Trial Outcomes & Findings for Metformin Effect on Brain Function in Insulin Resistant Elderly People (NCT NCT03733132)

NCT ID: NCT03733132

Last Updated: 2024-06-18

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 40 participants
• Primary outcome timeframe: Baseline, 10 months
• Results posted on: 2024-06-18

Participant Flow

Participant milestones

Measure	Placebo Participants in the placebo group received Placebo Oral Tablets identical to the metformin tablets for 10 months. Placebo Oral Tablet: Placebo treatment of identical tablets to metformin group	Metformin Participants in Metformin group received an escalating dose of Metformin hydrochloride tablets up to a dose of 2500mg for 10 months. Metformin Hydrochloride: Metformin treatment of 2500mg for 10 months in the Metformin group
Overall Study STARTED	20	20
Overall Study COMPLETED	20	20
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Metformin Effect on Brain Function in Insulin Resistant Elderly People

Baseline characteristics by cohort

Measure	Placebo n=20 Participants Participants in the placebo group received Placebo Oral Tablets identical to the metformin tablets for 10 months. Placebo Oral Tablet: Placebo treatment of identical tablets to metformin group	Metformin n=20 Participants Participants in Metformin group received an escalating dose of Metformin hydrochloride tablets up to a dose of 2500mg for 10 months. Metformin Hydrochloride: Metformin treatment of 2500mg for 10 months in the Metformin group	Total n=40 Participants Total of all reporting groups
Age, Continuous	67.006 years STANDARD_DEVIATION 4.083 • n=5 Participants	67.584 years STANDARD_DEVIATION 5.375 • n=7 Participants	67.295 years STANDARD_DEVIATION 4.720 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants	13 Participants n=7 Participants	21 Participants n=5 Participants
Sex: Female, Male Male	12 Participants n=5 Participants	7 Participants n=7 Participants	19 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	18 Participants n=5 Participants	20 Participants n=7 Participants	38 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) White	19 Participants n=5 Participants	20 Participants n=7 Participants	39 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	20 participants n=5 Participants	20 participants n=7 Participants	40 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, 10 months

Population: If PCr, γ-ATP, α-ATP, or β-ATP signals were indiscernible from the background noise after processing then those spectra were discarded. Spectra processing was performed by one person, and processing steps were checked for fidelity by a second person. Twelve patients in the placebo group and 15 in the metformin group meet quality control criteria for both the pre- and post-scans.

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.

Outcome measures

Measure	Placebo n=12 Participants Participants in the placebo group received Placebo Oral Tablets identical to the metformin tablets for 10 months. Placebo Oral Tablet: Placebo treatment of identical tablets to metformin group	Metformin n=15 Participants Participants in Metformin group received an escalating dose of Metformin hydrochloride tablets up to a dose of 2500mg for 10 months. Metformin Hydrochloride: Metformin treatment of 2500mg for 10 months in the Metformin group
Change From Baseline in Brain PCr/ATP Ratio as Measured by Phosphorus Magnetic Spectroscopy (31P-MRS) After 10 Months of Metformin Administration	-0.045 PCr/ATP ratio Standard Deviation 0.258	-0.016 PCr/ATP ratio Standard Deviation 0.483

PRIMARY outcome

Timeframe: Baseline, 10 months

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

Outcome measures

Measure	Placebo n=20 Participants Participants in the placebo group received Placebo Oral Tablets identical to the metformin tablets for 10 months. Placebo Oral Tablet: Placebo treatment of identical tablets to metformin group	Metformin n=20 Participants Participants in Metformin group received an escalating dose of Metformin hydrochloride tablets up to a dose of 2500mg for 10 months. Metformin Hydrochloride: Metformin treatment of 2500mg for 10 months in the Metformin group
Change From Baseline in Cognitive Function as Measured by NIH Toolbox After 10 Months of Metformin Administration	1.450 t-score Standard Deviation 4.968	2.900 t-score Standard Deviation 5.543

SECONDARY outcome

Timeframe: Baseline, 10 months

Population: One participant in each group was not able to be analyzed due to lack of sufficent scan quality.

AA sagittal 3D MPRAGE sequence with 0.7mm isotropic voxels (TR=2400, TE=2.57, TI=1100, FA=8) will be used to acquire high-resolution structural data for volumetric analysis of brain region changes related to metformin. To measure white matter information: 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.

Outcome measures

Measure	Placebo n=19 Participants Participants in the placebo group received Placebo Oral Tablets identical to the metformin tablets for 10 months. Placebo Oral Tablet: Placebo treatment of identical tablets to metformin group	Metformin n=19 Participants Participants in Metformin group received an escalating dose of Metformin hydrochloride tablets up to a dose of 2500mg for 10 months. Metformin Hydrochloride: Metformin treatment of 2500mg for 10 months in the Metformin group
Change From Baseline in Brain Structure as Measured by MRI After 10 Months of Metformin Administration	-2255.098 mm cubed Standard Deviation 11757.866	1588.247 mm cubed Standard Deviation 30282.932

SECONDARY outcome

Timeframe: Baseline, 10 months

Population: 2 participants in each group were unable to be measured for mitochondrial respiration. 2 were due to instrumentation malfunction and 2 were due to inability to collect enough muscle tissue for mitochondrial isolation on one or both study dates.

High-resolution respirometry will be used to analyze oxygen consumption in isolated mitochondria from skeletal muscle biopsy samples while simultaneously quantifying reactive oxygen species (ROS) production using amplex red. An increase in mitochondrial respiration is indicative of increased mitochondrial function which is a positive outcome.

