with Mild Cognitive Impairment, run by Columbia University at 1 site in United States.
Trial summary
Hyperinsulinemia and type 2 diabetes (T2D) are important potential risk factors for cognitive decline and Alzheimer's disease (AD). Two thirds of the US adult population are at risk for hyperinsulinemia and T2D, and half of the population 85 years and older have AD. Read more about this study
- Who is it for?
- Ages 55 to 90 years
- Conditions the study is for
- Mild Cognitive Impairment
- What is being tested?
- Metformin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 80 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Jun 2008to Feb 2012
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 90 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age range: 55 years to 90 years. The main rationale for this inclusion criteria is to follow the standard set by the Alzheimer's Disease Cooperative Study (ADCS).
- Memory complaint expressed by the participant and recognized by the informant. The memory complaint must represent a change from previous functioning based on information provided by both subject and informant.
- Fluent in English or Spanish.
- Mini-Mental State Examination (MMSE) equal or more than 20.
- Subjects must fulfill criteria for amnestic mild cognitive impairment (MCI). Guidelines for the diagnosis of MCI: Subjects must score below a predetermined cut-off score on the logical memory II delayed paragraph recall sub-test of the Wechsler Memory Scale Revised (WMS-R) or the selective reminding test (SRT).
- Global Clinical Dementia Rating (CDR) score must be 0.5 at screening.
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- Subjects without a known history of diabetes or diabetes that has never been treated with medications. If diabetes is diagnosed during screening or they have a history of diabetes not treated in the last 12 months they will be excluded if their Hemoglobin A1c (HbA1c) is > 6.5. In addition, a diagnosis of diabetes can be made if the HbA1c is 6.5% or more.
- Overweight or obese by National Heart, Lung, and Blood Institute (NHLBI) criteria (Body Mass Index (BMI) of more or equal of 25 kg/ m2).
- No contraindications to metformin treatment.
- Hachinski score less or equal to 4.
- Hamilton score less or equal to 12 on the 17 item scale.
- General cognition and functional performance such that a diagnosis of dementia cannot be made at the time of screening based on DSM-IV criteria.
- Vision and hearing must be sufficient for compliance with testing procedures.
Who cannot join
- Individuals with dementia
- MMSE < 20
- Subjects with neurologic diseases associated to neurologic deficits.
- Subjects with current psychiatric diagnoses such as depression, bipolar disorder or schizophrenia.
- Subjects with uncontrolled hypertension (systolic blood pressure more than 160 mmHg or diastolic blood pressure more than 95 mmHg.
- Subjects with a history of active cancer or cancer within last five years, with the exception of squamous or basal cell carcinoma of the skin.
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- Subjects who for any reason may not complete the study as judged by the study physician.
- Subjects with a known history of diabetes treated with medications.
- Subjects with a new or old diagnosis of diabetes, never treated, with a HbA1c of more than 6.5 .
- Contraindications to metformin: Contraindications to metformin use include a creatinine of > 1.5, liver disease by history or by elevated transaminases, congestive heart failure, and alcohol abuse.
- Use of cholinesterase inhibitors.
- Presence of diabetes, even if the HbA1c is less or equal to 6.5.
- Inability to lie down for any reason.
- Presence of any metallic implant.
- Claustrophobia.
- Any contraindication to magnetic resonance imaging (MRI) or fluorodeoxyglucose (FDG) positron emission tomography (PET).
Trial locations and contacts
1 site in 1 country.
United States1 site
Columbia University Medical Center
New York, New York, 10032
About this study
Official title: Metformin in the Prevention of Alzheimer's Disease
Hyperinsulinemia and type 2 diabetes (T2D) are important potential risk factors for cognitive decline and Alzheimer's disease (AD). Two thirds of the US adult population are at risk for hyperinsulinemia and T2D, and half of the population 85 years and older have AD. Peripheral hyperinsulinemia can impair the clearance of amyloid beta in the brain, the main culprit in AD. Thus, the investigators hypothesize that lowering peripheral insulin in overweight persons with amnestic mild cognitive impairment (AMCI), a transition state between normal cognition and AD, can decrease the risk of cognitive decline and progression to AD. The investigators propose to conduct a phase II double blinded placebo controlled randomized clinical trial of metformin, a safe and effective medication that prevents hyperinsulinemia and diabetes, to test this hypothesis among 80 overweight persons aged 55 to 90 years with AMCI. The main outcome of the study will be changes in performance in a memory test (total recall of the Selective Reminding Test) and the Score a test of general cognitive function used in clinical trials (the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog)). Another aim is to compare brain function in an area affected by Alzheimer's disease between the metformin and placebo group mean changes from beginning to end among 40 participants using a PET scan.
