Metformin Effect on Brain Function in Insulin Resistant Elderly People

NCT03733132 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 18-0040121R21AG060139-01
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

Alzheimer's disease (AD) and other forms of dementia are rapidly increasing with the aging of the population, and show a clear preponderance among people with insulin resistance. Metformin, an insulin sensitizer, is being examined in clinical trials as an anti-aging drug. However, very little objective data is available regarding metformin's effect on the brain, a major organ affected by aging.

Conditions

Insulin Resistance; Obesity; Obesity, Abdominal

Keywords

Insulin Resistance; Cognition; Cognitive Impairment; Brain Function

Outcome Measures

Primary Outcomes (2)

• Change From Baseline in Brain PCr/ATP Ratio as Measured by Phosphorus Magnetic Spectroscopy (31P-MRS) After 10 Months of Metformin Administration

  Multivoxel spectroscopic imaging of the brain will be performed using our dual-tuned single-channel-proton eight-channel-phosphorus head coil. A single 2.5 cm thick slice will be prescribed to encompass the temporal and occipital lobes, and weighted MRSI will be performed using a 16x16 matrix to acquire nominal 2.5 cm3 voxels. Multivoxel phosphorus magnetic resonance spectroscopic imaging data were reconstructed and quantified using jMRUI 6.0. Spectra were preprocessed by (a) truncating the data to 768 points, then 0-filling to 1024 points; (b) apodizing with a 5 Hz Lorenzian; and (c) aligning the data such that the PCr peak was set to 0 Hz. Next, 2 voxels from occipital lobe were selected, extracted, and averaged together into a single free induction decay in order to reduce noise. The outcome measure PCr/ATP ratio is a marker of ATP resynthesis potential and is reported as a change from pre- to post-treatment.

  Baseline, 10 months

• Change From Baseline in Cognitive Function as Measured by NIH Toolbox After 10 Months of Metformin Administration

  The NIH Toolbox will be utilized to measure cognitive outcomes. The NIH Toolbox-Cognition Battery is composed of 7 tests (\~30 minutes) and our primary outcome measure will be the Total Cognition Composite score comprised from these 7 tests. Results are presented as a fully-adjusted T-score. For a single timepoint, T-scores are expected to have a population mean of 50, standard deviation of 10. For a single timepoint, higher T-scores indicate better cognitive test performance. An increase in T-score over time is considered a better outcome. At the individual level, a T-score \< 40 is considered low test performance. There were no clear clinically relevant thresholds for a change in T-score over 10 months at the start of this study. Comparison of the mean change in T-score over time in the Metformin treatment group to placebo is our analysis of interest

  Baseline, 10 months

Secondary Outcomes (3)

• Change From Baseline in Brain Structure as Measured by MRI After 10 Months of Metformin Administration

  Baseline, 10 months

• Change From Baseline in Muscle Mitochondrial Respiration as Measured by High-resolution Respirometry Following 10 Months of Metformin Administration

  Baseline, 10 months

• Change From Baseline in Muscle Mitochondrial ATP Production as Measured by Fluorometry Following 10 Months of Metformin Administration

  Baseline, 10 months

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Participants in placebo group will receive Placebo Oral Tablets identical to the metformin tablets for 10 months.

Drug: Placebo Oral Tablet

Metformin

ACTIVE COMPARATOR

Participants in placebo group will receive an escalating dose of Metformin hydrochloride tablets up to a dose of 2500mg for 10 months.

Drug: Metformin Hydrochloride

Interventions

Metformin Hydrochloride DRUG

Metformin treatment of 2500mg for 10 months in the Metformin group

Also known as: Metformin

Metformin

Placebo Oral Tablet DRUG

Placebo treatment of identical tablets to metformin group

Also known as: Placebo

Placebo

Eligibility Criteria

• Age: 65 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Older Adult (65+)

You may qualify if:

• Age \>/= 65 years
• Abdominal girth \> 102 cm in men and \> 88 cm in women-
• Fasting glucose \>/= 100-140 mg/dL
• Non-smoker
• English language proficiency

You may not qualify if:

• Coronary artery disease or heart failure
• A known medical condition that in the judgment of the investigator might interfere with the completion of the protocol such as the following examples:
• Inpatient psychiatric treatment in the past 6 months
• Presence of a known adrenal disorder
• Abnormal liver function test results (Transaminase \>2 times the upper limit of normal); testing required for subjects taking medications known to affect liver function or with diseases known to affect liver function
• Abnormal renal function tests results (calculated GFR \<60 mL/min/1.73m2); testing required for subjects with diabetes duration of greater than 5 years post onset of puberty
• Active gastroparesis
• If on antihypertensive, thyroid, anti-depressant or lipid lowering medication, lack of stability on the medication for the past 2 months prior to enrollment in the study
• Uncontrolled thyroid disease (TSH undetectable or \>10 mlU/L): testing required within here months prior to admission for subjects with a goiter, positive antibodies, or who are on thyroid hormone replacement, and within one year otherwise
• Abuse of alcohol or recreational drugs
• Infectious process not anticipated to resolve prior to study procedures (e.g. meningitis, pneumonia, osteomyelitis)
• Uncontrolled arterial hypertension (Resting diastolic blood pressure \>90 mmHg and/or systolic blood pressure \>160 mmHg) at the time of screening
• Oral steroids
• A recent injury to body or limb, muscular disorder, use of any medication, any carcinogenic disease, or other significant medical disorder if that injury, medication or disease in the judgment of the investigator will affect the completion of the protocol
• Any metal in the body that could interfere with magnetic resonance imaging (MRI) including pacemaker or implanted defibrillator, neurostimulators, ear implants, metal fragments within the body, metal joints, rods, pins, plates or screws

Sponsors & Collaborators

• Mayo Clinic: lead
• National Institute on Aging (NIA): collaborator

Study Sites (1)

Mayo Clinic in Rochester

Rochester, Minnesota, 55905, United States

Location

Related Links

• Mayo Clinic Clinical Trials

MeSH Terms

Conditions

Insulin Resistance; Obesity; Obesity, Abdominal; Cognitive Dysfunction

Interventions

Metformin

Condition Hierarchy (Ancestors)

Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Cognition Disorders; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Results Point of Contact

• Title: K Sreekumaran Nair, M.D., Ph.D.
• Organization: Mayo Clinic

Nair@mayo.edu

507-255-2415

Study Officials

• K Sreekumaran Nair, M.D., Ph.D.

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Study will be a double-blind, placebo-controlled, randomized design.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine and Consultant in Endocrinology and Metabolism

Study Record Dates

• First Submitted: October 16, 2018
• First Posted: November 7, 2018
• Study Start: March 15, 2019
• Primary Completion: April 5, 2023
• Study Completion: April 5, 2023
• Last Updated: June 18, 2024
• Results First Posted: June 18, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)