<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/NCT02986659</url>
  </required_header>
  <id_info>
    <org_study_id>IRB00034977</org_study_id>
    <nct_id>NCT02986659</nct_id>
  </id_info>
  <brief_title>Genomic Outcomes of Metformin</brief_title>
  <acronym>GOMET</acronym>
  <official_title>Genomic Outcomes of Metformin</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Wake Forest University Health Sciences</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute on Aging (NIA)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Wake Forest University Health Sciences</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Medical scientists have found that people with diabetes who take the drug Metformin have less&#xD;
      age-related disease than those taking other treatments and researchers believe it may prevent&#xD;
      numerous diseases and conditions that effect older people. In addition, metformin extends&#xD;
      lifespan in some animal models of human disease. The purpose of this study is to see if&#xD;
      taking Metformin causes changes in blood cells consistent with improved health and longevity&#xD;
      in people who do not have diabetes. In this study Metformin will be compared to placebo. A&#xD;
      placebo is a substance, like a sugar pill, that is not thought to have any effect on a&#xD;
      participants disease or condition. In this study participants will either receive the active&#xD;
      study medication, Metformin or placebo which is not active. Placebos are used in research&#xD;
      studies to see if the drug being studied really does have an effect.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The number of older adults is projected to increase dramatically by 2050. Aging-related&#xD;
      diseases and conditions still seriously compromise the quality of life among most older&#xD;
      adults. Several pharmaceutical agents, such as metformin, have been tested to extend lifespan&#xD;
      and delay aging-related diseases and dysfunctions in mice. Metformin, a biguanide&#xD;
      antidiabetic drug, reduces the risk for developing type-2 diabetes in persons at risk by over&#xD;
      one-third with few adverse effects (e.g., gastrointestinal irritation). Metformin prevents&#xD;
      type-2 diabetes primarily through decreasing hepatic glucose synthesis, as well as enhancing&#xD;
      insulin sensitivity and increasing peripheral glucose uptake. The molecular mechanisms remain&#xD;
      unclear, although a number of potential mechanism such as activation of AMP-activated protein&#xD;
      kinase (AMPK) and inhibition of mitochondrial glycerophosphate dehydrogenase have been&#xD;
      proposed. The fact that metformin treatment in persons with type-2 diabetes has been&#xD;
      associated with reduced risk of other aging-related diseases and conditions, including&#xD;
      cardiovascular disease, cancer and cognitive decline supports the possibility of the&#xD;
      beneficial effects of metformin on healthy aging. It is imperative to capitalize on these&#xD;
      leads to extend health span among older adults.&#xD;
&#xD;
      To translate animal findings to human intervention trials, appropriate aging biomarkers are&#xD;
      needed. Methylomic and transcriptomic profiles in relevant cells may reflect molecular&#xD;
      features that mediate effects of both genetic and environmental factors on aging-related&#xD;
      functional decline and disease. The roles of monocytes have been implicated in development of&#xD;
      many aging-related diseases such as cardiovascular disease, cancer and neurodegenerative&#xD;
      disease. In a cross-sectional association study of 1,200 monocyte samples, we identified&#xD;
      1,794 age-associated methylation sites and 2,704 age-associated transcripts, which were&#xD;
      over-represented in two networks (autophagy and oxidative phosphorylation) and suggestive of&#xD;
      decline in those functions with age. Both autophagy and oxidative phosphorylation are&#xD;
      considered as key contributors to the aging process, and their dysfunctions have been linked&#xD;
      to aging-related diseases. Changes in these aging-related omic biomarkers may be early&#xD;
      indicators of cellular damage or disruption that eventually leads to age-related&#xD;
      dysfunctions. Assessment of these aging biomarkers in response to therapeutic intervention&#xD;
      may also provide molecular insight for personalizing treatment. The investigators propose a&#xD;
      pilot study to examine changes in aging-related omic profiles after 3 months of metformin&#xD;
      treatment in 35 monocyte samples from older adults using a randomized, double-blind,&#xD;
      placebo-controlled crossover study design.&#xD;
&#xD;
      Our overarching goal of the pilot study is to evaluate the utility of using the aging-related&#xD;
      omic biomarkers as an indicator of pharmacologic responses in the anti-aging therapeutic&#xD;
      intervention trials through the following specific aims. Although this pilot study does not&#xD;
      have sufficient power to definitively test all the aims, it will provide essential&#xD;