Read the detailed description
The prevalence of Alzheimer's disease (AD) is expected to quadruple by the year 2047. There are no known curative or preventive measures for AD. Current treatment options for AD only address symptoms, and no treatments are available that focus on delaying the actual disease process. One of the currently accepted hypothesis of the pathogenesis of AD is that the main culprit is the accumulation of Aβ in the brain, and this process has become a target for treatments and preventive measures. Amnestic mild cognitive impairment (MCI) has been used to describe a transitional state between normal cognitive function and AD, and has thus been targeted for interventions. Persons with MCI progress to AD at the rate of nearly 10% to 15% per year. The criteria most commonly used for the definition of AD dementia from MCI. The investigators propose to use these criteria with slight modification to recruit persons for a pilot trail of AD prevention in persons with amnestic MCI.
Peripheral hyperinsulinemia (high insulin levels) potentially impair Aβ clearance, and in this study we are proposing to use metformin, an insulin lowering agent, to prevent AD by improving Aβ clearance in the brain. The insulin resistance syndrome and hyperinsulinemia are common in individuals with and without diabetes, and are related to increased risk of cardiovascular and cerebrovascular outcomes. Hyperinsulinemia predicts the development of diabetes; therefore, diabetes can be considered a consequence and a marker of past hyperinsulinemia. According to NHANES III data, more than 40% of the population over the age of 60 years has problems of glucose intolerance or diabetes, all related to insulin resistance and hyperinsulinemia. The investigators have found that the risk of AD in individuals without diabetes increases with increasing levels of fasting insulin, and that high insulin levels are related to a faster decline in memory scores. The high prevalence of hyperinsulinemia and diabetes (49% of the elderly in Northern Manhattan) and its biological plausibility as a risk factor for cognitive decline and AD has attracted increasing attention. In this application we are targeting hyperinsulinemia, the most important risk factor for AD identified in the elderly population of Northern Manhattan. The risk of AD attributable to hyperinsulinemia or diabetes in Northern Manhattan was 39%, and is higher in Hispanics and African-Americans, who have a higher prevalence of diabetes and insulin resistance, and will comprise the majority of our sample.
- Conditions
- Mild Cognitive Impairment
- Being tested
- Metformin, Placebo
- Keywords
- Metformin, Mild Cognitive Impairment (MCI), Alzheimer's Disease (AD), Overweight, Insulin
- Medical subject headings
- Cognitive Dysfunction, Alzheimer Disease, Overweight, Insulin Resistance
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MetforminDrug
Also called Glucophage
Metformin 1000 mg twice a day titrated from 500 mg once a day
PlaceboDrug
Placebo identical to metformin 2 tablets twice a day titrated from one table once a day
| Study group | Role | What they receive |
|---|---|---|
| Matching Placebo | Placebo comparator | Placebo identical to metformin Receives: Drug: Placebo |
| Metformin | Experimental | Metformin 1000 mg twice a day Receives: Drug: Metformin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Total Recall Score in the Selective Reminding Test
The Selective Reminding Test measures verbal learning and delayed recall through a multiple-trial list-learning paradigm. Patients are presented aurally with a list of 12 words for trial 1 and are asked to recall as many as possible. For trials 2-6, there is a selective presentation of only those words not recalled on the previous trial. Trial 7 is similar to the other trials but is assessed after an 11-minute delay. The score for the selective reminding test is the unweighted average of seven individual study results (min=0 and max=84) Higher scores indicate a better cognitive performance. The total recall score from the first visit was subtracted from that of the last visit to calculate the change in score (total words recalled).
Measured: 12 months
Change in Score of the Alzheimer's Disease Assessment Scale-cognitive Subscale (ADAS-cog)
The ADAS-cog is an aggregate for several cognitive tests intended to provide a global cognitive score and consists of 11 tasks. The tasks (and corresponding score range)) are Word Recall (0-10), Naming (0-4), Commands (0-5), Constructional Praxis (0-5) Ideational Praxis (0-5), Orientation (0-8), Word Recognition (0-12), Language (0-5), Word Finding Difficulty (0-5), and Remembering Test Instructions (1-5). The range of aggregate scores (sum of scores) is 1 to 69, with higher scores meaning worse cognitive performance. The change was calculated subtracting the baseline score from the final visit score.
Measured: 12 months
Secondary outcomes (1)
Change in Relative Glucose Uptake (rCMRg) in the Posterior Cingulate-precuneus.
Change in relative glucose uptake (rCMRgl) in the posterior cingulate-precuneus measured with subscale (ADAS-Cog) from brain [18]F-labeled 2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET). The unit for rCMRgl is %. The results presented are absolute differences in rCMRgl, presented in % units; the change was calculated subtracting the baseline rCMRgl from the follow-up rCMRgl
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Feb 2008 (estimated)
- Study start1 Jun 2008
- Primary completionFeb 2012
- Study completionFeb 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Mild Cognitive ImpairmentStudies of the same condition, open and under way.
