Metformin in Alzheimer's Dementia Prevention

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.

Conditions

• Mild Cognitive Impairment

Interventions

DRUG

Placebo oral tablet

Placebo tablet identical to metformin, up to 4 tablets a day

DRUG

extended release metformin

Metformin extended release 500 mg tablets, up to 4 tablets a day

Sponsors & Collaborators

• Johns Hopkins University

  collaborator OTHER

• National Institute on Aging (NIA)

  collaborator NIH

• University of Rochester

  collaborator OTHER

• University of Iowa

  collaborator OTHER

• Boston University

  collaborator OTHER

• Wake Forest University

  collaborator OTHER

• Rush University

  collaborator OTHER

• Pennington Biomedical Research Center

  collaborator OTHER

• University of Miami

  collaborator OTHER

• Emory University

  collaborator OTHER

• Georgetown University

  collaborator OTHER

• NYU Langone Health

  collaborator OTHER

• University of California, Berkeley

  collaborator OTHER

• The University of Texas Health Science Center at San Antonio

  collaborator OTHER

• University of Washington

  collaborator OTHER

• State University of New York - Upstate Medical University

  collaborator OTHER

• University of Texas Southwestern Medical Center

  collaborator OTHER

• University at Buffalo

  collaborator OTHER

• University of Cincinnati

  collaborator OTHER

• Eastern Virginia Medical School

  collaborator OTHER

• Medical College of Wisconsin

  collaborator OTHER

• University of Kansas Medical Center

  collaborator OTHER

• University of New Mexico

  collaborator OTHER

• Stanford University

  collaborator OTHER

• University of California, Irvine

  collaborator OTHER

• Cornell University

  collaborator OTHER

• Columbia University

  lead OTHER

Principal Investigators

• José A Luchsinger, MD · Columbia University

Study Design

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

QUADRUPLE

Model

PARALLEL

Eligibility

Min Age

55 Years

Max Age

90 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2021-03-22

Primary Completion

2026-05-12

Completion

2027-04-30

FDA Drug

Yes

Countries

• United States

Study Locations