Metformin in Amnestic Mild Cognitive Impairment (MCI)

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Amnestic Mild Cognitive Impairment	Drug: metformin; Drug: placebo	Phase 2

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Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	80 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Prevention
Official Title:	Metformin in the Prevention of Alzheimer's Disease
Study Start Date :	February 2008
Actual Primary Completion Date :	February 2012
Actual Study Completion Date :	February 2012

Arms and Interventions

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Arm	Intervention/treatment
Placebo Comparator: P; placebo identical to metformin.	Drug: placebo; placebo identical to metformin 2 tablets twice a day titrated from one table once a day
Experimental: metformin; metformin 1000 mg twice a day	Drug: metformin; metformin 1000 mg twice a day titrated from 500 mg once a day; Other Name: glucophage

Outcome Measures

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Primary Outcome Measures :

1. Total Recall in the Selective Reminding Test [ Time Frame: 12 MONTHS ]
2. ADAS-cog [ Time Frame: 12 months ]
   Alzheimer's Disease Assessment Scale-cognitive subscale

Secondary Outcome Measures :

1. rCMRgl in the posterior cingulate-precuneus. [ Time Frame: 12 months ]
   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).

Other Outcome Measures:

1. Plasma Amyloid beta-42 [ Time Frame: 12 months ]

Eligibility Criteria

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Ages Eligible for Study:	55 Years to 90 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

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Locations

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

Sponsors and Collaborators

Columbia University

Institute for the Study of Aging (ISOA)

National Institute on Aging (NIA)

Investigators

Principal Investigator:	Jose A Luchsinger, MD	Columbia University

More Information

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Publications:

Luchsinger JA, Tang MX, Shea S, Mayeux R. Hyperinsulinemia and risk of Alzheimer disease. Neurology. 2004 Oct 12;63(7):1187-92.

Responsible Party:	José A. Luchsinger, Associate Professor of Medicine and Epidemiology at NYPH/CUMC, Columbia University
ClinicalTrials.gov Identifier:	NCT00620191 History of Changes
Other Study ID Numbers:	AAAC7231; R0153596 ( Other Grant/Funding Number: NIA )
First Posted:	February 21, 2008
Last Update Posted:	March 14, 2013
Last Verified:	March 2013

Keywords provided by José A. Luchsinger, Columbia University:

metformin; mild cognitive impairment; alzheimer's disease; overweight; insulin

Additional relevant MeSH terms:

Alzheimer Disease; Cognitive Dysfunction; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies	Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders; Metformin; Hypoglycemic Agents; Physiological Effects of Drugs