Metformin in Amnestic Mild Cognitive Impairment

Overview[ - collapse ][ - ]

Purpose 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, we hypothesize the 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. We 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.
ConditionAmnestic Mild Cognitive Impairment
InterventionDrug: metformin
Drug: placebo
PhasePhase 2
SponsorColumbia University
Responsible PartyColumbia University
ClinicalTrials.gov IdentifierNCT00620191
First ReceivedFebruary 7, 2008
Last UpdatedMarch 13, 2013
Last verifiedMarch 2013

Tracking Information[ + expand ][ + ]

First Received DateFebruary 7, 2008
Last Updated DateMarch 13, 2013
Start DateFebruary 2008
Estimated Primary Completion DateFebruary 2012
Current Primary Outcome Measures
  • Total Recall in the Selective Reminding Test [Time Frame: 12 MONTHS] [Designated as safety issue: No]
  • ADAS-cog [Time Frame: 12 months] [Designated as safety issue: No]Alzheimer's Disease Assessment Scale-cognitive subscale
Current Secondary Outcome MeasuresrCMRgl in the posterior cingulate-precuneus. [Time Frame: 12 months] [Designated as safety issue: No]Change in relative glucose uptake (rCMRgl) in the posterior cingulate-precuneus measured with subscale (ADAS-Cog). The secondary outcome was brain [18]F-labeled 2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET).

Descriptive Information[ + expand ][ + ]

Brief TitleMetformin in Amnestic Mild Cognitive Impairment
Official TitleMetformin in the Prevention of Alzheimer's Disease
Brief 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.
Peripheral hyperinsulinemia can impair the clearance of amyloid beta in the brain, the main
culprit in AD. Thus, we hypothesize the 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. We 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
1. SPECIFIC AIMS:

The goal of this study is to conduct a phase II placebo controlled randomized trial of
metformin lasting 12 months in the prevention of memory decline in 80 persons with
amnestic MCI in order to collect preliminary data on efficacy, safety, and feasibility.

- Our primary aim is to compare changes in total recall of the Selective Reminding
Test and changes in the modified Alzheimer's Disease Assessment Scale-Cognitive
Subscale (ADAS-COG) between metformin and placebo on an intent to treat basis..

- Our secondary aim is to compare relative glucose uptake (rCMRgl) in the posterior
cingulate-precuneus measured with brain [18]F-labeled 2-deoxy-2-fluoro-D-glucose
(FDG) positron emission tomography (PET).

- Our exploratory aim is to compare plasma amyloid beta (Aβ) 42 between metformin
and placebo.

2. BACKGROUND AND SIGNIFICANCE:

- Burden of Alzheimer's disease. 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. We propose to use these
criteria with slight modification to recruit persons for a pilot trail of AD
prevention in persons with amnestic MCI.

- Hyperinsulinemia, diabetes, and risk of AD. 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. We 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

- Choice of metformin as treatment agent:. The Diabetes prevention program (DPP) is
a trial of metformin vs. lifestyle intervention (diet and exercise) vs. Placebo in
the prevention of onset of diabetes in 3,234 individuals without diabetes at
baseline. It found that both metformin and lifestyle intervention were successful
in preventing diabetes vs. placebo in 3 years of follow-up and in reducing insulin
levels. Serious adverse events of metformin including hospitalizations and
hypoglycemia were similar to placebo. More recently, another agent that lowers
insulin levels, rosiglitazone, was tested in similar fashion for the prevention of
diabetes and found effective, and is now being tested in AD given its insulin
decreasing properties. However, rosiglitazone's safety profile is not as good as
metformin- it can cause, edema and heart failure(21), and is not widely using in
clinical practice in persons without diabetes, as metformin is.

3. METHODS. PARTICIPANTS: In general the participants are persons who meet criteria for
Amnestic Mild Cognitive Impairment, do not have treated diabetes, and are overweight or
obese (BMI >25 Kg/m2).

- Inclusion criteria:

*
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.


- Age range: 55 years to 90 years. The main rationale for this inclusion
criteria is to follow the standard set by the ADCS

- Sex distribution: men and women.
- Languages: fluent in English or Spanish.
-
MMSE equal or more than 20. The rationale for this cutoff is that the
population of Washington Heights is heterogeneous in educational and cultural
background. Persons with low educational attainment may have a score of 20
without having dementia.


