MAP will be a multisite phase II/III 1:1 randomized controlled trial of long-acting metformin (Glucophage XR) versus 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. 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 cortical thickness and white matter hyperintensity volume.

The data coordinating center and imaging core will be located at Johns 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.

ClinicalTrials.gov Identifier: NCT04098666