Metformin in Amnestic Mild Cognitive Impairment

NCT00620191 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: AAAC7231R01AG026413270901
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

Hyperinsulinemia and type 2 diabetes (T2D) are important potential risk factors for cognitive decline and Alzheimer's disease (AD). Two thirds of the US adult population are at risk for hyperinsulinemia and T2D, and half of the population 85 years and older have AD. Peripheral hyperinsulinemia can impair the clearance of amyloid beta in the brain, the main culprit in AD. Thus, the investigators hypothesize that lowering peripheral insulin in overweight persons with amnestic mild cognitive impairment (AMCI), a transition state between normal cognition and AD, can decrease the risk of cognitive decline and progression to AD. The investigators propose to conduct a phase II double blinded placebo controlled randomized clinical trial of metformin, a safe and effective medication that prevents hyperinsulinemia and diabetes, to test this hypothesis among 80 overweight persons aged 55 to 90 years with AMCI. The main outcome of the study will be changes in performance in a memory test (total recall of the Selective Reminding Test) and the Score a test of general cognitive function used in clinical trials (the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog)). Another aim is to compare brain function in an area affected by Alzheimer's disease between the metformin and placebo group mean changes from beginning to end among 40 participants using a PET scan.

Conditions

Mild Cognitive Impairment

Keywords

Metformin; Mild Cognitive Impairment (MCI); Alzheimer's Disease (AD); Overweight; Insulin

Outcome Measures

Primary Outcomes (2)

• Change in Total Recall Score in the Selective Reminding Test

  The Selective Reminding Test measures verbal learning and delayed recall through a multiple-trial list-learning paradigm. Patients are presented aurally with a list of 12 words for trial 1 and are asked to recall as many as possible. For trials 2-6, there is a selective presentation of only those words not recalled on the previous trial. Trial 7 is similar to the other trials but is assessed after an 11-minute delay. The score for the selective reminding test is the unweighted average of seven individual study results (min=0 and max=84) Higher scores indicate a better cognitive performance. The total recall score from the first visit was subtracted from that of the last visit to calculate the change in score (total words recalled).

  12 months

• Change in Score of the Alzheimer's Disease Assessment Scale-cognitive Subscale (ADAS-cog)

  The ADAS-cog is an aggregate for several cognitive tests intended to provide a global cognitive score and consists of 11 tasks. The tasks (and corresponding score range)) are Word Recall (0-10), Naming (0-4), Commands (0-5), Constructional Praxis (0-5) Ideational Praxis (0-5), Orientation (0-8), Word Recognition (0-12), Language (0-5), Word Finding Difficulty (0-5), and Remembering Test Instructions (1-5). The range of aggregate scores (sum of scores) is 1 to 69, with higher scores meaning worse cognitive performance. The change was calculated subtracting the baseline score from the final visit score.

  12 months

Secondary Outcomes (1)

• Change in Relative Glucose Uptake (rCMRg) in the Posterior Cingulate-precuneus.

  12 months

Other Outcomes (1)

• Change in Plasma Amyloid Beta-42

  12 months

Study Arms (2)

Matching Placebo

PLACEBO COMPARATOR

Placebo identical to metformin

Drug: Placebo

Metformin

EXPERIMENTAL

Metformin 1000 mg twice a day

Drug: Metformin

Interventions

Metformin DRUG

Metformin 1000 mg twice a day titrated from 500 mg once a day

Also known as: Glucophage

Metformin

Placebo DRUG

Placebo identical to metformin 2 tablets twice a day titrated from one table once a day

Matching Placebo

Eligibility Criteria

• Age: 55 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Memory complaint expressed by the participant and recognized by the informant. The memory complaint must represent a change from previous functioning based on information provided by both subject and informant.
• Fluent in English or Spanish.
• Mini-Mental State Examination (MMSE) equal or more than 20.
• Subjects must fulfill criteria for amnestic mild cognitive impairment (MCI). Guidelines for the diagnosis of MCI: Subjects must score below a predetermined cut-off score on the logical memory II delayed paragraph recall sub-test of the Wechsler Memory Scale Revised (WMS-R) or the selective reminding test (SRT).
• Global Clinical Dementia Rating (CDR) score must be 0.5 at screening.
• Subjects without a known history of diabetes or diabetes that has never been treated with medications. If diabetes is diagnosed during screening or they have a history of diabetes not treated in the last 12 months they will be excluded if their Hemoglobin A1c (HbA1c) is \> 6.5. In addition, a diagnosis of diabetes can be made if the HbA1c is 6.5% or more.
• Overweight or obese by National Heart, Lung, and Blood Institute (NHLBI) criteria (Body Mass Index (BMI) of more or equal of 25 kg/ m2).
• No contraindications to metformin treatment.
• Hachinski score less or equal to 4.
• Hamilton score less or equal to 12 on the 17 item scale.
• General cognition and functional performance such that a diagnosis of dementia cannot be made at the time of screening based on DSM-IV criteria.
• Vision and hearing must be sufficient for compliance with testing procedures.

You may not qualify if:

• Individuals with dementia
• MMSE \< 20
• Subjects with neurologic diseases associated to neurologic deficits.
• Subjects with current psychiatric diagnoses such as depression, bipolar disorder or schizophrenia.
• Subjects with uncontrolled hypertension (systolic blood pressure more than 160 mmHg or diastolic blood pressure more than 95 mmHg.
• Subjects with a history of active cancer or cancer within last five years, with the exception of squamous or basal cell carcinoma of the skin.
• Subjects who for any reason may not complete the study as judged by the study physician.
• Subjects with a known history of diabetes treated with medications.
• Subjects with a new or old diagnosis of diabetes, never treated, with a HbA1c of more than 6.5 .
• Contraindications to metformin: Contraindications to metformin use include a creatinine of \> 1.5, liver disease by history or by elevated transaminases, congestive heart failure, and alcohol abuse.
• Use of cholinesterase inhibitors.
• Presence of diabetes, even if the HbA1c is less or equal to 6.5.
• Inability to lie down for any reason.
• Presence of any metallic implant.
• Claustrophobia.

Sponsors & Collaborators

• Columbia University: lead
• Institute for the Study of Aging (ISOA): collaborator
• National Institute on Aging (NIA): collaborator

Study Sites (1)

Columbia University Medical Center

New York, New York, 10032, United States

Location

Related Publications (1)

• Luchsinger JA, Perez T, Chang H, Mehta P, Steffener J, Pradabhan G, Ichise M, Manly J, Devanand DP, Bagiella E. Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial. J Alzheimers Dis. 2016;51(2):501-14. doi: 10.3233/JAD-150493.

  PMID: 26890736 RESULT

MeSH Terms

Conditions

Cognitive Dysfunction; Alzheimer Disease; Overweight; Insulin Resistance

Interventions

Metformin

Condition Hierarchy (Ancestors)

Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Limitations and Caveats

The pilot study had a small sample size and relatively short duration, both for the whole sample, and the imaging sub-sample

Results Point of Contact

• Title: Jose Luchsinger
• Organization: Columbia University Medical Center

jal94@cumc.columbia.edu

212-3054730

Study Officials

• Jose A Luchsinger, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine and Epidemiology at NYPH/CUMC

Study Record Dates

• First Submitted: February 7, 2008
• First Posted: February 21, 2008
• Study Start: June 1, 2008
• Primary Completion: February 1, 2012
• Study Completion: February 1, 2012
• Last Updated: October 23, 2020
• Results First Posted: October 23, 2020

Record last verified: 2020-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)