- Subjects must fulfill criteria for amnestic mild cognitive impairment (MCI)
according to criteria developed for the population of Northern Manhattan by
one of the co-investigators in this study Jennifer Manly. The diagnosis of
mild cognitive impairment is reached by consensus between Drs. Luchsinger and
Dr. Manly based on information from the neuropsychological battery, the
presence of memory complaints, and the clinical dementia rating. This is the
standard procedure used in the Washington Heights Inwood Columbia Aging
Project (WHICAP) for the diagnosis of amnestic 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).
For the
logical memory II delayed paragraph recall the cutoffs are:

1. less than or equal to 8 for 16 or more years of education.

2. less than or equal to 4 for 8-15 years of education; 
c) less than or
equal to 2 for 0-7 years of education. For the SRT subjects must score
below a predetermined cut-off score. The cutoffs for the SRT are
calculated for each individual based on their age, gender, and education
level. For example, for a 75-year old African American woman with 6
years of education, an SRT total recall score of 25 yields a T-score of
42, which is in the normal range, while for an AA woman of the same age
with a master's degree (18 years of school), the T-score is 34 which is
in the impaired range. This woman would be classified as MCI if she met
the criteria for function.

- Global CDR score must be 0.5 at screening. The memory box score must be 0.5
or 1.0, with no more than two box scores other than memory rated as high as
1.0 and no box score rated greater than 1.0.
- *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 HbA1c is >
6.5. In addition, a diagnosis of diabetes can be made if the HbA1c is 6.5% or
more (American Diabetes Association, January 2010). The reason our study does
not include persons with diabetes is that some medications to treat diabetes
(sulfonylureas, insulin) INCREASE insulin levels. This would interfere with
our study, which is based on the premise that lowering insulin levels with
metformin will decrease the risk of memory impairment. The ADA recommends a
target of < 7 of HbA1c for diabetes treatment. Thus, persons with a HbA1c < 7
with a new diagnosis of diabetes do not require pharmacologic treatment. We
propose to include in our study persons with a new or previous diagnosis of
diabetes, never treated with any drug, who have a HbA1c of 6.9% or less. The
rationale for this cutoff is that we want to diminish the chances that
someone enrolled in the study with new diabetes or old diabetes without
pharmacologic treatment will require treatment during the 12 months of the
study. We will provide all participants with the results of their testing
including HbA1c. The participants and their physicians will have the
discretion to start diabetes treatment. If this happens we will record such
information and continue following the participants as randomized. These
participants (those diagnosed with diabetes started on treatment outside of
the study) would still be considered in Intent-to-treat analyses. All other
inclusion and exclusion criteria still apply to these participants including
body mass index.


- Overweight or obese by National Heart, Lung, and Blood Institute (NHLBI)
criteria (BMI of more or equal of 25 kg/ m2)(33). The main rationale for the
use of this criteria is that they predict insulin resistance in the general
population and we need to use criteria that are generalizable and standard
for a phase III trial. Measurement of insulin for the diagnosis of insulin
resistance is not standard in clinical practice, and there are no absolute
definitions of what constitutes insulin resistance. Using BMI criteria as a
surrogate of insulin resistance is an acceptable alternative used in research
and clinical practice. Glucose intolerance is not necessarily a proxy for
insulin resistance and may be a sign of insulin deficiency. Thus, we will not
use glucose intolerance as a criterion for entering the study.


- 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.

- Exclusion criteria:


- Individuals with dementia


- MMSE < 20
- At the time of telephone contact for screening, we may conduct
the Telephone Interview for Cognitive Status (TICS) if the potential
participant agrees. This procedure is currently followed in other Studies at
Columbia University to screen out persons who are unlikely to have any memory
impairment (we are recruiting persons with mild cognitive impairment). A
Score > 34 on the Telephone Interview for Cognitive Status (TICS) out of 41
is considered normal cognition. Persons with this score will not be invited
to participate.


- Subjects with neurologic diseases associated to neurologic deficits.


- Subjects with current psychiatric diagnoses such as depression, bipolar
disorder or schizophrenia.
- Normal individuals without cognitive
complaints.


- 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.


- 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
hemoglobin A1c 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. We will also exclude subjects
with a history of intolerance to metformin.
- Use of cholinesterase
inhibitors. The rationale for this exclusion is that the ADCS showed a
beneficial effect of donepezil at 12 months(16) which could confound our
study. We do not have survey data on the use of cholinesterase inhibitors,
but believe that their use is uncommon in persons with AMCI, particularly if
they are recruited from the community.

