<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03772964</url>
  </required_header>
  <id_info>
    <org_study_id>PRO17100535</org_study_id>
    <nct_id>NCT03772964</nct_id>
  </id_info>
  <brief_title>Effects of Metformin in a Non-Diabetic Patient Population</brief_title>
  <official_title>A Pilot Study: Metformin as an Inflammatory Modulating Therapy in Older Adults Without Diabetes</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Brian Zuckerbraun</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Pittsburgh</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Metformin has a well-established safety profile and it has become clear that metformin has&#xD;
      additional salutary effects, including anti-inflammatory, anti-aging, and anti-thrombotic&#xD;
      properties. In this study, subjects will provide both venous blood samples and stool samples&#xD;
      in addition to completing cognitive and physiologic testing at baseline, throughout a 90 day&#xD;
      exposure to metformin, and 30 days following exposure to metformin in order to evaluate their&#xD;
      immune, microbiome, cellular respiration, thrombotic, and inflammatory responses.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Metformin is considered first-line therapy for patients with type two diabetes with&#xD;
      hyperglycemia that cannot be controlled with lifestyle alone. Unlike other oral medications,&#xD;
      metformin is favored for its insulin-sensitizing effects resulting in improved glycemic&#xD;
      control, weight loss, and overall improvement of metabolic syndrome. Over the past fifteen&#xD;
      years, metformin has received significant attention for its other potential therapeutic uses.&#xD;
      Metformin has been found to decrease the rate of age-related illness progression improving&#xD;
      longevity, especially in the setting of cancer. Recent clinical trials across multiple&#xD;
      disease states have shown metformin to decrease all-cause mortality in diabetic and&#xD;
      non-diabetic patients. Additionally, in both animal models and human trails, metformin has&#xD;
      been shown to decrease the risk of arterial and venous thrombosis without affecting bleeding&#xD;
      time through its interaction with platelet mitochondria. Although the mechanisms by which&#xD;
      metformin effects longevity is an active area of both basic science and clinical research, it&#xD;
      clearly has anti-inflammatory properties which are both independent and dependent of glycemic&#xD;
      control. Recently, surgical outcomes have focused on optimizing older, deconditioned patients&#xD;
      prior to the operation with varying protocols referred to as prehabilitation. These programs&#xD;
      work to improve the body's response to the surgical stress resulting in improved wound&#xD;
      healing, decreased postoperative complications, and decreased hospital length of stay. The&#xD;
      affect of metformin, like increasing physical activity, has widespread affects on physiology.&#xD;
      The investigators, therefore, hypothesize that metformin administration to non-diabetic&#xD;
      adults will improve clinical outcomes to physiologic stress by improving underlying immune&#xD;
      and inflammatory responses, that can be deleterious.&#xD;
&#xD;
      Subjects will have venous samples collected to better understand the cellular response to&#xD;
      inflammation, thrombosis, and cellular respiration at baseline, at 4 time points throughout&#xD;
      the 90 day exposure to metformin, and 30 days following the completion of exposure to&#xD;
      metformin. At the same time points, subjects will have stool samples collected in order to&#xD;
      assess changes in their microbiome. Finally, subjects will undergo cognitive testing through&#xD;
      the NIH toolbox as well as physiologic testing including (six-minute walk test, grip strength&#xD;
      as measured by a dynamometer, and a short physical performance battery) at baseline, after 90&#xD;
      days of exposure, and again 30 days after the completion of exposure.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 22, 2019</start_date>
  <completion_date type="Actual">March 31, 2020</completion_date>
  <primary_completion_date type="Actual">March 31, 2020</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <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.</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Ex Vivo Cytokine Response of Peripheral Blood Mononucleocytes (PBMC) to Inflammatory Stimuli Compared to Baseline, Throughout Exposure, and Following Exposure to Metformin.</measure>
    <time_frame>Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Quantify the Bacterial Population Profile of the Microbiome Via Stool Samples.</measure>
    <time_frame>Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)</time_frame>
    <description>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 &quot;healthier&quot; 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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measure the Rate of Clotting of Peripheral Blood With Whole Blood Aggregometry in Response to Collagen.</measure>
    <time_frame>Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)</time_frame>
    <description>Aggregometry area under the curve with the Y-axis being % aggregometry and the X-axis time in minutes.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measure the Rate of Thrombosis of Peripheral Blood.</measure>
    <time_frame>Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)</time_frame>
    <description>The endpoints for isolated platelets include platelet activation as measured by FACS for CD62p.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes From Baseline in Short Physical Performance Battery (SPPB) During and Following Exposure to Metformin.</measure>
    <time_frame>Day 0 (baseline), 90, and 120 (30 days post metformin exposure)</time_frame>
    <description>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).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes From Baseline in Grip Strength Via a Dynamometer During and Following Exposure to Metformin.</measure>
