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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 500mg exposure | Experimental | Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days. |
|
| 1000mg exposure | Experimental | Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days. |
|
| 1500mg exposure | Experimental | Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days. |
|
| Placebo | Placebo Comparator | Subjects will be exposed to placebo for up to 90 days. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| MetFORMIN Hydrochloride ER | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Brian Zuckerbraun, MD | University of Pittsburgh | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Pittsburgh Medical Center | Pittsburgh | Pennsylvania | 15209 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25993908 | Background | Randriamboavonjy V, Mann WA, Elgheznawy A, Popp R, Rogowski P, Dornauf I, Drose S, Fleming I. Metformin reduces hyper-reactivity of platelets from patients with polycystic ovary syndrome by improving mitochondrial integrity. Thromb Haemost. 2015 Aug 31;114(3):569-78. doi: 10.1160/TH14-09-0797. Epub 2015 May 21. | |
| 27805009 | Background |
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There is no current plan to make individual participant data available to other researchers.
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| ID | Title | Description |
|---|---|---|
| FG000 | 500mg Exposure | Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days. MetFORMIN Hydrochloride ER: 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. |
| FG001 | 1000mg Exposure | Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days. MetFORMIN Hydrochloride ER: 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. |
| FG002 | 1500mg Exposure | Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days. MetFORMIN Hydrochloride ER: 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. |
| FG003 | Placebo | Subjects will be exposed to placebo for up to 90 days. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 500mg Exposure | Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days. MetFORMIN Hydrochloride ER: 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Samples collected. Results were not yielded as they were not adequate to run samples with the available staffing. | Posted | Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) |
|
Adverse events were monitored from the time of randomization for 120 days.
Unexpected serious adverse events including significant illness, hospitalization, emergent or urgent surgery or procedure, psychiatric hospitalization or inpatient rehabilitation, would require the study team to discontinue the subject's participation.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 500mg Exposure | Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days. MetFORMIN Hydrochloride ER: 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastrointestinal symptoms | Gastrointestinal disorders | Systematic Assessment | Bloating, flatus, nausea, heartburn, or diarrhea were captured as a single entity and summarized as gastrointestinal symptoms. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Brian Zuckerbraun | University of Pittsburgh | (412) 647-3065 | zuckerbraunbs@upmc.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 18, 2019 | Feb 8, 2022 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D013927 | Thrombosis |
| ID | Term |
|---|---|
| D016769 | Embolism and Thrombosis |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D008687 | Metformin |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
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Subjects will act as their own controls: data will be collect on each subject at baseline, throughout exposure and following, exposure to metformin.
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|
| Placebo | Drug | 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. |
|
| 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. | 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. | 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). | 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. | 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. | 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. | 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. | Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) |
| Xin G, Wei Z, Ji C, Zheng H, Gu J, Ma L, Huang W, Morris-Natschke SL, Yeh JL, Zhang R, Qin C, Wen L, Xing Z, Cao Y, Xia Q, Lu Y, Li K, Niu H, Lee KH, Huang W. Metformin Uniquely Prevents Thrombosis by Inhibiting Platelet Activation and mtDNA Release. Sci Rep. 2016 Nov 2;6:36222. doi: 10.1038/srep36222. |
| 27275778 | Background | Alazawi W, Pirmadjid N, Lahiri R, Bhattacharya S. Inflammatory and Immune Responses to Surgery and Their Clinical Impact. Ann Surg. 2016 Jul;264(1):73-80. doi: 10.1097/SLA.0000000000001691. |
| 9195352 | Background | Kato M, Suzuki H, Murakami M, Akama M, Matsukawa S, Hashimoto Y. Elevated plasma levels of interleukin-6, interleukin-8, and granulocyte colony-stimulating factor during and after major abdominal surgery. J Clin Anesth. 1997 Jun;9(4):293-8. doi: 10.1016/s0952-8180(97)00006-8. |
| 10686974 | Background | Lin E, Calvano SE, Lowry SF. Inflammatory cytokines and cell response in surgery. Surgery. 2000 Feb;127(2):117-26. doi: 10.1067/msy.2000.101584. |
| 15006565 | Background | Jansson K, Redler B, Truedsson L, Magnuson A, Matthiessen P, Andersson M, Norgren L. Intraperitoneal cytokine response after major surgery: higher postoperative intraperitoneal versus systemic cytokine levels suggest the gastrointestinal tract as the major source of the postoperative inflammatory reaction. Am J Surg. 2004 Mar;187(3):372-7. doi: 10.1016/j.amjsurg.2003.12.019. |
| 23819011 | Background | Whelan SP, Zuckerbraun BS. Mitochondrial signaling: forwards, backwards, and in between. Oxid Med Cell Longev. 2013;2013:351613. doi: 10.1155/2013/351613. Epub 2013 May 29. |
| 21307647 | Background | Waltz P, Carchman EH, Young AC, Rao J, Rosengart MR, Kaczorowski D, Zuckerbraun BS. Lipopolysaccaride induces autophagic signaling in macrophages via a TLR4, heme oxygenase-1 dependent pathway. Autophagy. 2011 Mar;7(3):315-20. doi: 10.4161/auto.7.3.14044. |
| 8810959 | Background | Keel M, Schregenberger N, Steckholzer U, Ungethum U, Kenney J, Trentz O, Ertel W. Endotoxin tolerance after severe injury and its regulatory mechanisms. J Trauma. 1996 Sep;41(3):430-7; discussion 437-8. doi: 10.1097/00005373-199609000-00008. |
| 18945255 | Background | Loomba R, Lutchman G, Kleiner DE, Ricks M, Feld JJ, Borg BB, Modi A, Nagabhyru P, Sumner AE, Liang TJ, Hoofnagle JH. Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2009 Jan;29(2):172-82. doi: 10.1111/j.1365-2036.2008.03869.x. Epub 2008 Oct 9. |