- More trials run by Columbia UniversityThe sponsor's other registered studies.
- 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 2
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 80 participants (actual)
Sponsor and investigators
- Lead sponsor
- Columbia University
- Sponsor type
- University, hospital or other
- Collaborators
- Institute for the Study of Aging (ISOA), National Institute on Aging (NIA)
- Responsible party
- Principal investigator, José A. Luchsinger, Columbia University
- Investigators
- Jose A Luchsinger, MD, Principal investigator, Columbia University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00620191
- Sponsor's protocol ID
- AAAC7231
- Other IDs
- R01AG026413, 270901
- Acronym
- MCI
- Status last verified
- Sep 2020
- First submitted
- 7 Feb 2008
- Last updated
- 23 Oct 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Luchsinger JA, Perez T, Chang H, Mehta P, Steffener J, Pradabhan G, Ichise M, Manly J, Devanand DP, Bagiella E. Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial. J Alzheimers Dis. 2016;51(2):501-14. doi: 10.3233/JAD-150493.
PubMed 26890736
Study at a glance
From the registry record, last updated by the sponsor on 23 Oct 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Metformin in the Prevention of Alzheimer's Disease
- ClinicalTrials.gov ID
- NCT00620191
- Acronym / sponsor ID
- MCI / AAAC7231
- Conditions
- Mild Cognitive Impairment
- Keywords
- Metformin, Mild Cognitive Impairment (MCI), Alzheimer's Disease (AD), Overweight, Insulin
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 80 participants (actual)
- Lead sponsor
- Columbia UniversityUniversity, hospital or other
- Collaborators
- Institute for the Study of Aging (ISOA), National Institute on Aging (NIA)
- Study start
- 1 Jun 2008 (actual)
- Primary completion
- Feb 2012 (actual)
- Study completion
- Feb 2012 (actual)
- First posted
- 21 Feb 2008 (estimated)
- Results
- Posted 23 Oct 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Hyperinsulinemia and type 2 diabetes (T2D) are important potential risk factors for cognitive decline and Alzheimer's disease (AD). Two thirds of the US adult population are at risk for hyperinsulinemia and T2D, and half of the population 85 years and older have AD. Peripheral hyperinsulinemia can impair the clearance of amyloid beta in the brain, the main culprit in AD. Thus, the investigators hypothesize that lowering peripheral insulin in overweight persons with amnestic mild cognitive impairment (AMCI), a transition state between normal cognition and AD, can decrease the risk of cognitive decline and progression to AD. The investigators propose to conduct a phase II double blinded placebo controlled randomized clinical trial of metformin, a safe and effective medication that prevents hyperinsulinemia and diabetes, to test this hypothesis among 80 overweight persons aged 55 to 90 years with AMCI. The main outcome of the study will be changes in performance in a memory test (total recall of the Selective Reminding Test) and the Score a test of general cognitive function used in clinical trials (the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog)). Another aim is to compare brain function in an area affected by Alzheimer's disease between the metformin and placebo group mean changes from beginning to end among 40 participants using a PET scan.
Detailed description
The prevalence of Alzheimer's disease (AD) is expected to quadruple by the year 2047. There are no known curative or preventive measures for AD. Current treatment options for AD only address symptoms, and no treatments are available that focus on delaying the actual disease process. One of the currently accepted hypothesis of the pathogenesis of AD is that the main culprit is the accumulation of Aβ in the brain, and this process has become a target for treatments and preventive measures. Amnestic mild cognitive impairment (MCI) has been used to describe a transitional state between normal cognitive function and AD, and has thus been targeted for interventions. Persons with MCI progress to AD at the rate of nearly 10% to 15% per year. The criteria most commonly used for the definition of AD dementia from MCI. The investigators propose to use these criteria with slight modification to recruit persons for a pilot trail of AD prevention in persons with amnestic MCI.