- Exclusion criteria for brain imaging study:


- Presence of diabetes, even if the HbA1c is less or equal to 6.5. The reason
for this is that FDG PET uptake will be affected by glucose levels.


- Inability to lie down for any reason.


- Presence of any metallic implant.


- Claustrophobia.


- Any contraindication to MRI or FDG PET as determined by the staff of the
hatch center (MRI) or Kreitchman center (PET). A safety screen form from the
MRI research center is attached.

SCREENING AND RECRUITMENT: We will advertise within the medical center, using free
newsletters in the Community of Washington heights, using paid print media, using free and
paid internet media, and using radio. If we are contacted for participation, we will screen
for exclusion criteria. If persons feel comfortable with cognitive testing over the phone,
we will administer the Telephone Interview for Cognitive Status (TICS). We will have access
to WebCis, the internet based clinical information system from Columbia University Medical
Center (CUMC), which we will use to ascertain exclusion criteria. If the person meets
criteria for AMCI, they will be invited to participate in the study and randomized to
metformin or placebo within one month.

The sources of the participants will be:1) The Associates in Internal Medicine (AIM)
practice of Columbia University; 2) the Memory Disorders Clinic (MDC) at AIM; 3) The
Community of Washington Heights. We expect that 50% of participants will be Hispanic, 30%
Black, and 20% Non-Hispanic White, 70% women, and 30% men.

RANDOMIZATION. We propose the use of random permuted blocks as the method of randomization
to ensure balance in the groups given the small sample size. If participants are included in
the study we will do APOE-ε4 genotyping and use this information for block randomization.

SCHEDULE OF ASSESSMENTS. We will collect medical history and concomitant medication data at
every visit. Participants will be examined at 3 month intervals. Imaging studies will be
conducted only at baseline and after the 12 month visit.

METFORMIN AND PLACEBO. Metformin Dosing Schedule and side effects: Metformin and matching
placebo will be provided by Merck-Lipha of France. The medication and placebo will be
managed and dispensed by the Research Pharmacy at Columbia University Medical Center.
Persons will first be given metformin 500 mg once a day at baseline. At day-7 the dose will
be increased to 500 mg twice a day. At day 14, the dose will be increased to 500 mg three
times a day. At day 21, the dose will be recommended to 1000 mg twice a day. At day 28, we
will call the patient via telephone to ascertain that they are tolerating the dose of 1000
mg twice a day, the usual maximum dose recommended in clinical practice. If the participants
report not tolerating a dose of metformin, they will be asked to remain at the lowest
tolerated dose. The most common side effect of metformin is gastrointestinal intolerance. At
baseline, 3 month, 6 month, 9 month visit and at the end of the study we will measure renal
function, liver function, and complete blood count to monitor side effects. This information
will be made available to the data safety monitoring board of the study.

NEUROPSYCHOLOGICAL BATTERY. All measures will be available in English and Spanish. The
neuropsychological battery includes our 2 co-primary outcomes, the Buschke Selective
Reminding test, and the modified ADAS-Cog. In addition, our battery includes the ADCS
Clinical Global Impression of Change-Mild cognitive impairment, the Clinical Dementia
Rating, the Digit Span Backwards, the Hamilton Rating Scale for Depression, the Logical
Memory Test, the Mini Mental State Examination, and the neuropsychiatric inventory.

OTHER ASSESSMENTS:

We will assess body mass index (BMI), blood pressure, heart rate, respiratory rate, and
conduct a physical exam to search for contraindications to metformin including cardiac
disease. Will also perform an EKG at baseline.

LABORATORY MEASURES. Plasma Aβ40 and Aβ42 have been suggested as markers of AD and high Aβ42
has been shown to predict AD progression in Northern Manhattan . They will be measured in
all participants at baseline and at the end of the study from EDTA plasma stored a -80
degrees F using published procedures.

General chemistry, liver function tests, and complete blood count will be done as shown in
the timetable to monitor for contraindications and side effects of metformin. In persons
with no available information on TSH, B12, and RPR, necessary measures to rule out secondary
cognitive impairment, we will obtain them at baseline. HsCRP, insulin, lipids, adiponectin,
and HbA1c are inflammatory and metabolic intermediate variables and will be measured to
ascertain the effects of metformin and to explore mechanisms for a benefit of metformin on
the outcomes. APOE-ε4 genotyping will also be conducted.

