MAP

(MAP Trial)

Recruiting at 22 trial locations

Overseen By Wendy Qiu, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Trial Phase: Phase 2 & 3

Sponsor: Columbia University

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 16

Duration: 18 months

326 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are using medications for diabetes or those that might cause cognitive impairment. It's best to discuss your specific medications with the study team.

What evidence supports the effectiveness of the drug Metformin for Alzheimer's disease?

Research suggests that Metformin, a drug commonly used to treat diabetes, may help improve memory and thinking skills in people with mild cognitive impairment, a condition that can lead to Alzheimer's disease. A study showed that participants taking Metformin had better recall in memory tests compared to those who did not take the drug. ^{1 2 3 4 5}

Is metformin generally safe for humans?

Metformin is generally safe for humans, with no serious adverse events reported in a study involving participants with mild cognitive impairment. However, some people may experience gastrointestinal symptoms, and a small percentage may not tolerate the medication. ^{1 2 3 5 6}

How does the drug metformin differ from other treatments for Alzheimer's disease?

Metformin is unique in Alzheimer's treatment because it is primarily an antidiabetic drug that may help by reducing insulin resistance and inflammation, which are linked to Alzheimer's. Unlike other Alzheimer's treatments, metformin's potential benefits are being explored due to its effects on diabetes-related pathways that might influence brain health. ^{1 2 3 5 7}

Research Team

José A Luchsinger, MD

Principal Investigator

Columbia University

Eligibility Criteria

This trial is for men and women aged 55-90 with early or late mild cognitive impairment (MCI), specifically those who have memory concerns but not a diagnosis of Alzheimer's. Participants must not have diabetes, be overweight or obese, and able to attend study visits or available by phone. They should also have sufficient vision and hearing for tests.

Inclusion Criteria

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.

My education level is between 8-15 years.

My education level is between 0-7 years and my score is between 3-6.

Exclusion Criteria

You cannot participate in the study if you have a low body mass index, kidney disease with an estimated glomerular filtration rate of less than 45 mL/min, liver disease other than non-fatty liver disease or class III or IV congestive heart failure, moderate to severe depression, dementia, or a history of intolerance to metformin. You also cannot participate if you have had a cerebrovascular accident with residual neurological deficits, neurologic diseases associated with neurological deficits, active cancer or a history of cancer in the last two years (except for certain types of skin cancer), uncontrolled hypertension, or are planning to move to another city or state within the next 24 months. Additionally, you cannot participate if you have a known history of diabetes or if it is discovered during screening using HbA1c criteria. You also cannot participate if you are taking certain medications or treatments, such as aducanumab or amyloid modifying treatments for Alzheimer's disease, or if you are pregnant or planning to become pregnant. Finally, you cannot participate if you are unable to undergo phlebotomy.

Have you noticed changes in your memory?

I have never been diagnosed with Alzheimer's disease.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Telephone pre-screening and in-person screening

Titration

Participants undergo a 30-day titration period where the metformin/placebo dose is increased from 500 mg a day to a maximum of 2,000 mg a day

4 weeks

In-person visits every 10 days

Treatment

Participants receive the study medication or placebo for 18 months with regular assessments

18 months

Baseline, 6-month, 12-month, and 18-month visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 month

Follow-up brain MRI and PET scans for participants who had baseline imaging

Treatment Details

Interventions

• Metformin

Trial Overview The MAP trial is testing extended-release metformin against a placebo in individuals without diabetes who are at risk for Alzheimer's. Over 18 months, participants will take increasing doses of the drug/placebo while undergoing neuropsychological tests, physical exams, brain scans, and bloodwork to monitor changes in memory function.

Participant Groups

Group I: metformin users Experimental Treatment 1 Intervention

Extended release metformin 500 mg tablets up to 2,000 mg (4 tablets) a day once at night. The maximum dose will be attempted during a titration period in the first month of the study.

Group II: metformin non-users Placebo Group 1 Intervention

Placebo tablets identical to extended release metformin 500 mg tablets up to 4 tablets a day once at night. The maximum dose will be attempted during a titration period in the first month of the study.

Metformin is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Glucophage for:

• Type 2 diabetes

Approved in United States as Glucophage for:

• Type 2 diabetes

Approved in Canada as Glucophage for:

• Type 2 diabetes

Approved in Japan as Glucophage for:

• Type 2 diabetes

Approved in China as Glucophage for:

• Type 2 diabetes

Approved in Switzerland as Glucophage for:

• Type 2 diabetes

Who Is Running the Clinical Trial?

Columbia University

Lead Sponsor

Trials

1,529

Recruited

2,832,000+

University of Rochester

Collaborator

Trials

883

Recruited

555,000+

Georgetown University

Collaborator

Trials

355

Recruited

142,000+

Emory University

Collaborator

Trials

1,735

Recruited

2,605,000+

NYU Langone Health

Collaborator

Trials

1,431

Recruited

838,000+

University of Washington

Collaborator

Trials

1,858

Recruited

2,023,000+

Cornell University

Collaborator

Trials

179

Recruited

14,090,000+

University of Texas Southwestern Medical Center

Collaborator

Trials

1,102

Recruited

1,077,000+

University at Buffalo

Collaborator

Trials

139

Recruited

105,000+

University of Cincinnati

Collaborator

Trials

442

Recruited

639,000+

References

1. Australia pubmed.ncbi.nlm.nih.gov

Metformin and Alzheimer's disease, dementia and cognitive impairment: a systematic review protocol. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Antidiabetic Drugs for the Risk of Alzheimer Disease in Patients With Type 2 DM Using FAERS. [2020]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Antidiabetic Drugs in the Treatment of Alzheimer's Disease. [2023]

5. France pubmed.ncbi.nlm.nih.gov

Diabetes: Risk factor and translational therapeutic implications for Alzheimer's disease. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Metformin, other antidiabetic drugs, and risk of Alzheimer's disease: a population-based case-control study. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: study protocol for a randomised controlled trial (ELAD study). [2022]