Metformin Effect on Brain Function in Insulin Resistant Elderly People

• ClinicalTrials.gov Identifier: NCT03733132
• Recruitment Status: Active, not recruiting
• First Posted: November 7, 2018
• Last Update Posted: December 8, 2022
• Sponsor: Mayo Clinic
• Collaborator: National Institute on Aging (NIA)
• Information provided by (Responsible Party): K. Sreekumaran Nair, Mayo Clinic

Tracking Information

• First Submitted Date: October 16, 2018
• First Posted Date: November 7, 2018
• Last Update Posted Date: December 8, 2022
• Actual Study Start Date: March 15, 2019
• Estimated Primary Completion Date: April 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 6, 2018)

Change from baseline in brain ATP production as measured by phosphorus Magnetic Spectroscopy (31P-MRS) after 10 months of metformin administration [ Time Frame: Baseline, 10 months ]

Multivoxel chemical shift imaging (dual-tuned proton (Helmholtz pair)/phosphorus (loop) flex coil will be applied such that the phosphorus loop overlies the right DLPFC, WIP 1071, axial 1.5 cm slice prescribed to encompass the right dorsolateral prefrontal cortex, 12x12 matrix reconstructed to 16x16 matrix, 1.5 cm nominal isotropic voxels, TR=1500) will be used to acquire phosphorus metabolite information from the right DLPFC

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 6, 2018)

• Change from baseline in brain structure as measured by functional MRI (fMRI) after 10 months of metformin administration [ Time Frame: Baseline, 10 months ]
  An axial 2D symmetric multi-slice (SMS) diffusion tensor imaging (DTI) sequence with 60 diffusion directions, 5 B0 acquisitions and 2mm isotropic voxels (TR=3000, TE=73, FA=90, ETL 43, both A-P and P-A phase encoding for B0 images) will be used to acquire white matter integrity data related to metformin.
• Change from baseline in cognitive function as measured by NIH Toolbox Cognitive Battery after 10 months of metformin administration [ Time Frame: Baseline, 10 months ]
• Change from baseline in muscle mitochondrial respiration as measured by oximetry. [ Time Frame: Baseline, 10 months ]
  Oxygen flux in isolated muscle mitochondria will be measured using a titrated substrate protocol on an Oroboros oximetry instrument.
• Change from baseline in brain blood flow as measured by functional MRI after 10 months of metformin administration [ Time Frame: Baseline, 10 months ]
  To measure global brain blood flow information: An axial 3D pseudo-continuous arterial spin labelling (pCASL) sequence (WIP 818) with 4mm isotropic voxels (TI1=1800, TI2=3600, iPat ≤ 2) will be used to acquire quantitative blood flow measurements (flow in ml/100g/min) throughout the brain.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Metformin Effect on Brain Function in Insulin Resistant Elderly People
• Official Title: Metformin Effect on Brain Function in Insulin Resistant Elderly People
• 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.

Detailed Description

Insulin resistance is highly prevalent with advancing age. Metformin is an insulin sensitizer and is currently being extensively investigated for its potential anti-aging effect. However, only very limited information is available on metformin effect on brain, which is a major organ affected by aging. With appropriate experimental design, the investigators are attempting to understand the mechanism of metformin treatment on the physiology of the brain as well as cognitive effects. These studies may uncover relationships that could be favorably manipulated to decrease health risks associated with insulin sensitivity and the effect on the brain.

The study results may lead to a breakthrough in providing either definitive data or sufficiently strong preliminary data regarding metformin's effect on elderly people with insulin resistance, on whether the drug enhances brain mitochondrial function in conjunction with improvement of brain functional network and cognitive function.

The overall hypothesis is that metformin administration to elderly people with insulin resistance enhances brain mitochondrial function in conjunction with improvement of brain function. To test this hypothesis, the investigators will address the following Specific Aims:

1. Determine whether 40 weeks of metformin administration in elderly people (> 65 years) with insulin resistance enhances brain mitochondrial ATP production. The investigators will measure brain ATP production by 31P-MRS.
2. Determine the effect of 40 weeks of metformin administration in elderly people (> 65 years) with insulin resistance on blood flow and functional network in different areas of brain. As a secondary outcome, the investigators will measure structural changes in white and grey matter areas of brain to determine whether metformin has any effect on brain structure.
3. Determine the effect of 40 weeks of metformin administration in elderly people (> 65 years) with insulin resistance on cognitive function. The investigators will utilize the computerized NIH Toolbox to measure cognitive outcomes.

The investigators will also associate outcomes from our specific aims with improvements in whole-body insulin sensitivity and skeletal muscle mitochondrial function.

The investigators propose to complete 40 weeks of study in 40 elderly (> 65 years) participants with fasting glucose between 100 to 140 mg/dl and abdominal girth of >102 cm in men and > 88 cm in women. All participants will be those who are not oral hypoglycemic agents including metformin. In this double-blind placebo trial, the investigators will randomly assign the participants to placebo or metformin in an escalated dose to reach a maximum of 2500 mg per day.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Study will be a double-blind, placebo-controlled, randomized design.

Primary Purpose: Basic Science

Condition

• Insulin Resistance
• Obesity
• Obesity, Abdominal

Intervention

• Drug: Metformin Hydrochloride
  Metformin treatment of 2500mg for 10 months in the Metformin group
  Other Name: Metformin
• Drug: Placebo Oral Tablet
  Placebo treatment of identical tablets to metformin group
  Other Name: Placebo

Study Arms

• Placebo Comparator: Placebo
  Participants in placebo group will receive Placebo Oral Tablets identical to the metformin tablets for 10 months.
  Intervention: Drug: Placebo Oral Tablet
• Active Comparator: Metformin
  Participants in placebo group will receive an escalating dose of Metformin hydrochloride tablets up to a dose of 2500mg for 10 months.
  Intervention: Drug: Metformin Hydrochloride

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: December 7, 2021): 60
• Original Estimated Enrollment (submitted: November 6, 2018): 40
• Estimated Study Completion Date: June 2023
• Estimated Primary Completion Date: April 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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
• Medications that may impact study end points such as mitochondrial biology eg. beta blockers
• Anti-hyperglycemic drugs including metformin
• Any other medication that the investigator believes is a contraindication to the subject's participation

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 65 Years and older (Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03733132
• Other Study ID Numbers: 18-004012; 1R21AG060139-01 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: K. Sreekumaran Nair, Mayo Clinic
• Original Responsible Party: Same as current
• Current Study Sponsor: Mayo Clinic
• Original Study Sponsor: Same as current
• Collaborators: National Institute on Aging (NIA)

Investigators

• Principal Investigator: K Sreekumaran Nair, M.D., Ph.D.; Mayo Clinic

• PRS Account: Mayo Clinic
• Verification Date: December 2022