    <time_frame>Day 0 (baseline), 90, and 120 (30 days post metformin exposure)</time_frame>
    <description>Grip strength over time.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mitochondrial Respiration in Both PBMCs and Platelets.</measure>
    <time_frame>Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)</time_frame>
    <description>Oxidative phosphorylation, respiration, and complex activity will be tested using an Oroboros respirometer.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mitochondrial Content in Both PBMCs and Platelets.</measure>
    <time_frame>Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measure Biogenesis of PBMCs.</measure>
    <time_frame>Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)</time_frame>
    <description>Biogenesis will be determined by measuring RNA for PGC1a, NRF-1, and Tfam.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">32</enrollment>
  <condition>Inflammatory Response</condition>
  <arm_group>
    <arm_group_label>500mg exposure</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>1000mg exposure</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>1500mg exposure</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Subjects will be exposed to placebo for up to 90 days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>MetFORMIN Hydrochloride ER</intervention_name>
    <description>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.</description>
    <arm_group_label>1000mg exposure</arm_group_label>
    <arm_group_label>1500mg exposure</arm_group_label>
    <arm_group_label>500mg exposure</arm_group_label>
    <other_name>Metformin ER</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>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.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥55 and ≤85 years of age&#xD;
&#xD;
          2. Non-diabetic&#xD;
&#xD;
          3. Adjusted risk analysis index (RAI) 20-42&#xD;
&#xD;
          4. Estimated glomerular filtration rate &gt;45&#xD;
&#xD;
          5. No evidence of hepatic dysfunction on comprehensive metabolic panel&#xD;
&#xD;
          6. No clinical evidence of cardiac failure&#xD;
&#xD;
          7. Existing University of Pittsburgh Medical Center Patients&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Hypersensitivity to metformin or any component of the formulation&#xD;
&#xD;
          2. Acute or chronic metabolic acidosis with or without coma&#xD;
&#xD;
          3. Pregnant or breastfeeding females&#xD;
&#xD;
          4. Evidence or history of hepatic, renal, or cardiopulmonary failure&#xD;
&#xD;
          5. Excessive acute or chronic ethanol use&#xD;
&#xD;
          6. Planned or known hospital admission, exposure to anesthesia, or surgical intervention&#xD;
             30 days prior to study or scheduled 30 days after the trial initiation&#xD;
&#xD;
          7. Laboratory analysis showing HbgA1c &gt;6.1 or eGFR &lt;44 on baseline labs&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>55 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Brian Zuckerbraun, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Pittsburgh</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Pittsburgh Medical Center</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15209</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>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.</citation>
    <PMID>25993908</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>27805009</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>27275778</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>9195352</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>10686974</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>15006565</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>23819011</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>21307647</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>8810959</PMID>
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  <reference>
    <citation>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.</citation>
    <PMID>18945255</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>20398632</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>19587680</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>22262811</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>20304770</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>24393785</PMID>
  </reference>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>February 28, 2018</study_first_submitted>
  <study_first_submitted_qc>December 8, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 12, 2018</study_first_posted>
  <results_first_submitted>March 3, 2022</results_first_submitted>
  <results_first_submitted_qc>December 15, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">January 11, 2023</results_first_posted>
  <disposition_first_submitted>March 25, 2021</disposition_first_submitted>
  <disposition_first_submitted_qc>December 15, 2022</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">January 11, 2023</disposition_first_posted>
  <last_update_submitted>December 15, 2022</last_update_submitted>
  <last_update_submitted_qc>December 15, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">January 11, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Pittsburgh</investigator_affiliation>
    <investigator_full_name>Brian Zuckerbraun</investigator_full_name>
    <investigator_title>Chief, Division of General/Trauma and Acute Care Surgery, Professor of Surgery</investigator_title>
  </responsible_party>
  <keyword>prefrail</keyword>
  <keyword>non-diabetic</keyword>
  <keyword>metformin</keyword>
  <keyword>thrombosis</keyword>
  <keyword>microbiome</keyword>
  <keyword>cellular respiration</keyword>
  <keyword>short physical performance batter</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metformin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>There is no current plan to make individual participant data available to other researchers.</ipd_description>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>May 18, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/64/NCT03772964/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>500mg Exposure</title>