      preliminary data for developing a full scale research program.&#xD;
&#xD;
        -  Aim 1A: To test the effects of the metformin treatment on transcriptomic profiles and&#xD;
           related functional changes in human monocytes,&#xD;
&#xD;
        -  Aim 1B: To explore the effects of the metformin treatment on methylomic profiles in&#xD;
           human monocytes,&#xD;
&#xD;
        -  Aim 2: To investigate the longitudinal relationship between transcriptional and&#xD;
           functional changes in human monocytes during the metformin treatment and&#xD;
&#xD;
        -  Aim 3: To test the effects of the metformin treatment on frailty and other aging-related&#xD;
           physical and cognitive measures and investigate the longitudinal relationship between&#xD;
           these changes and transcriptional changes.&#xD;
&#xD;
      A randomized, double-blind, placebo-controlled crossover trial in 30 participants using&#xD;
      metformin and matching placebo will be used. In the absence of a treatment by sequence&#xD;
      interaction effect, this design can increase study power for evaluating treatment effects by&#xD;
      allowing each participant to be his/her own control. The period effect may be minimum because&#xD;
      the primary outcomes, methylation and transcriptional measures, are relatively stable&#xD;
      overtime.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 3, 2016</start_date>
  <completion_date type="Actual">November 15, 2018</completion_date>
  <primary_completion_date type="Actual">November 15, 2018</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Health Services Research</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in eigengene scores</measure>
    <time_frame>baseline, 12 weeks, 24 weeks</time_frame>
    <description>Individual methylation sites and transcripts, especially the eigengenes of autophage, oxidative phosphorylation and protein synthesis networks Methylomic and transcriptomic profiles in monocytes will be quantified using the Illumina HumanMethylation450 BeadChip and the Illumina HumanHT-12 v4 Expression BeadChips, respectively. All of these measures will be aggregated into one eigengene score.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">34</enrollment>
  <condition>Coronary Artery Disease</condition>
  <condition>Mild Cognitive Impairment</condition>
  <condition>Obesity, Abdominal</condition>
  <condition>Hypertension</condition>
  <arm_group>
    <arm_group_label>Metformin then Placebo</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Metformin dosing at 425, 850 and 1700 mg with GLUCOPHAGE® (metformin hydrochloride) Tablets. Treatment with metformin will be initiated at a dose of 425 mg (half pill) taken orally once a day at night for 7 days. After the week, the participant will be called to assess tolerance and will be asked to increase dose to one pill at night at a dose of 850 mg for one week. At the end of the second week, participants will be called again and if they tolerated the second dose, they will be asked to take two 850 mg pills, one in the morning and one at night, for a total dose of 1700 mg which is within the range of the usual effective dose of 1500 to 2000 mg/day for the remainder of the 3 months. Will then cross over to 3 months on placebo.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo then Metormin</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Dietary Supplement: Placebo with Methylcellulose capsules. Treatment with placebo will be initiated at a dose of a half pill taken orally once a day at night for 7 days. After the week, the participant will be called to assess tolerance and will be asked to increase dose to one pill at night for one week. At the end of the second week, participants will be called again and if they tolerated the second dose, they will be asked to take two pills, one in the morning and one at night for the remainder of the 3 months. After 3 months on placebo, participants will then cross over to 3 months of metformin as described in the other arm.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin</intervention_name>
    <arm_group_label>Metformin then Placebo</arm_group_label>
    <arm_group_label>Placebo then Metormin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <arm_group_label>Metformin then Placebo</arm_group_label>
    <arm_group_label>Placebo then Metormin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age 65 - 79&#xD;
&#xD;
        Must meet criteria from one or more of the following groups:&#xD;
&#xD;
        Group 1 (Can have 1 or 2 of these, but not all 3)&#xD;
&#xD;
          -  History of coronary artery disease (MI/heart attack, stroke, heart failure, or&#xD;
             peripheral artery disease)&#xD;
&#xD;
          -  Cancer, with no active treatment in the last year&#xD;
&#xD;
          -  MCI (MoCA &gt;18&lt;26 -inclusive of 1 point if &lt;12 years of education Group 2&#xD;
&#xD;
          -  Decline physical function (walking speed &lt; 1 m/s) Group 3 (Either or both)&#xD;
&#xD;
          -  Abdominal obesity (&gt;88cm women, &gt;102cm men) AND hypertension (treated or resting blood&#xD;
             pressure &gt;140/90&#xD;
&#xD;
