A Phase 1/2 interventional study of MetFORMIN Hydrochloride ER and Placebo in Inflammatory Response, sponsored by Brian Zuckerbraun. Completed at 1 site in United States. Open to participants aged 55 Years to 85 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2023-01-11.
Sponsored by Brian Zuckerbraun · Phase 1/2, Interventional, and Basic science
Metformin has a well-established safety profile and it has become clear that metformin has additional salutary effects, including anti-inflammatory, anti-aging, and anti-thrombotic properties. In this study, subjects will provide both venous blood samples and stool samples in addition to completing cognitive and physiologic testing at baseline, throughout a 90 day exposure to metformin, and 30 days following exposure to metformin in order to evaluate their immune, microbiome, cellular respiration, thrombotic, and inflammatory responses.
Metformin is considered first-line therapy for patients with type two diabetes with hyperglycemia that cannot be controlled with lifestyle alone. Unlike other oral medications, metformin is favored for its insulin-sensitizing effects resulting in improved glycemic control, weight loss, and overall improvement of metabolic syndrome. Over the past fifteen years, metformin has received significant attention for its other potential therapeutic uses. Metformin has been found to decrease the rate of age-related illness progression improving longevity, especially in the setting of cancer. Recent clinical trials across multiple disease states have shown metformin to decrease all-cause mortality in diabetic and non-diabetic patients. Additionally, in both animal models and human trails, metformin has been shown to decrease the risk of arterial and venous thrombosis without affecting bleeding time through its interaction with platelet mitochondria. Although the mechanisms by which metformin effects longevity is an active area of both basic science and clinical research, it clearly has anti-inflammatory properties which are both independent and dependent of glycemic control. Recently, surgical outcomes have focused on optimizing older, deconditioned patients prior to the operation with varying protocols referred to as prehabilitation. These programs work to improve the body's response to the surgical stress resulting in improved wound healing, decreased postoperative complications, and decreased hospital length of stay. The affect of metformin, like increasing physical activity, has widespread affects on physiology. The investigators, therefore, hypothesize that metformin administration to non-diabetic adults will improve clinical outcomes to physiologic stress by improving underlying immune and inflammatory responses, that can be deleterious.
Subjects will have venous samples collected to better understand the cellular response to inflammation, thrombosis, and cellular respiration at baseline, at 4 time points throughout the 90 day exposure to metformin, and 30 days following the completion of exposure to metformin. At the same time points, subjects will have stool samples collected in order to assess changes in their microbiome. Finally, subjects will undergo cognitive testing through the NIH toolbox as well as physiologic testing including (six-minute walk test, grip strength as measured by a dynamometer, and a short physical performance battery) at baseline, after 90 days of exposure, and again 30 days after the completion of exposure.
This is the only study on the registry with Brian Zuckerbraun as lead sponsor.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.
Drug: MetFORMIN Hydrochloride ER
Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days.
Drug: MetFORMIN Hydrochloride ER
Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.
Drug: MetFORMIN Hydrochloride ER
Subjects will be exposed to placebo for up to 90 days.
Drug: Placebo
Subjects will be exposed to 500mg, 1000mg, or 1500mg of daily ER Metformin, by mouth, for up to 90 days. Subjects will have their venous blood sampled and baseline, throughout the trial, and following completion of their metformin exposure.
Also known as: Metformin ER
Subjects will be exposed to placebo, by mouth, for up to 90 days. Subjects will have their venous blood sampled and baseline, throughout the trial, and following completion of their metformin exposure.
Ex Vivo Cytokine Response of Peripheral Blood Mononucleocytes (PBMC) to Inflammatory Stimuli Compared to Baseline, Throughout Exposure, and Following Exposure to Metformin.
Venous blood samples will be gathered throughout the study in order to quantify the changes in cytokine expression (FN-γ, IL-10, IL12p40, IL-12p70, IL-1α, IL1β, IL-2, IL-6, IL-8, IP-10, MCP-1, MIP-1α, MIP-1β, TNF-α) following ex vivo PBMC exposure to endotoxin.
Time frame: Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)
Quantify the Bacterial Population Profile of the Microbiome Via Stool Samples.
Bacterial communities using 16S rRNA sequencing in relationship to metformin dosing over time. Species richness or diversity in the sample is measured by Choa1 metric. Chao1 is an estimate of how many species are present in an ecosystem. In general, having more species is considered to be "healthier" and these values typically range from 100-200 for fecal samples. The Chao1 index over numerous samples across time are explored to understand treatment effects.