          <description>Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
        </group>
        <group group_id="P2">
          <title>1000mg Exposure</title>
          <description>Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
        </group>
        <group group_id="P3">
          <title>1500mg Exposure</title>
          <description>Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
        </group>
        <group group_id="P4">
          <title>Placebo</title>
          <description>Subjects will be exposed to placebo for up to 90 days.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="8"/>
                <participants group_id="P3" count="8"/>
                <participants group_id="P4" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="7">Could not attend final in-person evaluation due to COVID-19 shut down limitations</participants>
                <participants group_id="P2" count="8"/>
                <participants group_id="P3" count="8"/>
                <participants group_id="P4" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>500mg Exposure</title>
          <description>Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
        </group>
        <group group_id="B2">
          <title>1000mg Exposure</title>
          <description>Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
        </group>
        <group group_id="B3">
          <title>1500mg Exposure</title>
          <description>Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
        </group>
        <group group_id="B4">
          <title>Placebo</title>
          <description>Subjects will be exposed to placebo for up to 90 days.</description>
        </group>
        <group group_id="B5">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="8"/>
            <count group_id="B2" value="8"/>
            <count group_id="B3" value="8"/>
            <count group_id="B4" value="8"/>
            <count group_id="B5" value="32"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="68" spread="6"/>
                    <measurement group_id="B2" value="70" spread="6"/>
                    <measurement group_id="B3" value="71" spread="4"/>
                    <measurement group_id="B4" value="68" spread="6"/>
                    <measurement group_id="B5" value="70" spread="5.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="5"/>
                    <measurement group_id="B5" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B5" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="7"/>
                    <measurement group_id="B4" value="8"/>
                    <measurement group_id="B5" value="29"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Ex Vivo Cytokine Response of Peripheral Blood Mononucleocytes (PBMC) to Inflammatory Stimuli Compared to Baseline, Throughout Exposure, and Following Exposure to Metformin.</title>
        <description>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.</description>
        <time_frame>Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)</time_frame>
        <population>Samples collected. Results were not yielded as they were not adequate to run samples with the available staffing.</population>
        <group_list>
          <group group_id="O1">
            <title>500mg Exposure</title>
            <description>Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O2">
            <title>1000mg Exposure</title>
            <description>Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O3">
            <title>1500mg Exposure</title>
            <description>Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O4">
            <title>Placebo</title>
            <description>Subjects will be exposed to placebo for up to 90 days.&#xD;
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.</description>
          </group>
        </group_list>
        <measure>
          <title>Ex Vivo Cytokine Response of Peripheral Blood Mononucleocytes (PBMC) to Inflammatory Stimuli Compared to Baseline, Throughout Exposure, and Following Exposure to Metformin.</title>
          <description>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.</description>
          <population>Samples collected. Results were not yielded as they were not adequate to run samples with the available staffing.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Quantify the Bacterial Population Profile of the Microbiome Via Stool Samples.</title>
        <description>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 &quot;healthier&quot; 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.</description>
        <time_frame>Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>500mg Exposure</title>
            <description>Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O2">
            <title>1000mg Exposure</title>
            <description>Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O3">
            <title>1500mg Exposure</title>
            <description>Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O4">
            <title>Placebo</title>
            <description>Subjects will be exposed to placebo for up to 90 days.</description>
          </group>
        </group_list>
        <measure>
          <title>Quantify the Bacterial Population Profile of the Microbiome Via Stool Samples.</title>
          <description>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 &quot;healthier&quot; 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.</description>
          <units>Index</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Day 0</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="136.5" spread="19.0"/>
                    <measurement group_id="O2" value="107.6" spread="13.3"/>
                    <measurement group_id="O3" value="128.1" spread="10.5"/>
                    <measurement group_id="O4" value="141.5" spread="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 30</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="139.9" spread="16.2"/>
