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Effects of Metformin in a Non-Diabetic Patient Population

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03772964
Recruitment Status : Completed
First Posted : December 12, 2018
Last Update Posted : May 6, 2020
Sponsor:
Information provided by (Responsible Party):
Brian Zuckerbraun, University of Pittsburgh

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.

Condition or disease Intervention/treatment Phase
Inflammatory Response Drug: MetFORMIN Hydrochloride ER Phase 1 Phase 2

Detailed Description:

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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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 32 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Subjects will act as their own controls: data will be collect on each subject at baseline, throughout exposure and following, exposure to metformin.
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: A Pilot Study: Metformin as an Inflammatory Modulating Therapy in Older Adults Without Diabetes
Actual Study Start Date : January 22, 2019
Actual Primary Completion Date : March 31, 2020
Actual Study Completion Date : March 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 500mg exposure
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 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.
Other Name: Metformin ER

Experimental: 1000mg exposure
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 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.
Other Name: Metformin ER

Experimental: 1500mg exposure
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 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.
Other Name: Metformin ER




Primary Outcome Measures :
  1. Ex vivo cytokine response of peripheral blood mononucleocytes (PBMC) to inflammatory stimuli compared to baseline, throughout exposure, and following exposure to metformin. [ Time Frame: Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) ]
    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.


Secondary Outcome Measures :
  1. Quantify the bacterial population profile of the microbiome via stool samples. [ Time Frame: Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) ]
    Changes in the bacterial communities using 16S rRNA sequencing in relationship to metformin dosing overtime.

  2. Measure the rate of clotting of peripheral blood with whole blood aggregometry in response to collagen. [ Time Frame: Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) ]
  3. Measure the rate of thrombosis of peripheral blood. [ Time Frame: Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) ]
    The endpoints for isolated platelets include platelet activation as measured by FACS for CD62p.

  4. Changes from baseline in Short Physical Performance Battery (SPPB) during and following exposure to metformin. [ Time Frame: Day 0 (baseline), 90, and 120 (30 days post metformin exposure) ]
  5. Changes from baseline in grip strength via a dynamometer during and following exposure to metformin. [ Time Frame: Day 0 (baseline), 90, and 120 (30 days post metformin exposure) ]
  6. Mitochondrial respiration in both PBMCs and platelets. [ Time Frame: Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) ]
    Oxidative phosphorylation, respiration, and complex activity will be tested using an Oroboros respirometer.

  7. Mitochondrial content in both PBMCs and platelets. [ Time Frame: Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) ]
    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.

  8. Measure biogenesis of PBMCs. [ Time Frame: Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure) ]
    Biogenesis will be determined by measuring RNA for PGC1a, NRF-1, and Tfam.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   55 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

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

Exclusion Criteria:

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03772964


Locations
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United States, Pennsylvania
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States, 15209
Sponsors and Collaborators
Brian Zuckerbraun
Investigators
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Principal Investigator: Brian Zuckerbraun, MD University of Pittsburgh
Publications:

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Responsible Party: Brian Zuckerbraun, Chief, Division of General/Trauma and Acute Care Surgery, Professor of Surgery, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT03772964    
Other Study ID Numbers: PRO17100535
First Posted: December 12, 2018    Key Record Dates
Last Update Posted: May 6, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There is no current plan to make individual participant data available to other researchers.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Brian Zuckerbraun, University of Pittsburgh:
prefrail
non-diabetic
metformin
thrombosis
microbiome
cellular respiration
short physical performance batter
Additional relevant MeSH terms:
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Metformin
Hypoglycemic Agents
Physiological Effects of Drugs