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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 : Not yet recruiting
First Posted : September 23, 2019
Last Update Posted : November 12, 2019
Sponsor:
Collaborators:
Johns Hopkins University
National Institute on Aging (NIA)
University of Rochester
University of Iowa
Weill Medical College of Cornell University
Boston University
Wake Forest University
Rush University
Pennington Biomedical Research Center
University of Miami
Emory University
Georgetown University
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 of long acting metformin (Glucophage XR) vs. matching placebo among 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 duration of the trial will be 24 months and will have 5 visits: baseline, 6-months, 12-months, 18-months, and 24-months. The trial will be preceded by a screening phase followed by randomization and a titration period in which long-acting metformin 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. During this titration period subjects will also undergo repeated cognitive testing (3 times in addition to baseline) to account for practice effects and establish a cognitive baseline. Participants will remain in the trial on the tolerated dose of metformin or placebo, and included in the analyses on an intent to treat basis. We expect the attrition rate to be 10% a year. Neuropsychological battery, clinical interviews, physical exam, and phlebotomy will be conducted at baseline and repeated every 6 months during 24 months, for a total of 5 visits. Brain MRI will be conducted in approximately half of the participants (186). The baseline MRI will be conducted after the end of the titration period and after the 24 months assessment. Medication compliance will be assessed every 6 months. Adverse events will be checked every month via telephone call, text, or email, or in person during the scheduled in-person assessments every six months. 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 hippocampal volume and white matter hyperintensity volume. The data coordinating center and Imaging Core will be located at John Hopkins University. 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: Treatment
Official Title: Metformin in Alzheimer's Dementia Prevention
Estimated Study Start Date : August 1, 2020
Estimated Primary Completion Date : March 30, 2024
Estimated Study Completion Date : April 30, 2024


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



Information from the National Library of Medicine

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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:

  • Subjects must have subjective memory concern reported by subject, study partner, or clinician.
  • A mini-mental state exam between ≥ 24 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.
  • Subjects 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 subjects to be placed on other diabetes medications that may confound our study.
  • Overweight or obese by National Heart, Lung, and Blood Institute (NHLBI) criteria (BMI ≥ 25 kg/m squared). The justification for this criterion is that subjects that have normal BMI are less likely to have a metabolic response to metformin.
  • 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.
  • Subjects with contraindications to MRI will still be able to participate in the study but will not be able to undergo MRI.

Exclusion Criteria:

  • Use of metformin for any indication.
  • Contraindications to metformin: Contraindications to metformin include renal disease, liver disease by history or by elevated transaminases, congestive heart failure, and alcohol abuse. Although metformin can be used at glomerular filtration rates (GFR) as low as 30 ml/min, the maximum dose of 2,000 mg a day can be used only down to a GFR of 60 ml/min. Thus, we will exclude participants with a calculated GFR of < 60 ml/min. We will also exclude subjects with a history of intolerance to metformin used for indications other than diabetes.
  • History of cerebrovascular accident with residual neurological deficits.

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: Jose A Luchsinger, MD 2123054730 jal94@cumc.columbia.edu

Locations
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United States, District of Columbia
Georgetown University
Washington, District of Columbia, United States, 20007
Contact: Raymon Turner, MD         
United States, Florida
University of Miami
Miami, Florida, United States, 33136
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30329
United States, Illinois
Rush University Medical Center
Chicago, Illinois, United States, 60612
Contact: Zoe Arvanitakis, MD         
United States, Louisiana
Pennington Biomedical Research Center
Baton Rouge, Louisiana, United States, 70808
Contact: Jeffrey Keller, PhD         
United States, Massachusetts
Boston University
Boston, Massachusetts, United States, 02118
Contact: Robert Stern         
United States, New York
Weill Cornell Medical College
New York, New York, United States, 10021
Contact: Michael Lin         
Columbia University Medical Center
New York, New York, United States, 10032
United States, North Carolina
Wake Forest University Health Sciences
Winston-Salem, North Carolina, United States, 27157
United States, Washington
University of Washington
Seattle, Washington, United States, 98104
Contact: Angela Hanson, MD         
Sponsors and Collaborators
Columbia University
Johns Hopkins University
National Institute on Aging (NIA)
University of Rochester
University of Iowa
Weill Medical College of Cornell University
Boston University
Wake Forest University
Rush University
Pennington Biomedical Research Center
University of Miami
Emory University
Georgetown University
Investigators
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Principal Investigator: Jose A Luchsinger, MD Columbia University Irving Medical Center

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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: November 12, 2019
Last Verified: November 2019
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