                    <measurement group_id="O2" value="130.7" spread="19.4"/>
                    <measurement group_id="O3" value="128.1" spread="13.2"/>
                    <measurement group_id="O4" value="144.75" spread="13.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 60</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="121.4" spread="20.8"/>
                    <measurement group_id="O2" value="137.9" spread="17.7"/>
                    <measurement group_id="O3" value="128.6" spread="12.7"/>
                    <measurement group_id="O4" value="134.3" spread="9.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 90</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="137.8" spread="27.8"/>
                    <measurement group_id="O2" value="135" spread="18.9"/>
                    <measurement group_id="O3" value="138.2" spread="10.3"/>
                    <measurement group_id="O4" value="152" spread="20.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 120</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="134" spread="23.6"/>
                    <measurement group_id="O2" value="142.2" spread="17.3"/>
                    <measurement group_id="O3" value="144.2" spread="16.5"/>
                    <measurement group_id="O4" value="159.2" spread="5.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Beta Diversity - Differences between Samples and Sample groups</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>Comparisons between samples and sample groups (beta-diversity), were evaluated with ADONIS (aka PERMANOVA) comparisons of differences between sample groups.</non_inferiority_desc>
            <p_value>&lt;0.01</p_value>
            <method>ADONISBeta Diversity</method>
            <method_desc>Comparisons between samples and sample groups (beta-diversity) were evaluated with ADONIS (aka PERMANOVA)</method_desc>
            <param_type>R2</param_type>
            <param_value>0.071435</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
            <estimate_desc>R2 values estimate the amount of variation explained by each variable.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Measure the Rate of Clotting of Peripheral Blood With Whole Blood Aggregometry in Response to Collagen.</title>
        <description>Aggregometry area under the curve with the Y-axis being % aggregometry and the X-axis time in minutes.</description>
        <time_frame>Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)</time_frame>
        <population>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.</population>
        <group_list>
          <group group_id="O1">
            <title>500mg Exposure</title>
            <description>Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O2">
            <title>1000mg Exposure</title>
            <description>Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O3">
            <title>1500mg Exposure</title>
            <description>Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O4">
            <title>Placebo</title>
            <description>Subjects will be exposed to placebo for up to 90 days.&#xD;
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.</description>
          </group>
        </group_list>
        <measure>
          <title>Measure the Rate of Clotting of Peripheral Blood With Whole Blood Aggregometry in Response to Collagen.</title>
          <description>Aggregometry area under the curve with the Y-axis being % aggregometry and the X-axis time in minutes.</description>
          <population>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.</population>
          <units>arbitrary units*mins</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>0 days</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="8"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="8"/>
                    <count group_id="O4" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="56.3" spread="40"/>
                    <measurement group_id="O2" value="67" spread="38"/>
                    <measurement group_id="O3" value="196" spread="376"/>
                    <measurement group_id="O4" value="83.3" spread="69"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>30 day change from day 0</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="8"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="8"/>
                    <count group_id="O4" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-34.7" spread="24.5"/>
                    <measurement group_id="O2" value="8.9" spread="50.1"/>
                    <measurement group_id="O3" value="-166.7" spread="409"/>
                    <measurement group_id="O4" value="-29.6" spread="104.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>60 days change from day 0</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="8"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="8"/>
                    <count group_id="O4" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-28.3" spread="54"/>
                    <measurement group_id="O2" value="-23.5" spread="44.5"/>
                    <measurement group_id="O3" value="-139.8" spread="376.3"/>
                    <measurement group_id="O4" value="-49.4" spread="86.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>90 days change from day 0</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="6"/>
                    <count group_id="O2" value="5"/>
                    <count group_id="O3" value="7"/>
                    <count group_id="O4" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.6" spread="57.6"/>
                    <measurement group_id="O2" value="2.4" spread="84.5"/>
                    <measurement group_id="O3" value="-222.5" spread="456.2"/>
                    <measurement group_id="O4" value="-66.6" spread="102.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>120 days change from day 0</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="6"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="6"/>
