Principal Investigator
Enrollment Status
Clinical Trial ID
Clinical Trial 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
Funding Agency/Sponsor
Other
Disease
Movement Disorders
Enrollment Eligibility
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.