Time frame: Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)
Measure the Rate of Clotting of Peripheral Blood With Whole Blood Aggregometry in Response to Collagen.
Aggregometry area under the curve with the Y-axis being % aggregometry and the X-axis time in minutes.
Time frame: Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)
Measure the Rate of Thrombosis of Peripheral Blood.
The endpoints for isolated platelets include platelet activation as measured by FACS for CD62p.
Time frame: Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)
Changes From Baseline in Short Physical Performance Battery (SPPB) During and Following Exposure to Metformin.
The SPPB is a group of measures that combines the results of the gait speed, chair stand and balance tests. The minimum is zero (worse performance) and the maximum is 12 (best performance).
Time frame: Day 0 (baseline), 90, and 120 (30 days post metformin exposure)
Changes From Baseline in Grip Strength Via a Dynamometer During and Following Exposure to Metformin.
Grip strength over time.
Time frame: Day 0 (baseline), 90, and 120 (30 days post metformin exposure)
Mitochondrial Respiration in Both PBMCs and Platelets.
Oxidative phosphorylation, respiration, and complex activity will be tested using an Oroboros respirometer.
Time frame: Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)
Mitochondrial Content in Both PBMCs and Platelets.
Mitochondrial content will be measured by staining for mitotracker, and mitochondrial DNA oxidation will be determined by co-localizing staining for 8-hydroxydeoxyguanosine (8-OHdG). Markers of autophagy will be determined by measuring LC-3 flux, p62, beclin-1, and ATG7 protein levels.
Time frame: Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)
Measure Biogenesis of PBMCs.
Biogenesis will be determined by measuring RNA for PGC1a, NRF-1, and Tfam.
Time frame: Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)
| Milestone | 500mg Exposure | 1000mg Exposure | 1500mg Exposure | Placebo |
|---|---|---|---|---|
| Started | 8 | 8 | 8 | 8 |
| Completed | 7 | 8 | 8 | 8 |
| Not completed | 1 | 0 | 0 | 0 |
Venous blood samples will be gathered throughout the study in order to quantify the changes in cytokine expression (FN-γ, IL-10, IL12p40, IL-12p70, IL-1α, IL1β, IL-2, IL-6, IL-8, IP-10, MCP-1, MIP-1α, MIP-1β, TNF-α) following ex vivo PBMC exposure to endotoxin.
No measurements were reported for this outcome.
Bacterial communities using 16S rRNA sequencing in relationship to metformin dosing over time. Species richness or diversity in the sample is measured by Choa1 metric. Chao1 is an estimate of how many species are present in an ecosystem. In general, having more species is considered to be "healthier" and these values typically range from 100-200 for fecal samples. The Chao1 index over numerous samples across time are explored to understand treatment effects.
| Index | 500mg Exposure | 1000mg Exposure | 1500mg Exposure | Placebo |
|---|---|---|---|---|
| Day 0 | 136.5 ± 19.0 | 107.6 ± 13.3 | 128.1 ± 10.5 | 141.5 ± 15 |
| Day 30 | 139.9 ± 16.2 | 130.7 ± 19.4 | 128.1 ± 13.2 | 144.75 ± 13.2 |
| Day 60 | 121.4 ± 20.8 | 137.9 ± 17.7 | 128.6 ± 12.7 | 134.3 ± 9.8 |
| Day 90 | 137.8 ± 27.8 | 135 ± 18.9 | 138.2 ± 10.3 | 152 ± 20.5 |
| Day 120 | 134 ± 23.6 | 142.2 ± 17.3 | 144.2 ± 16.5 | 159.2 ± 5.7 |
Aggregometry area under the curve with the Y-axis being % aggregometry and the X-axis time in minutes.
| arbitrary units*mins | 500mg Exposure | 1000mg Exposure | 1500mg Exposure | Placebo |
|---|---|---|---|---|
| 0 days | 56.3 ± 40 | 67 ± 38 | 196 ± 376 | 83.3 ± 69 |
| 30 day change from day 0 | -34.7 ± 24.5 | 8.9 ± 50.1 | -166.7 ± 409 | -29.6 ± 104.8 |
| 60 days change from day 0 | -28.3 ± 54 | -23.5 ± 44.5 | -139.8 ± 376.3 | -49.4 ± 86.7 |
| 90 days change from day 0 | 1.6 ± 57.6 | 2.4 ± 84.5 | -222.5 ± 456.2 | -66.6 ± 102.6 |
| 120 days change from day 0 | -49.2 ± 84.2 | 1.0 ± 28.9 | -196.7 ± 410.6 | -47.6 ± 103.0 |
The endpoints for isolated platelets include platelet activation as measured by FACS for CD62p.