                    <count group_id="O4" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-49.2" spread="84.2"/>
                    <measurement group_id="O2" value="1.0" spread="28.9"/>
                    <measurement group_id="O3" value="-196.7" spread="410.6"/>
                    <measurement group_id="O4" value="-47.6" spread="103.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.6057</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Measure the Rate of Thrombosis of Peripheral Blood.</title>
        <description>The endpoints for isolated platelets include platelet activation as measured by FACS for CD62p.</description>
        <time_frame>Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)</time_frame>
        <population>These data were not able to be collected due to storage issues and lab shutdowns during the COVID-19 pandemic.</population>
        <group_list>
          <group group_id="O1">
            <title>500mg Exposure</title>
            <description>Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O2">
            <title>1000mg Exposure</title>
            <description>Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O3">
            <title>1500mg Exposure</title>
            <description>Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O4">
            <title>Placebo</title>
            <description>Subjects will be exposed to placebo for up to 90 days.</description>
          </group>
        </group_list>
        <measure>
          <title>Measure the Rate of Thrombosis of Peripheral Blood.</title>
          <description>The endpoints for isolated platelets include platelet activation as measured by FACS for CD62p.</description>
          <population>These data were not able to be collected due to storage issues and lab shutdowns during the COVID-19 pandemic.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes From Baseline in Short Physical Performance Battery (SPPB) During and Following Exposure to Metformin.</title>
        <description>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).</description>
        <time_frame>Day 0 (baseline), 90, and 120 (30 days post metformin exposure)</time_frame>
        <population>Notably, one patient in the 500mg and 1000mg group was unable to finish the 120d testing secondary to COVID-19 limitations.</population>
        <group_list>
          <group group_id="O1">
            <title>500mg Exposure</title>
            <description>Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O2">
            <title>1000mg Exposure</title>
            <description>Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O3">
            <title>1500mg Exposure</title>
            <description>Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O4">
            <title>Placebo</title>
            <description>Participants were exposed to oral placebo for up to 90 days.</description>
          </group>
        </group_list>
        <measure>
          <title>Changes From Baseline in Short Physical Performance Battery (SPPB) During and Following Exposure to Metformin.</title>
          <description>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).</description>
          <population>Notably, one patient in the 500mg and 1000mg group was unable to finish the 120d testing secondary to COVID-19 limitations.</population>
          <units>Units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>0d</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="8"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="8"/>
                    <count group_id="O4" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.2" spread=".9"/>
                    <measurement group_id="O2" value="10.8" spread="1.3"/>
                    <measurement group_id="O3" value="11.1" spread="0.9"/>
                    <measurement group_id="O4" value="10.6" spread="1.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>90d, change from 0d</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="8"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="8"/>
                    <count group_id="O4" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.3" spread="1.4"/>
                    <measurement group_id="O2" value="0.4" spread="0.7"/>
                    <measurement group_id="O3" value="0.4" spread="0.5"/>
                    <measurement group_id="O4" value="1.0" spread="1.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>120d, change from 0d</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                    <count group_id="O2" value="7"/>
                    <count group_id="O3" value="8"/>
                    <count group_id="O4" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0" spread="0.6"/>
                    <measurement group_id="O2" value="0.2" spread="1.0"/>
                    <measurement group_id="O3" value="0.3" spread="1.3"/>
                    <measurement group_id="O4" value="0.5" spread=".8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.001</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes From Baseline in Grip Strength Via a Dynamometer During and Following Exposure to Metformin.</title>
        <description>Grip strength over time.</description>
        <time_frame>Day 0 (baseline), 90, and 120 (30 days post metformin exposure)</time_frame>
        <population>Notably, one patient in the 500mg and 1000mg group was unable to finish the 120d testing secondary to COVID-19 limitations.</population>
        <group_list>
          <group group_id="O1">
            <title>500mg Exposure</title>
            <description>Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O2">
            <title>1000mg Exposure</title>
            <description>Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O3">
            <title>1500mg Exposure</title>
            <description>Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O4">
            <title>Placebo</title>
            <description>Subjects exposed to placebo for up to 90d</description>
          </group>
        </group_list>
        <measure>
