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Metformin in Alzheimer's Dementia Prevention (MAP)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04098666
Recruitment Status : Recruiting
First Posted : September 23, 2019
Last Update Posted : August 31, 2022
Sponsor:
Collaborators:
Johns Hopkins University
National Institute on Aging (NIA)
University of Rochester
University of Iowa
Boston University
Wake Forest University
Rush University
Pennington Biomedical Research Center
University of Miami
Emory University
Georgetown University
NYU Langone Health
University of California, Berkeley
The University of Texas Health Science Center at San Antonio
University of Washington
Information provided by (Responsible Party):
José A. Luchsinger, Columbia University

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 370 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 24 months and have 5 visits: baseline, 6-months, 12-months, 18-months, and 24-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 24. 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 clinical outcome will be changes in the Alzheimer's Disease Cooperative Study Preclinical Alzheimer's Cognitive Composite. Secondary subclinical outcomes will be changes in cortical thickness AD signature areas, changes in white matter hyperintensity volume, changes in brain amyloid burden, changes in brain tau burden, and changes in plasma biomarkers of amyloid, tau, and neurodegeneration. 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.

Condition or disease Intervention/treatment Phase
Mild Cognitive Impairment Drug: Placebo oral tablet Drug: extended release metformin Phase 2 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 370 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: randomized 1:1 placebo controlled double blinded
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: the study will be placebo controlled
Primary Purpose: Prevention
Official Title: Metformin in Alzheimer's Dementia Prevention
Actual Study Start Date : March 22, 2021
Estimated Primary Completion Date : March 31, 2026
Estimated Study Completion Date : April 30, 2026


Arm Intervention/treatment
Experimental: metformin users
Extended 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.
Drug: extended release metformin
Metformin extended release 500 mg tablets, up to 4 tablets a day
Other Name: Metformin

Placebo Comparator: metformin non-users
Placebo tablets identical to dxtended 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.
Drug: Placebo oral tablet
Placebo tablet identical to metformin, up to 4 tablets a day
Other Name: Placebo




Primary Outcome Measures :
  1. Free and Cued Selective Reminding Test (FCSRT) [ Time Frame: 24 months ]
    Total recall of the FCSRT


Secondary Outcome Measures :
  1. Alzheimer's Disease Cooperative Study Preclinical Alzheimer's Cognitive Composite (PACC-ADCS) [ Time Frame: 24 months ]
    Composite of 4 tests:The FCSRT, 2. The Delayed Recall score on the Logical Memory IIa subtest from the Wechsler Memory Scale, The Digit Symbol Substitution Test score, from the Wechsler Adult Intelligence Scale-Revised, and the Mini Mental Status total score.

  2. Cortical Thickness [ Time Frame: 24 months ]
    Cortical thickness in areas affected by Alzheimer's disease from 3T MRI

  3. White matter hyper intensity volume (WMH) [ Time Frame: 24 months ]
    total WMH volume adjusted for cranial size

  4. Brain amyloid [ Time Frame: 24 months ]
    Changes in whole brain Amyloid beta standardized uptake value ratio (SUVR) and in incident amyloid positivity. Brain amyloid will be ascertained using 18F-Florbetaben

  5. Brain Tau [ Time Frame: 24 months ]
    Changes in tau SUVR in a composite brain region comprising medial and inferolateral temporal cortex. Tau will be measured using 18F-MK6240

  6. plasma amyloid [ Time Frame: 24 months ]
    Changes in amyloid beta 42/40 ratio measured using Simoa Assays

  7. plasma tau [ Time Frame: 24 months ]
    changes in plasma total tau measured using Simoa assays

  8. plasma neurofilament light [ Time Frame: 24 months ]
    changes in plasma neurofilament light measured using Simoa assays



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   55 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Diagnosis of aMCI:

  • Participants must have subjective memory concern 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.
  • 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:

      • 9-11 for 16 or more years of education
      • 5-9 for 8-15 years of education
      • 3-6 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.
  • Sex distribution: all eligible men and women will be included and no one will be excluded because of gender.
  • Languages: fluent in English or Spanish. We have reliable, well-validated Spanish tests for all outcome measures.
  • Participants without a known history of diabetes. If diabetes is diagnosed during screening (hemoglobin A1c of 6.5 % or greater) they will also be excluded. The main justification for this exclusion is the potential for these participants to be placed on other diabetes medications that may confound our study.
  • General cognition and functional performance such that a diagnosis of dementia cannot be made at the time of screening based on DSM-V criteria.
  • Vision and hearing must be sufficient for compliance with testing procedures.
  • Must have an informant to come to all appointments or be available by telephone at follow-up visits.

Study Partner Inclusion Criteria

  • The study partner can provide an independent evaluation of functioning for a person enrolled in the MAP study as a participant
  • The study partner agrees to attend study visits with the MAP participant or be available by telephone.