BRAIN IMAGING. A subsample of the study will compare on an intention-to-treat basis between
the metformin and placebo group mean changes from the beginning to end of the trial in
uptake of fluorodeoxyglucose (FDG) in the posterior cingulate-precuneous measured with brain
positron emission tomography (PET) in 40 non-diabetic patients out of the 80 study subjects.
PET imaging will be performed with a HR+ scanner at Columbia Kreitchman PET Center. All
image analysis will be performed with MEDX and FSL (FMRIB) Software Library). There will
also be a brain magnetic resonance imaging (MRI). MRI images co-registered to the PET images
allow accurate structural localization of metabolic changes and correction of brain atrophy.
Participants will be scanned on a 1.5T Philips Intera dedicated research scanner. Four sets
of structural images will be obtained from each subject during their MRI scanning session.
The total imaging time will be 30 minutes. As part of standard procedures, a
neuroradiologist conducts a clinical evaluation to rule out tumors, strokes, and other
lesions. Any significant abnormality is discussed with the study investigator, who then
takes appropriate action, including discussion of the abnormality with the participant, and
with the participant's permission, with the participant's physician of choice. If the
participant has no physician, we will facilitate one at Columbia University Medical Center.
PET and MR images will be spatially normalized to a custom template image in standard
Montreal Neurological Institute (MNI) space. The spatial normalization will allow assessing
any changes in the metabolic rate of glucose as a result of the intervention through a
statistical parametric mapping approach. These spatial parameters will be applied to the
co-registered PET images thereby transforming them into standardized space.

STATISTICAL ANALYSES. The primary analyses will be conducted on an intention-to-treat basis.
We will use ANACOVA to compare changes from baseline to 12 months in all outcomes between
metformin and placebo. We will adjust for variables found to be different between the
metformin and placebo groups at baseline. The primary analyses are those for the primary
aim, secondary aim, and exploratory aim.

We will also secondary analyses examining completers, and also examining changes in
metabolic markers and other cognitive measures.

I
Study TypeInterventional
Study PhasePhase 2
Study DesignAllocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention
ConditionAmnestic Mild Cognitive Impairment
InterventionDrug: metformin
metformin 1000 mg twice a day titrated from 500 mg once a day
Other Names:
glucophageDrug: placebo
placebo identical to metformin 2 tablets twice a day titrated from one table once a day
Other Names:
placebo
Study Arm (s)
  • Placebo Comparator: P
    placebo identical to metformin.
  • Experimental: metformin
    metformin 1000 mg twice a day

Recruitment Information[ + expand ][ + ]

Recruitment StatusCompleted
Estimated Enrollment80
Estimated Completion DateFebruary 2012
Estimated Primary Completion DateFebruary 2012
Eligibility Criteria
Inclusion Criteria:

- Age range: 55 to 90 years;

- Sex distribution: men and women;

- Languages: fluent in English or Spanish.

- Subjects must score below a pre-determined cut-off score on the logical memory II
delayed paragraph recall sub-test of the Wechsler Memory Scale Revised (WMS-R)26:

1. less than or equal to 8 for 16 or more years of education.;

2. less than or equal to 4 for 8-15 years of education;

3. less than or equal to 2 for 0-7 years of education.

- Global Clinical dementia rating (CDR) score must be 0.5 at screening. The memory box
score must be 0.5 or 1.0, with no more than two box scores other than memory rated as
high as 1.0 and no box score rated greater than 1.0.

- 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 HbA1c is >
6.5.

- BMI ≥ 25 kg/m2

- No contraindications to metformin treatment.

- 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.

Exclusion Criteria:

- Subjects with uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or
diastolic blood pressure ≥ 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;

- Subjects who for any reason may not complete the study as judged by the study
physician;

- Abnormal TSH, B12, and RPR.

- Contraindications to metformin use include a creatinine of > 1.5, liver disease by
history or by elevated transaminases, congestive heart failure, and alcohol abuse.

- We will also exclude subjects with a history of intolerance to metformin.
GenderBoth
Ages55 Years
Accepts Healthy VolunteersNo
ContactsNot Provided
Location CountriesUnited States

Administrative Information[ + expand ][ + ]

NCT Number NCT00620191
Other Study ID NumbersAAAC7231
Has Data Monitoring CommitteeYes
Information Provided ByColumbia University
Study SponsorColumbia University
CollaboratorsInstitute for the Study of Aging (ISOA)
National Institute on Aging (NIA)
Investigators Principal Investigator: Jose A Luchsinger, MD Columbia University
Verification DateMarch 2013

Locations[ + expand ][ + ]

Columbia University Medical Center
New York, New York, United States, 10032