| 20398632 | Background | Hou X, Song J, Li XN, Zhang L, Wang X, Chen L, Shen YH. Metformin reduces intracellular reactive oxygen species levels by upregulating expression of the antioxidant thioredoxin via the AMPK-FOXO3 pathway. Biochem Biophys Res Commun. 2010 May 28;396(2):199-205. doi: 10.1016/j.bbrc.2010.04.017. Epub 2010 Apr 14. |
| 19587680 | Background | Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009 Jul 16;460(7253):392-5. doi: 10.1038/nature08221. Epub 2009 Jul 8. |
| 22262811 | Background | Algire C, Moiseeva O, Deschenes-Simard X, Amrein L, Petruccelli L, Birman E, Viollet B, Ferbeyre G, Pollak MN. Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res (Phila). 2012 Apr;5(4):536-43. doi: 10.1158/1940-6207.CAPR-11-0536. Epub 2012 Jan 18. |
| 20304770 | Background | Smith DL Jr, Elam CF Jr, Mattison JA, Lane MA, Roth GS, Ingram DK, Allison DB. Metformin supplementation and life span in Fischer-344 rats. J Gerontol A Biol Sci Med Sci. 2010 May;65(5):468-74. doi: 10.1093/gerona/glq033. Epub 2010 Mar 19. |
| 24393785 | Background | Pernicova I, Korbonits M. Metformin--mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2014 Mar;10(3):143-56. doi: 10.1038/nrendo.2013.256. Epub 2014 Jan 7. |
| BG001 | 1000mg Exposure | Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days. MetFORMIN Hydrochloride ER: 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. |
| BG002 | 1500mg Exposure | Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days. MetFORMIN Hydrochloride ER: 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. |
| BG003 | Placebo | Subjects will be exposed to placebo for up to 90 days. |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG001 | 1000mg Exposure | Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days. MetFORMIN Hydrochloride ER: 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. |
| OG002 | 1500mg Exposure | Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days. MetFORMIN Hydrochloride ER: 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. |
| OG003 | Placebo | Subjects will be exposed to placebo for up to 90 days. Placebo: 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. |
|
| Secondary | 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. | Posted | Mean | Standard Deviation | Index | Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) |
|
|
|
|
| Secondary | 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. | Samples were collected and processed at each time point for each participant. When sample processing did not yeild any result (processing failure) no data could be yeilded and therefore can not be presented. | Posted | Mean | Standard Deviation | arbitrary units*mins | Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) |
|
|
|
|
| Secondary | Measure the Rate of Thrombosis of Peripheral Blood. | The endpoints for isolated platelets include platelet activation as measured by FACS for CD62p. | These data were not able to be collected due to storage issues and lab shutdowns during the COVID-19 pandemic. | Posted | Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) |
|
|
| Secondary | 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). | Notably, one patient in the 500mg and 1000mg group was unable to finish the 120d testing secondary to COVID-19 limitations. | Posted | Mean | Standard Deviation | Units on a scale | Day 0 (baseline), 90, and 120 (30 days post metformin exposure) |
|
|
|
|
| Secondary | Changes From Baseline in Grip Strength Via a Dynamometer During and Following Exposure to Metformin. | Grip strength over time. | Notably, one patient in the 500mg and 1000mg group was unable to finish the 120d testing secondary to COVID-19 limitations. | Posted | Mean | Standard Deviation | mmHg | Day 0 (baseline), 90, and 120 (30 days post metformin exposure) |
|
|
|
|
| Secondary | Mitochondrial Respiration in Both PBMCs and Platelets. | Oxidative phosphorylation, respiration, and complex activity will be tested using an Oroboros respirometer. | Samples were collected. Cell processing did not allow for the analysis of any data from collected samples. No data were therefore able to be collected. | Posted | Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) |
|
|
| Secondary | 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. | Samples were collected. Cell processing did not allow for the analysis of any data from collected samples. No data were therefore able to be collected. | Posted | Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) |
|
|
| Secondary | Measure Biogenesis of PBMCs. | Biogenesis will be determined by measuring RNA for PGC1a, NRF-1, and Tfam. | Samples were collected. Cell processing did not allow for the analysis of any data from collected samples. No data were therefore able to be collected. | Posted | Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) |
|
|
| 0 |
| 8 |
| 0 |
| 8 |
| 5 |
| 8 |
| EG001 | 1000mg Exposure | Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days. MetFORMIN Hydrochloride ER: 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. | 0 | 8 | 0 | 8 | 3 | 8 |
| EG002 | 1500mg Exposure | Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days. MetFORMIN Hydrochloride ER: 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. | 0 | 8 | 0 | 8 | 6 | 8 |
| EG003 | Placebo | Subjects will be exposed to placebo for up to 90 days. | 0 | 8 | 0 | 8 | 5 | 8 |
|
| Upper respiratory infection | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Upper respiratory infection including sinusitis, common cold, congestion |
|
| Joint pain or fracture | Musculoskeletal and connective tissue disorders | Systematic Assessment | Joint pain or fracture |
|
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| Day 30 |
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| Day 60 |
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| Day 90 |
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| Day 120 |
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| 30 day change from day 0 |
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| 60 days change from day 0 |
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| 90 days change from day 0 |
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| 120 days change from day 0 |
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| 90d, change from 0d |
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| 120d, change from 0d |
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| 90 days, compared to 0 days |
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| 120 days, compared to 0 days |
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