          <title>Changes From Baseline in Grip Strength Via a Dynamometer During and Following Exposure to Metformin.</title>
          <description>Grip strength over time.</description>
          <population>Notably, one patient in the 500mg and 1000mg group was unable to finish the 120d testing secondary to COVID-19 limitations.</population>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>0 days</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="8"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="8"/>
                    <count group_id="O4" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="28.2" spread="10.3"/>
                    <measurement group_id="O2" value="28.9" spread="8.3"/>
                    <measurement group_id="O3" value="25.7" spread="7.8"/>
                    <measurement group_id="O4" value="25.7" spread="9.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>90 days, compared to 0 days</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="8"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="8"/>
                    <count group_id="O4" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-5.3" spread="12.5"/>
                    <measurement group_id="O2" value="-0.4" spread="3.1"/>
                    <measurement group_id="O3" value="-.2" spread="2.1"/>
                    <measurement group_id="O4" value="-.3" spread="3.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>120 days, compared to 0 days</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                    <count group_id="O2" value="7"/>
                    <count group_id="O3" value="8"/>
                    <count group_id="O4" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".1" spread="4.8"/>
                    <measurement group_id="O2" value="1.1" spread="2.7"/>
                    <measurement group_id="O3" value=".3" spread="3.0"/>
                    <measurement group_id="O4" value="-.6" spread="2.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.69</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mitochondrial Respiration in Both PBMCs and Platelets.</title>
        <description>Oxidative phosphorylation, respiration, and complex activity will be tested using an Oroboros respirometer.</description>
        <time_frame>Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)</time_frame>
        <population>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.</population>
        <group_list>
          <group group_id="O1">
            <title>500mg Exposure</title>
            <description>Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O2">
            <title>1000mg Exposure</title>
            <description>Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O3">
            <title>1500mg Exposure</title>
            <description>Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O4">
            <title>Placebo</title>
            <description>Subjects will be exposed to placebo for up to 90 days.</description>
          </group>
        </group_list>
        <measure>
          <title>Mitochondrial Respiration in Both PBMCs and Platelets.</title>
          <description>Oxidative phosphorylation, respiration, and complex activity will be tested using an Oroboros respirometer.</description>
          <population>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.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mitochondrial Content in Both PBMCs and Platelets.</title>
        <description>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.</description>
        <time_frame>Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)</time_frame>
        <population>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.</population>
        <group_list>
          <group group_id="O1">
            <title>500mg Exposure</title>
            <description>Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O2">
            <title>1000mg Exposure</title>
            <description>Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O3">
            <title>1500mg Exposure</title>
            <description>Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O4">
            <title>Placebo</title>
            <description>Subjects will be exposed to placebo for up to 90 days.</description>
          </group>
        </group_list>
        <measure>
          <title>Mitochondrial Content in Both PBMCs and Platelets.</title>
          <description>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.</description>
          <population>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.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Measure Biogenesis of PBMCs.</title>
        <description>Biogenesis will be determined by measuring RNA for PGC1a, NRF-1, and Tfam.</description>
        <time_frame>Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)</time_frame>
        <population>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.</population>
        <group_list>
          <group group_id="O1">
            <title>500mg Exposure</title>
            <description>Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O2">
            <title>1000mg Exposure</title>
            <description>Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O3">
            <title>1500mg Exposure</title>
            <description>Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
          </group>
          <group group_id="O4">
            <title>Placebo</title>
            <description>Subjects will be exposed to placebo for up to 90 days.</description>
          </group>
        </group_list>
        <measure>
          <title>Measure Biogenesis of PBMCs.</title>
          <description>Biogenesis will be determined by measuring RNA for PGC1a, NRF-1, and Tfam.</description>
          <population>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.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were monitored from the time of randomization for 120 days.</time_frame>
      <desc>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.</desc>
      <group_list>
        <group group_id="E1">
          <title>500mg Exposure</title>
