Effects of Metformin in a Non-Diabetic Patient Population

NCT03772964 | Completed Phase 1 Results FDA Drug

• 1 other identifier: PRO17100535
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Inflammatory Response

Keywords

prefrail; non-diabetic; metformin; thrombosis; microbiome; cellular respiration; short physical performance batter

Outcome Measures

Primary Outcomes (1)

• 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)

Secondary Outcomes (8)

• Quantify the Bacterial Population Profile of the Microbiome Via Stool Samples.

  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.

  Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)

• Measure the Rate of Thrombosis of Peripheral Blood.

  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.

  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.

  Day 0 (baseline), 90, and 120 (30 days post metformin exposure)

Study Arms (4)

500mg exposure

EXPERIMENTAL

Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.

Drug: MetFORMIN Hydrochloride ER

1000mg exposure

EXPERIMENTAL

Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days.

Drug: MetFORMIN Hydrochloride ER

1500mg exposure

EXPERIMENTAL

Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.

Drug: MetFORMIN Hydrochloride ER

Placebo

PLACEBO COMPARATOR

Subjects will be exposed to placebo for up to 90 days.

Drug: Placebo

Interventions

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.

Also known as: Metformin ER

1000mg exposure; 1500mg exposure; 500mg exposure

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.

Placebo

Eligibility Criteria

• Age: 55 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥55 and ≤85 years of age
• Non-diabetic
• Adjusted risk analysis index (RAI) 20-42
• Estimated glomerular filtration rate \>45
• No evidence of hepatic dysfunction on comprehensive metabolic panel
• No clinical evidence of cardiac failure
• Existing University of Pittsburgh Medical Center Patients

You may not qualify if:

• Hypersensitivity to metformin or any component of the formulation
• Acute or chronic metabolic acidosis with or without coma
• Pregnant or breastfeeding females
• Evidence or history of hepatic, renal, or cardiopulmonary failure
• Excessive acute or chronic ethanol use
• Planned or known hospital admission, exposure to anesthesia, or surgical intervention 30 days prior to study or scheduled 30 days after the trial initiation
• Laboratory analysis showing HbgA1c \>6.1 or eGFR \<44 on baseline labs

Sponsors & Collaborators

• Brian Zuckerbraun: lead

Study Sites (1)

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15209, United States

Location

Related Publications (15)

• 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.

  PMID: 25993908 BACKGROUND

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  PMID: 27805009 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.

  PMID: 27275778 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.

  PMID: 9195352 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.

  PMID: 10686974 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.

  PMID: 15006565 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.

  PMID: 23819011 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.

  PMID: 21307647 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.

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• 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.

  PMID: 18945255 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.

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• 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.

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• 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.

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• 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.

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MeSH Terms

Conditions

Thrombosis

Interventions

Metformin

Condition Hierarchy (Ancestors)

Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Results Point of Contact

• Title: Dr. Brian Zuckerbraun
• Organization: University of Pittsburgh

zuckerbraunbs@upmc.edu

(412) 647-3065

Study Officials

• Brian Zuckerbraun, MD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Chief, Division of General/Trauma and Acute Care Surgery, Professor of Surgery

Model Details: Subjects will act as their own controls: data will be collect on each subject at baseline, throughout exposure and following, exposure to metformin.

Study Record Dates

• First Submitted: February 28, 2018
• First Posted: December 12, 2018
• Study Start: January 22, 2019
• Primary Completion: March 31, 2020
• Study Completion: March 31, 2020
• Last Updated: January 11, 2023
• Results First Posted: January 11, 2023

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)