Peripheral hyperinsulinemia (high insulin levels) potentially impair Aβ clearance, and in this study we are proposing to use metformin, an insulin lowering agent, to prevent AD by improving Aβ clearance in the brain. The insulin resistance syndrome and hyperinsulinemia are common in individuals with and without diabetes, and are related to increased risk of cardiovascular and cerebrovascular outcomes. Hyperinsulinemia predicts the development of diabetes; therefore, diabetes can be considered a consequence and a marker of past hyperinsulinemia. According to NHANES III data, more than 40% of the population over the age of 60 years has problems of glucose intolerance or diabetes, all related to insulin resistance and hyperinsulinemia. The investigators have found that the risk of AD in individuals without diabetes increases with increasing levels of fasting insulin, and that high insulin levels are related to a faster decline in memory scores. The high prevalence of hyperinsulinemia and diabetes (49% of the elderly in Northern Manhattan) and its biological plausibility as a risk factor for cognitive decline and AD has attracted increasing attention. In this application we are targeting hyperinsulinemia, the most important risk factor for AD identified in the elderly population of Northern Manhattan. The risk of AD attributable to hyperinsulinemia or diabetes in Northern Manhattan was 39%, and is higher in Hispanics and African-Americans, who have a higher prevalence of diabetes and insulin resistance, and will comprise the majority of our sample.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Matching Placebo | Placebo comparator | Drug: PlaceboPlacebo identical to metformin |
| Metformin | Experimental | Drug: MetforminMetformin 1000 mg twice a day |
Who may qualify
- Ages
- 55 to 90 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- Age range: 55 years to 90 years. The main rationale for this inclusion criteria is to follow the standard set by the Alzheimer's Disease Cooperative Study (ADCS).
- Memory complaint expressed by the participant and recognized by the informant. The memory complaint must represent a change from previous functioning based on information provided by both subject and informant.
- Fluent in English or Spanish.
- Mini-Mental State Examination (MMSE) equal or more than 20.
- Subjects must fulfill criteria for amnestic mild cognitive impairment (MCI). Guidelines for the diagnosis of MCI: Subjects must score below a predetermined cut-off score on the logical memory II delayed paragraph recall sub-test of the Wechsler Memory Scale Revised (WMS-R) or the selective reminding test (SRT).
Key exclusion criteria (16 listed)
- Individuals with dementia
- MMSE < 20
- Subjects with neurologic diseases associated to neurologic deficits.
- Subjects with current psychiatric diagnoses such as depression, bipolar disorder or schizophrenia.
- Subjects with uncontrolled hypertension (systolic blood pressure more than 160 mmHg or diastolic blood pressure more than 95 mmHg.
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 |
|---|---|---|
| MetforminAlso: GlucophageMetformin 1000 mg twice a day titrated from 500 mg once a day | Drug | Metformin |
| PlaceboPlacebo identical to metformin 2 tablets twice a day titrated from one table once a day | Drug | Matching Placebo |
Primary outcome
Change in Total Recall Score in the Selective Reminding Test
Time frame: 12 months
The Selective Reminding Test measures verbal learning and delayed recall through a multiple-trial list-learning paradigm. Patients are presented aurally with a list of 12 words for trial 1 and are asked to recall as many as possible. For trials 2-6, there is a selective presentation of only those words not recalled on the previous trial. Trial 7 is similar to the other trials but is assessed after an 11-minute delay. The score for the selective reminding test is the unweighted average of seven individual study results (min=0 and max=84) Higher scores indicate a better cognitive performance. The total recall score from the first visit was subtracted from that of the last visit to calculate the change in score (total words recalled).
Change in Score of the Alzheimer's Disease Assessment Scale-cognitive Subscale (ADAS-cog)
Time frame: 12 months
The ADAS-cog is an aggregate for several cognitive tests intended to provide a global cognitive score and consists of 11 tasks. The tasks (and corresponding score range)) are Word Recall (0-10), Naming (0-4), Commands (0-5), Constructional Praxis (0-5) Ideational Praxis (0-5), Orientation (0-8), Word Recognition (0-12), Language (0-5), Word Finding Difficulty (0-5), and Remembering Test Instructions (1-5). The range of aggregate scores (sum of scores) is 1 to 69, with higher scores meaning worse cognitive performance. The change was calculated subtracting the baseline score from the final visit score.
1 secondary outcome
Change in Relative Glucose Uptake (rCMRg) in the Posterior Cingulate-precuneus.
Time frame: 12 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Oct 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 26890736Luchsinger JA, Perez T, Chang H, Mehta P, Steffener J, Pradabhan G, Ichise M, Manly J, Devanand DP, Bagiella E. Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial. J Alzheimers Dis. 2016;51(2):501-14. doi: 10.3233/JAD-150493.
- Individual participant dataSharing planned: No
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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.
Jose A Luchsinger, MD principal investigator
Columbia University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Metformin in people with Mild Cognitive Impairment, run by Columbia University at 1 site in United States.
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 13 inclusion and 16 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 23 Oct 2020. 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 United States. 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. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
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?
Yes. Results are posted in the registry (first posted 23 Oct 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Change in Total Recall Score in the Selective Reminding Test (time frame: 12 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?
On the ClinicalTrials.gov record for NCT00620191, which also lists 1 linked publication.
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 23 Oct 2020.