          <description>Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
        </group>
        <group group_id="E2">
          <title>1000mg Exposure</title>
          <description>Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
        </group>
        <group group_id="E3">
          <title>1500mg Exposure</title>
          <description>Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.&#xD;
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.</description>
        </group>
        <group group_id="E4">
          <title>Placebo</title>
          <description>Subjects will be exposed to placebo for up to 90 days.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="8"/>
                <counts group_id="E4" subjects_affected="5" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Gastrointestinal symptoms</sub_title>
                <description>Bloating, flatus, nausea, heartburn, or diarrhea were captured as a single entity and summarized as gastrointestinal symptoms.</description>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="8"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="8"/>
                <counts group_id="E4" events="5" subjects_affected="5" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Joint pain or fracture</sub_title>
                <description>Joint pain or fracture</description>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <description>Upper respiratory infection including sinusitis, common cold, congestion</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Brian Zuckerbraun</name_or_title>
      <organization>University of Pittsburgh</organization>
      <phone>(412) 647-3065</phone>
      <email>zuckerbraunbs@upmc.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03772964
org study id: PRO17100535
nct id: NCT03772964
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
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.
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.
primary purpose: Basic Science
masking: Triple (Participant, Care Provider, Investigator)
measure: 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)
description: 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.
measure: 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)
description: 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.
measure: 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)
description: Aggregometry area under the curve with the Y-axis being % aggregometry and the X-axis time in minutes.
measure: Measure the Rate of Thrombosis of Peripheral Blood.
time frame: Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)
description: The endpoints for isolated platelets include platelet activation as measured by FACS for CD62p.
measure: 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)
description: 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).
measure: 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)
description: Grip strength over time.
measure: Mitochondrial Respiration in Both PBMCs and Platelets.
time frame: Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)
description: Oxidative phosphorylation, respiration, and complex activity will be tested using an Oroboros respirometer.
measure: Mitochondrial Content in Both PBMCs and Platelets.
time frame: Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)
description: 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.
measure: Measure Biogenesis of PBMCs.
time frame: Day 0 (baseline), 30, 60, 90, and 120 (30 days post metformin exposure)
description: Biogenesis will be determined by measuring RNA for PGC1a, NRF-1, and Tfam.
arm group label: 500mg exposure
arm group type: Experimental
description: Subjects will be exposed to 500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.
arm group label: 1000mg exposure
arm group type: Experimental
description: Subjects will be exposed to 1000mg of daily MetFORMIN Hydrochloride ER for up to 90 days.
arm group label: 1500mg exposure
arm group type: Experimental
description: Subjects will be exposed to 1500mg of daily MetFORMIN Hydrochloride ER for up to 90 days.
arm group label: Placebo
arm group type: Placebo Comparator
description: Subjects will be exposed to placebo for up to 90 days.
intervention type: Drug
intervention name: MetFORMIN Hydrochloride ER
description: 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.
arm group label: 1000mg exposure
arm group label: 1500mg exposure
arm group label: 500mg exposure
other name: Metformin ER
intervention type: Drug
intervention name: Placebo
description: 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.
arm group label: Placebo
criteria: 
gender: All
minimum age: 55 Years
maximum age: 85 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Brian Zuckerbraun, MD
role: Principal Investigator
affiliation: University of Pittsburgh
facility: 
country: United States
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PMID: 25993908
citation: 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.
PMID: 27805009
citation: 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
citation: 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
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PMID: 10686974
citation: 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
citation: 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
citation: 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
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PMID: 8810959
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PMID: 18945255
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PMID: 20398632
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PMID: 24393785
responsible party type: Sponsor-Investigator
investigator affiliation: University of Pittsburgh
investigator full name: Brian Zuckerbraun
investigator title: Chief, Division of General/Trauma and Acute Care Surgery, Professor of Surgery
mesh term: Metformin
sharing ipd: No
ipd description: There is no current plan to make individual participant data available to other researchers.
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 