No measurements were reported for this outcome.
The SPPB is a group of measures that combines the results of the gait speed, chair stand and balance tests. The minimum is zero (worse performance) and the maximum is 12 (best performance).
| Units on a scale | 500mg Exposure | 1000mg Exposure | 1500mg Exposure | Placebo |
|---|---|---|---|---|
| 0d | 11.2 ± .9 | 10.8 ± 1.3 | 11.1 ± 0.9 | 10.6 ± 1.3 |
| 90d, change from 0d | -0.3 ± 1.4 | 0.4 ± 0.7 | 0.4 ± 0.5 | 1.0 ± 1.0 |
| 120d, change from 0d | 0 ± 0.6 | 0.2 ± 1.0 | 0.3 ± 1.3 | 0.5 ± .8 |
Grip strength over time.
| mmHg | 500mg Exposure | 1000mg Exposure | 1500mg Exposure | Placebo |
|---|---|---|---|---|
| 0 days | 28.2 ± 10.3 | 28.9 ± 8.3 | 25.7 ± 7.8 | 25.7 ± 9.2 |
| 90 days, compared to 0 days | -5.3 ± 12.5 | -0.4 ± 3.1 | -.2 ± 2.1 | -.3 ± 3.5 |
| 120 days, compared to 0 days | .1 ± 4.8 | 1.1 ± 2.7 | .3 ± 3.0 | -.6 ± 2.0 |
Oxidative phosphorylation, respiration, and complex activity will be tested using an Oroboros respirometer.
No measurements were reported for this outcome.
Mitochondrial content will be measured by staining for mitotracker, and mitochondrial DNA oxidation will be determined by co-localizing staining for 8-hydroxydeoxyguanosine (8-OHdG). Markers of autophagy will be determined by measuring LC-3 flux, p62, beclin-1, and ATG7 protein levels.
No measurements were reported for this outcome.
Biogenesis will be determined by measuring RNA for PGC1a, NRF-1, and Tfam.
No measurements were reported for this outcome.
Collected over Adverse events were monitored from the time of randomization for 120 days.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| 500mg Exposure | 0/8 (0%) | 0/8 (0%) | 5/8 (62.5%) |
| 1000mg Exposure | 0/8 (0%) | 0/8 (0%) | 3/8 (37.5%) |
| 1500mg Exposure | 0/8 (0%) | 0/8 (0%) | 6/8 (75%) |
| Placebo | 0/8 (0%) | 0/8 (0%) | 5/8 (62.5%) |
| Event | 500mg Exposure | 1000mg Exposure | 1500mg Exposure | Placebo |
|---|---|---|---|---|
| Gastrointestinal symptomsGastrointestinal disorders | 5/8 | 1/8 | 4/8 | 5/8 |
| Upper respiratory infectionRespiratory, thoracic and mediastinal disorders | 0/8 | 2/8 | 2/8 | 2/8 |
| Joint pain or fractureMusculoskeletal and connective tissue disorders | 2/8 | 0/8 | 2/8 | 2/8 |
| Age, Continuous(years) | 500mg Exposure | 1000mg Exposure | 1500mg Exposure | Placebo | Total |
|---|---|---|---|---|---|
| Mean | 68 ± 6 | 70 ± 6 | 71 ± 4 | 68 ± 6 | 70 ± 5.5 |
| Sex: Female, Male(Participants) | 500mg Exposure | 1000mg Exposure | 1500mg Exposure | Placebo | Total |
|---|---|---|---|---|---|
| Female | 5 | 3 | 4 | 5 | 17 |
| Male | 3 | 5 | 4 | 3 | 15 |
| Race (NIH/OMB)(Participants) | 500mg Exposure | 1000mg Exposure | 1500mg Exposure | Placebo | Total |
|---|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 | 0 |
| Black or African American | 1 | 1 | 1 | 0 | 3 |
| White | 7 | 7 | 7 | 8 | 29 |
| More than one race | 0 | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 | 0 |
Documents are hosted by the registry — open the source record to download them.
Plan to share: No — There is no current plan to make individual participant data available to other researchers.
This study is completed, as verified in Dec 2022. You cannot join it, but the record below documents what was studied.
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