Outcome measures

Measure	Placebo n=18 Participants Participants in the placebo group received Placebo Oral Tablets identical to the metformin tablets for 10 months. Placebo Oral Tablet: Placebo treatment of identical tablets to metformin group	Metformin n=18 Participants Participants in Metformin group received an escalating dose of Metformin hydrochloride tablets up to a dose of 2500mg for 10 months. Metformin Hydrochloride: Metformin treatment of 2500mg for 10 months in the Metformin group
Change From Baseline in Muscle Mitochondrial Respiration as Measured by High-resolution Respirometry Following 10 Months of Metformin Administration	-0.106 pmol/sec/mL/mg tissue mass Standard Deviation 2.752	-0.926 pmol/sec/mL/mg tissue mass Standard Deviation 2.674

SECONDARY outcome

Timeframe: Baseline, 10 months

Population: 5 participants in the placebo group and 6 in the metfomin group were unable to be analyzed. One in each group was due to the inability to collect enough muscle for mitochondrial isolation and the remainder were due to an equipment breakdown (power source - had to be externally source and repaired via service technician) that rendered the equipment unusable for multiple study days.

Concurrent to mitochondrial respiration, muscle mitochondrial ATP production will be measured using high-sensitivity fluorometry. An increase in mitochondrial ATP production shows increase mitochondrial efficiency which is a positive outcome.

Outcome measures

Measure	Placebo n=15 Participants Participants in the placebo group received Placebo Oral Tablets identical to the metformin tablets for 10 months. Placebo Oral Tablet: Placebo treatment of identical tablets to metformin group	Metformin n=14 Participants Participants in Metformin group received an escalating dose of Metformin hydrochloride tablets up to a dose of 2500mg for 10 months. Metformin Hydrochloride: Metformin treatment of 2500mg for 10 months in the Metformin group
Change From Baseline in Muscle Mitochondrial ATP Production as Measured by Fluorometry Following 10 Months of Metformin Administration	5.760 pmol/sec/ug mitochondrial protein Standard Deviation 13.218	8.899 pmol/sec/ug mitochondrial protein Standard Deviation 26.430

Adverse Events

Placebo

Serious events: 1 serious events

Other events: 9 other events

Deaths: 0 deaths

Metformin

Serious events: 0 serious events

Other events: 12 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=20 participants at risk Participants in the placebo group received Placebo Oral Tablets identical to the metformin tablets for 10 months. Placebo Oral Tablet: Placebo treatment of identical tablets to metformin group	Metformin n=20 participants at risk Participants in Metformin group received an escalating dose of Metformin hydrochloride tablets up to a dose of 2500mg for 10 months. Metformin Hydrochloride: Metformin treatment of 2500mg for 10 months in the Metformin group
Infections and infestations COVID-19 infection	5.0% 1/20 • Number of events 1 • 9 months	0.00% 0/20 • 9 months

Other adverse events

Measure	Placebo n=20 participants at risk Participants in the placebo group received Placebo Oral Tablets identical to the metformin tablets for 10 months. Placebo Oral Tablet: Placebo treatment of identical tablets to metformin group	Metformin n=20 participants at risk Participants in Metformin group received an escalating dose of Metformin hydrochloride tablets up to a dose of 2500mg for 10 months. Metformin Hydrochloride: Metformin treatment of 2500mg for 10 months in the Metformin group
Infections and infestations Infections and infestations: Other	5.0% 1/20 • Number of events 1 • 9 months	0.00% 0/20 • 9 months
General disorders Pain	0.00% 0/20 • 9 months	5.0% 1/20 • Number of events 1 • 9 months
Gastrointestinal disorders Gastroesophageal reflux disease	0.00% 0/20 • 9 months	10.0% 2/20 • Number of events 2 • 9 months
Gastrointestinal disorders Diarrhea	25.0% 5/20 • Number of events 7 • 9 months	35.0% 7/20 • Number of events 8 • 9 months
Social circumstances Social circumstances	0.00% 0/20 • 9 months	5.0% 1/20 • Number of events 1 • 9 months
Eye disorders Eye disorders	5.0% 1/20 • Number of events 1 • 9 months	0.00% 0/20 • 9 months
Infections and infestations COVID-19 Infection	10.0% 2/20 • Number of events 2 • 9 months	5.0% 1/20 • Number of events 1 • 9 months
General disorders Nausea	0.00% 0/20 • 9 months	10.0% 2/20 • Number of events 2 • 9 months
Gastrointestinal disorders Vomiting	0.00% 0/20 • 9 months	5.0% 1/20 • Number of events 1 • 9 months
General disorders Headache	0.00% 0/20 • 9 months	5.0% 1/20 • Number of events 1 • 9 months
Vascular disorders Stroke	0.00% 0/20 • 9 months	5.0% 1/20 • Number of events 1 • 9 months
Vascular disorders Hypertension	0.00% 0/20 • 9 months	5.0% 1/20 • Number of events 1 • 9 months
Injury, poisoning and procedural complications Fall	0.00% 0/20 • 9 months	5.0% 1/20 • Number of events 1 • 9 months
Blood and lymphatic system disorders Anemia	0.00% 0/20 • 9 months	10.0% 2/20 • Number of events 2 • 9 months
General disorders Weight loss	0.00% 0/20 • 9 months	5.0% 1/20 • Number of events 1 • 9 months
Gastrointestinal disorders Flatulence	0.00% 0/20 • 9 months	5.0% 1/20 • Number of events 1 • 9 months
Hepatobiliary disorders Hepatobiliary disorders	0.00% 0/20 • 9 months	5.0% 1/20 • Number of events 1 • 9 months

Additional Information

K Sreekumaran Nair, M.D., Ph.D.

Mayo Clinic

Phone: 507-255-2415

Email: Nair@mayo.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place