Metformin in Alzheimer's Dementia Prevention

• Status: Recruiting
• Trial end date: 2025-04-30
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2/Phase 3
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Columbia University
• Collaborators: Boston University; Emory University; Georgetown University; Johns Hopkins University; Louisiana State University Health Sciences Center in New Orleans; National Institute on Aging (NIA); NYU Langone Health; Pennington Biomedical Research Center; Rush University; University of California, Berkeley; University of Iowa; University of Miami; University of Rochester; Wake Forest University; Weill Medical College of Cornell University
• Treatments: Metformin

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.