Exclusion Criteria:

  • Use of metformin for any indication.
  • 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-fatty liver disease (e.g., cirrhosis) 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 used for indications other than diabetes.
  • 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).
  • Participants with active cancer or a history of cancer within the last two years, with the exception of squamous or basal cell carcinoma of the skin.
  • Participants who for any reason may not complete the study as judged by the study physician.
  • Participants planning to move to another city or state within the next 24 months.
  • Participants with a known history of diabetes. The rationale for this exclusion is persons with diabetes may already be on metformin or on other medications that increase insulin levels and could confound the trial.
  • Participants with diabetes discovered on screening based on American Diabetes Association criteria using HbA1c (HbA1c of 6.5% or greater). Although metformin could be a first treatment of diabetes for these participants, addition of treatments for diabetes by physicians could confound the study.
  • Use of aducanumab (Aduhelm™) of any other amyloid modifying treatment for AD.
  • Not able to undergo phlebotomy as reported by the participant or determined by the study coordinator or physician.
  • Participants with known, suspected, or plan for becoming pregnant.

Exclusion Criteria for MRI

Contraindications for MRI include inability to lie flat, claustrophobia, or presence of indwelling metal objects or implants that are not MRI compatible.

Exclusion Criteria for PET

History of adverse reactions to radiocontrast agents.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04098666


Contacts
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Contact: José A Luchsinger, MD 212-305-4730 jal94@cumc.columbia.edu
Contact: Sam Cammack, MA, MPH 212-305-7561 ac2239@columbia.edu

Locations
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United States, District of Columbia
Georgetown University Recruiting
Washington, District of Columbia, United States, 20007
Contact: Katie Seidenberg    202-687-5338    ks1891@georgetown.edu   
Contact: Brigid Reynolds, NP    202-687-3350    Brigid.Reynolds@georgetown.edu   
Principal Investigator: Raymond Turner, MD         
United States, Florida
University of Miami Recruiting
Miami, Florida, United States, 33136
Contact: Barry Baumel, MD         
Contact: Carmen Perez    305-243-0184    c.perez71@med.miami.edu   
Principal Investigator: Barry Baumel, MD         
United States, Georgia
Emory University Active, not recruiting
Atlanta, Georgia, United States, 30329
United States, Illinois
Rush University Medical Center Recruiting
Chicago, Illinois, United States, 60612
Contact: Zoe Arvanitakis, MD         
Contact: Bernardo Rivera    312-563-4896    bernardo_rivera@rush.edu   
Principal Investigator: Zoe Arvanitakis, MD         
United States, Louisiana
Pennington Biomedical Research Center Recruiting
Baton Rouge, Louisiana, United States, 70808
Contact: Erin LeJeune    225-763-0910    erin.lejeune@pbrc.edu   
Contact: Sara Goff, RN       Sara.goff@pbrc.edu   
Principal Investigator: Jeffrey Keller, PhD         
United States, Massachusetts
Boston University Recruiting
Boston, Massachusetts, United States, 02118
Contact: Alexa Puleio       puleioa@bu.edu   
Contact: Jane Mwicigi    617-358-6425    jmwicigi@bu.edu   
Principal Investigator: Wendy Qiu, MD         
United States, New York
New York University Langone Medical Center Recruiting
New York, New York, United States, 10016
Contact: Anaztasia Ulysse    212-263-0771    anaztasia.ulysse@nyulangone.org   
Contact: Jennifer Wong       Jennifer.Wong2@nyulangone.org   
Principal Investigator: Arjun Masukar, MD         
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Juan Vassallo    646-946-9158    jv2772@cumc.columbia.edu   
Contact: Erica Barrios    212-305-9748    emb2303@cumc.columbia.edu   
Principal Investigator: José A Luchsinger, MD         
United States, North Carolina
Wake Forest University Health Sciences Recruiting
Winston-Salem, North Carolina, United States, 27157
Contact: Hunter Ledford    336-716-3013    pledfor@wakehealth.edu   
Contact: Abigail O'Connell    336-716-7976    Abigail.oconnell@wakehealth.edu   
Principal Investigator: Suzanne Craft, PhD         
United States, Texas
The University of Texas Health Science Center San Antonio Not yet recruiting
San Antonio, Texas, United States, 78229
Contact: Maria Roth    210-450-3425    rothm@uthscsa.edu   
Principal Investigator: Sara Espinoza, MD         
United States, Washington
University of Washington Recruiting
Seattle, Washington, United States, 98104
Contact: Angela Hanson, MD         
Contact: Kristen Farris    206-897-6797    kmfarris@uw.edu   
Principal Investigator: Angela Hanson, MD         
Sponsors and Collaborators
Columbia University
Johns Hopkins University
National Institute on Aging (NIA)
University of Rochester
University of Iowa
Boston University
Wake Forest University
Rush University
Pennington Biomedical Research Center
University of Miami
Emory University
Georgetown University
NYU Langone Health
University of California, Berkeley
The University of Texas Health Science Center at San Antonio
University of Washington
Investigators
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Principal Investigator: José A Luchsinger, MD Columbia University
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Responsible Party: José A. Luchsinger, Professor of Medicine and Epidemiology, Columbia University
ClinicalTrials.gov Identifier: NCT04098666    
Other Study ID Numbers: AAAS6912
R01AG062624 ( U.S. NIH Grant/Contract )
First Posted: September 23, 2019    Key Record Dates
Last Update Posted: August 31, 2022
Last Verified: August 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: After reporting of main results

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Dementia
Alzheimer Disease
Cognitive Dysfunction
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurocognitive Disorders
Mental Disorders
Cognition Disorders
Tauopathies
Neurodegenerative Diseases
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs