Metformin in Alzheimer's Dementia Prevention
MAP
2 other identifiers
interventional
326
1 country
22
Brief Summary
MAP will be a multisite phase II/III 1:1 randomized controlled trial (RCT) of long acting metformin (reduced mass Glucophage XR) vs. matching placebo in 326 men and women with early and late aMCI, without diabetes, not treated with metformin, overweight or obese, aged 55 years to 90 years. The RCT will last 18 months and have 4 visits: baseline, 6-months, 12-months, and 18-months. The RCT will be preceded by a screening phase followed by randomization and a titration period in which drug/placebo will be titrated from 500 mg a day (one tablet) to 2,000 mg a day (4 tablets), in increments of 500 mg (one tablet) every 10 days. Participants will remain in the RCT on the tolerated dose, and included in analyses on an intent to treat basis. We expect the attrition rate to be 10%/year. Neuropsychological battery, clinical interviews, physical exam, and phlebotomy will be conducted at baseline and every 6 months. Brain MRI will be conducted in approximately half of the participants (186) twice, at baseline, and after the last study visit at month 18. We will also conduct brain amyloid Positron Emission Tomography (PET) using 18F-Florbetaben, and tau PET using 18F-MK6240 in half of the participants at baseline and end of the RCT. The primary clinical outcome of the study will be changes in the Free and Cued Selective Reminding Test. The secondary endpoints are 1) changes in global cognitive performance, measured with the Alzheimer's Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC); 2) changes in neurodegeneration, ascertained as cortical thickness in areas affected by AD on brain MRI; 3) changes in cerebrovascular disease, ascertained as white matter hyperintensities (WMH) volume on brain MRI; 4) Changes in whole brain amyloid ß (Aß) SUVR and in incident amyloid positivity; 5) Changes in tau SUVR in a composite brain region comprising medial and inferolateral temporal cortex; 6) Changes in plasma AD biomarkers. The data coordinating center and Imaging Core is located at John Hopkins University. The PET coordinating center is located at UC-Berkeley. The Clinical Coordinating and Monitoring Center and the central laboratory will be located at Columbia. The Research pharmacy function will be shared by the University of Rochester, which will dispense randomization kits, and the University of Iowa, which will receive bulk metformin and identical matching placebo from EMD Serono.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_2
Started Mar 2021
Longer than P75 for phase_2
22 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
September 19, 2019
CompletedFirst Posted
Study publicly available on registry
September 23, 2019
CompletedStudy Start
First participant enrolled
March 22, 2021
CompletedPrimary Completion
Last participant's last visit for primary outcome
April 30, 2026
ExpectedStudy Completion
Last participant's last visit for all outcomes
April 30, 2027
February 19, 2025
February 1, 2025
5.1 years
September 19, 2019
February 17, 2025
Conditions
Outcome Measures
Primary Outcomes (1)
Free and Cued Selective Reminding Test (FCSRT)
Total recall of the FCSRT
18 months
Secondary Outcomes (7)
Alzheimer's Disease Cooperative Study Preclinical Alzheimer's Cognitive Composite (PACC-ADCS)
18 months
APOE-ε4 genotype
18 months
White matter hyper intensity volume (WMH)
18 months
Brain amyloid
18 months
Brain Tau
18 months
- +2 more secondary outcomes
Study Arms (2)
metformin users
EXPERIMENTALExtended release metformin 500 mg tablets up to 2,000 mg (4 tablets) a day once at night. The maximum dose will be attempted during a titration period in the first month of the study.
metformin non-users
PLACEBO COMPARATORPlacebo tablets identical to extended release metformin 500 mg tablets up to 4 tablets a day once at night. The maximum dose will be attempted during a titration period in the first month of the study.
Interventions
Placebo tablet identical to metformin, up to 4 tablets a day
Metformin extended release 500 mg tablets, up to 4 tablets a day
Eligibility Criteria
You may qualify if:
- Diagnosis of aMCI: in general, the diagnosis of aMCI follows the definition in the 2011 National Institute on Aging (NIA)/ Alzheimer's association (AA) guidelines, without biomarkers. Participants must have:
- Subjective memory concerns reported by participant, study partner, or clinician.
- A mini-mental state exam between ≥ 22 for subjects with more than 8 years of education. For subjects with less than 8 years of education, a MMSE ≥ 20 will be allowed.
- Clinical Dementia Rating = 0.5. The memory box score must be at least 0.5. Information from the formal University of Washington CDR instrument, report by the participant of subjective cognitive complaints, and findings from the screening neuropsychological battery, can be used for this determination by the investigative team. For example, the University of Washington CDR can be 0, but the CDR memory box score can be deemed to be 0.5 based on cognitive complaints at screening and meeting the MCI neuropsychological criteria.
- General cognition and functional performance sufficiently preserved such that a diagnosis of Alzheimer's disease cannot be made by the site physician at the time of the screening visit.
- Abnormal memory function documented by scoring within the education adjusted ranges on the Logical Memory II subscale (Delayed Paragraph Recall, Paragraph A only) from the Wechsler Memory Scale-Revised.
- For early MCI:
- for 16 or more years of education
- for 8-15 years of education
- for 0-7 years of education
- For late MCI
- ≤ 8 for 16 or more years of education
- ≤ 4 for 8-15 years of education
- ≤ 2 for 0-7 years of education
- Age range: 55 years to 90 years.
- +7 more criteria
You may not qualify if:
- Use of metformin or any class of medication approved for treatment of diabetes, even if it is used for an indication other than diabetes (e.g., obesity), within one year of screening. These medications include GLP-1 agonists used for weight loss.
- Body mass index ≤ 20 k/m2.
- Metformin is contraindicated in persons with an estimated glomerular filtration rate (eGFR) of less than 30 mL/min. For persons with an eGFR of 30 to 45 mL/min, a reduction of the dose or discontinuation of the medication is recommended for those on metformin; in this range, it is also recommended that persons do not initiate metformin. Thus, participants with eGFR ≤ 45 mL/min will not be eligible to participate.
- The risk of lactic acidosis is increased in persons with liver disease and class III or IV congestive heart failure. Thus, persons with liver disease other than non-alcoholic fatty liver disease or class III or IV congestive heart failure will not be eligible to participate due to the risks of side effects.
- A history of intolerance to metformin.
- History of cerebrovascular accident with residual neurological deficits.
- Moderate to severe depression, indicated by a score in the Geriatric Depression Scale of 9/15 or higher.
- Dementia diagnosis
- Lack of capacity to consent
- Participants with neurologic diseases associated with neurologic deficits on clinical examination.
- Participants with other current Axis I psychiatric diagnoses such as bipolar disorder or schizophrenia.
- Alcohol or substance abuse or dependence in the past 6 months.
- Use of medications rated as being the likely cause of cognitive impairment. These include benzodiazepines in dose equivalents greater than 2 mg daily of lorazepam, and regular use of prescription narcotics.
- Normal individuals without cognitive complaints.
- Participants with uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 95 mmHg).
- +8 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Columbia Universitylead
- Johns Hopkins Universitycollaborator
- National Institute on Aging (NIA)collaborator
- University of Rochestercollaborator
- University of Iowacollaborator
- Boston Universitycollaborator
- Wake Forest Universitycollaborator
- Rush Universitycollaborator
- Pennington Biomedical Research Centercollaborator
- University of Miamicollaborator
- Emory Universitycollaborator
- Georgetown Universitycollaborator
- NYU Langone Healthcollaborator
- University of California, Berkeleycollaborator
- The University of Texas Health Science Center at San Antoniocollaborator
- University of Washingtoncollaborator
- State University of New York - Upstate Medical Universitycollaborator
- University of Texas Southwestern Medical Centercollaborator
- University at Buffalocollaborator
- University of Cincinnaticollaborator
- Eastern Virginia Medical Schoolcollaborator
- Medical College of Wisconsincollaborator
- University of Kansas Medical Centercollaborator
- University of New Mexicocollaborator
- Stanford Universitycollaborator
- University of California, Irvinecollaborator
- Cornell Universitycollaborator
Study Sites (22)
University of California - Irvine
Irvine, California, 92697, United States
Stanford University
Palo Alto, California, 94304, United States
Georgetown University
Washington D.C., District of Columbia, 20007, United States
University of Miami
Miami, Florida, 33136, United States
Emory University
Atlanta, Georgia, 30329, United States
Rush University Medical Center
Chicago, Illinois, 60612, United States
University of Kansas Medical Center
Wichita, Kansas, 67214, United States
Pennington Biomedical Research Center
Baton Rouge, Louisiana, 70808, United States
Boston University
Boston, Massachusetts, 02118, United States
University of New Mexico
Albuquerque, New Mexico, 87106, United States
University at Buffalo
Buffalo, New York, 14203, United States
New York University Langone Medical Center
New York, New York, 10016, United States
Columbia University Medical Center
New York, New York, 10032, United States
Cornell University
New York, New York, 10065, United States
SUNY Upstate Medical University
Syracuse, New York, 13210, United States
Wake Forest University Health Sciences
Winston-Salem, North Carolina, 27157, United States
University of Cincinnati
Cincinnati, Ohio, 45267, United States
University of Texas - Southwestern Medical Center
Dallas, Texas, 75390, United States
The University of Texas Health Science Center San Antonio
San Antonio, Texas, 78229, United States
Eastern Virginia Medical School
Norfolk, Virginia, 23507, United States
University of Washington
Seattle, Washington, 98104, United States
Medical College of Wisconsin
Milwaukee, Wisconsin, 53226, United States
Related Publications (1)
Kim AB, Arvanitakis Z. Insulin resistance, cognition, and Alzheimer disease. Obesity (Silver Spring). 2023 Jun;31(6):1486-1498. doi: 10.1002/oby.23761.
PMID: 37203336DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
José A Luchsinger, MD
Columbia University
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- QUADRUPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
- Masking Details
- the study will be placebo controlled
- Purpose
- PREVENTION
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Professor of Medicine and Epidemiology
Study Record Dates
First Submitted
September 19, 2019
First Posted
September 23, 2019
Study Start
March 22, 2021
Primary Completion (Estimated)
April 30, 2026
Study Completion (Estimated)
April 30, 2027
Last Updated
February 19, 2025
Record last verified: 2025-02
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
- Time Frame
- After reporting of main results
All datasets used/generated on the project will be made accessible and reusable by qualified individuals other than the original data generators via web-based resources with the capacity to store large and diverse datasets (such as data about clinical phenotypes, genetics, epigenetics, proteomics, and metabolomics) to enable multiple parallel approaches to data analysis and interpretation. All analytical methodologies will be made fully reproducible and transparent so that results can be vetted and existing analysis techniques quickly applied to new application areas. We will comply with the data sharing arrangement decided by NIA.