|First Submitted Date ICMJE||February 7, 2008|
|First Posted Date ICMJE||February 21, 2008|
|Last Update Posted Date||March 14, 2013|
|Start Date ICMJE||February 2008|
|Primary Completion Date||February 2012 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE
||ADAS-cog [ Time Frame: 12 months ]|
|Change History||Complete list of historical versions of study NCT00620191 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||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 F-labeled 2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET).
|Original Secondary Outcome Measures ICMJE
||plasma amyloid beta [ Time Frame: 12 months ]|
|Current Other Outcome Measures ICMJE
||Plasma Amyloid beta-42 [ Time Frame: 12 months ]|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Metformin in Amnestic Mild Cognitive Impairment|
|Official Title ICMJE||Metformin 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.|
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.
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.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 2|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
|Condition ICMJE||Amnestic Mild Cognitive Impairment|
|Publications *||Luchsinger JA, Tang MX, Shea S, Mayeux R. Hyperinsulinemia and risk of Alzheimer disease. Neurology. 2004 Oct 12;63(7):1187-92.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Completion Date||February 2012|
|Primary Completion Date||February 2012 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||55 Years to 90 Years (Adult, Senior)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT00620191|
|Other Study ID Numbers ICMJE||AAAC7231
R0153596 ( Other Grant/Funding Number: NIA )
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||José A. Luchsinger, Columbia University|
|Study Sponsor ICMJE||Columbia University|
|PRS Account||Columbia University|
|Verification Date||March 2013|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP