Metformin in Alzheimer's Dementia Prevention

Plain English Summary

Metformin in Alzheimer's Dementia Prevention is a Phase 3 clinical trial sponsored by Columbia University studying Mild Cognitive Impairment. This trial tests if metformin, a diabetes drug, can help prevent Alzheimer's dementia in people with early memory problems. It is for individuals aged 55-90 with mild cognitive impairment (MCI) who do not have diabetes and are overweight or obese. Participants will take either metformin or a placebo for 18 months, with regular check-ups and cognitive tests. Alternatives include lifestyle changes, other medications for cognitive health, and participation in other clinical trials. The trial aims to enroll 326 participants.

Official 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 an

Who Can Participate

Here is what you need to know about eligibility for this trial. You can join if you are between 55 and 90 years old and have been diagnosed with mild cognitive impairment (MCI). You must not have diabetes, be overweight or obese, and have a study partner to assist with appointments. You cannot join if you have a dementia diagnosis, a history of stroke with lasting effects, or certain other medical conditions like severe heart failure or liver disease. Individuals taking metformin or other diabetes medications, or those with very low kidney function, are also excluded. This trial is studying Mild Cognitive Impairment, so participants generally need a confirmed diagnosis.

What They're Measuring

The primary outcome measures how well participants' memory and thinking skills are maintained over 18 months, indicating if metformin helps preserve cognitive function. The specific primary outcome measures are: Free and Cued Selective Reminding Test (FCSRT) (18 months). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 3, the final and most rigorous stage before seeking FDA approval. Phase 3 trials involve 300-3,000+ patients across multiple sites and compare the new treatment directly against the current standard of care. These pivotal trials generate the evidence needed for regulatory review. About 58% of Phase 3 drugs receive FDA approval. Successful Phase 3 results typically lead to a New Drug Application submission.

Why This Trial Matters

This trial is important because it explores a widely available and inexpensive medication, metformin, as a potential preventative treatment for Alzheimer's dementia, addressing a significant unmet nee As a Phase 3 trial, positive results could directly lead to FDA approval, making this treatment available to the broader patient population. This research targets Mild Cognitive Impairment, where improved treatment options are needed.

Investor Insight

This trial signals potential for a new, accessible preventative therapy for a large market of individuals at risk for Alzheimer's, with metformin being a well-established drug, suggesting a potentiall Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage.

Is This Trial Right for Me?

Ask your doctor about the potential benefits and risks of metformin for cognitive health and if it's appropriate for you. Understand that you will be randomly assigned to receive either metformin or a placebo, and you will need to attend regular study visits for 18 months. Be prepared for potential side effects of metformin, such as gastrointestinal issues, and ensure you have a reliable study partner available. The trial is being conducted at 20 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: QUADRUPLE
• Enrollment: 326 participants

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

Primary Outcomes

• Free and Cued Selective Reminding Test (FCSRT) (18 months)

Secondary Outcomes

• Alzheimer's Disease Cooperative Study Preclinical Alzheimer's Cognitive Composite (PACC-ADCS) (18 months)
• APOE-ε4 genotype (18 months)
• White matter hyper intensity volume (WMH) (18 months)
• Brain amyloid (18 months)
• Brain Tau (18 months)

Full Eligibility Criteria

Inclusion Criteria:

Diagnosis of aMCI: in general, the diagnosis of aMCI follows the definition in the 2011 National Institute on Aging (NIA)/ Alzheimer's association (AA) guidelines, without biomarkers. Participants must have:

* Subjective memory concerns 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. Information from the formal University of Washington CDR instrument, report by the participant of subjective cognitive complaints, and findings from the screening neuropsychological battery, can be used for this determination by the investigative team. For example, the University of Washington CDR can be 0, but the CDR memory box score can be deemed to be 0.5 based on cognitive complaints at screening and meeting the MCI neuropsychological criteria.
* 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 or any class of medication approved for treatment of diabetes, even if it is used for an indication other than diabetes (e.g., obesity), within one year of screening. These medications include GLP-1 agonists used for weight loss.
* 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-alcoholic fatty liver disease 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.
* 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

Trial Locations

• University of California - Irvine, Irvine, California, United States
• Stanford University, Palo Alto, California, United States
• Georgetown University, Washington D.C., District of Columbia, United States
• University of Miami, Miami, Florida, United States
• Emory University, Atlanta, Georgia, United States
• Rush University Medical Center, Chicago, Illinois, United States
• University of Kansas Medical Center, Wichita, Kansas, United States
• Pennington Biomedical Research Center, Baton Rouge, Louisiana, United States
• Boston University, Boston, Massachusetts, United States
• University of New Mexico, Albuquerque, New Mexico, United States
• ...and 10 more locations

Frequently Asked Questions

Related Conditions

• Alzheimer's Disease
• Mild Cognitive Impairment
• Dementia Prevention
• Type 2 Diabetes
• Metabolic Syndrome
• Obesity
• Cardiovascular Disease
• Vascular Dementia
• Aging Brain
• Neurodegenerative Diseases

More Mild Cognitive Impairment Trials

View all Mild Cognitive Impairment clinical trials