          -  Abdominal obesity (&gt;88cm women, &gt;102cm men) AND hyperlipidemia (treated or fasting&#xD;
             total cholesterol &gt;240 English literacy Willing to provide informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  eGFR &lt;45&#xD;
&#xD;
          -  Type 2 diabetes (HbA1c&gt;6.5) or type 1 diabetes&#xD;
&#xD;
          -  Any tobacco or nicotine product use in the past year&#xD;
&#xD;
          -  Low vitamin B12 Levels (&lt; 300 pg/mL)&#xD;
&#xD;
          -  Self-reported severe difficulty or inability to walk 400m or climb 10 steps (from Q 2&#xD;
             and 19 on PAT-D)&#xD;
&#xD;
          -  Self-reported difficulty or inability to perform basic ADL functions (from Q 10, 13,&#xD;
             14, 16 on PAT-D)&#xD;
&#xD;
          -  Excessive alcohol use (&gt;14 drinks/week)&#xD;
&#xD;
          -  Cancer requiring treatment in past year (except skin)&#xD;
&#xD;
          -  Dementia - diagnosed and/or MoCA score &lt;18&#xD;
&#xD;
          -  Parkinson's or other neurological disease&#xD;
&#xD;
          -  Chronic liver disease or cirrhosis&#xD;
&#xD;
          -  End stage renal disease or on dialysis&#xD;
&#xD;
          -  Rheumatic conditions (Rheumatoid arthritis, lupus, and any other autoimmune disease&#xD;
             the -PI deems them to be ineligible for)&#xD;
&#xD;
          -  Thyroid problems the PI deems them to be ineligible for&#xD;
&#xD;
          -  Gout&#xD;
&#xD;
          -  Involved in another interventional study&#xD;
&#xD;
          -  Hemoglobin &lt;8 or diagnosed with anemia&#xD;
&#xD;
          -  Recent unintentional weight change (+/- 10 lbs. in the last 12 months)&#xD;
&#xD;
          -  BMI &lt;18.5&#xD;
&#xD;
          -  Likely to not follow the protocol&#xD;
&#xD;
          -  PI deems unfit to participate&#xD;
&#xD;
          -  Already taking Metformin or any other drug intended to treat diabetes&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>65 Years</minimum_age>
    <maximum_age>79 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jingzhong Ding, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Wake Forest University Health Sciences</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Wake Forest Health Sciences</name>
      <address>
        <city>Winston-Salem</city>
        <state>North Carolina</state>
        <zip>27157</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2019</verification_date>
  <study_first_submitted>October 27, 2016</study_first_submitted>
  <study_first_submitted_qc>December 5, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 8, 2016</study_first_posted>
  <disposition_first_submitted>October 8, 2019</disposition_first_submitted>
  <disposition_first_submitted_qc>October 8, 2019</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">October 22, 2019</disposition_first_posted>
  <last_update_submitted>October 25, 2019</last_update_submitted>
  <last_update_submitted_qc>October 25, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">November 6, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Coronary Artery Disease</mesh_term>
    <mesh_term>Obesity, Abdominal</mesh_term>
    <mesh_term>Cognitive Dysfunction</mesh_term>
  </condition_browse>
  <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>
  </patient_data>
  <pending_results>
    <submitted>April 29, 2022</submitted>
    <submission_canceled>May 2, 2022</submission_canceled>
    <submitted>May 3, 2022</submitted>
    <returned>May 31, 2022</returned>
    <submitted>July 12, 2023</submitted>
    <returned>August 1, 2023</returned>
    <submitted>September 8, 2023</submitted>
  </pending_results>
  <!-- Results have not yet been posted, but a results disposition has been submitted           -->
</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/NCT02986659
org study id: IRB00034977
nct id: NCT02986659
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Medical scientists have found that people with diabetes who take the drug Metformin have less
      age-related disease than those taking other treatments and researchers believe it may prevent
      numerous diseases and conditions that effect older people. In addition, metformin extends
      lifespan in some animal models of human disease. The purpose of this study is to see if
      taking Metformin causes changes in blood cells consistent with improved health and longevity
      in people who do not have diabetes. In this study Metformin will be compared to placebo. A
      placebo is a substance, like a sugar pill, that is not thought to have any effect on a
      participants disease or condition. In this study participants will either receive the active
      study medication, Metformin or placebo which is not active. Placebos are used in research
      studies to see if the drug being studied really does have an effect.
The number of older adults is projected to increase dramatically by 2050. Aging-related
      diseases and conditions still seriously compromise the quality of life among most older
      adults. Several pharmaceutical agents, such as metformin, have been tested to extend lifespan
      and delay aging-related diseases and dysfunctions in mice. Metformin, a biguanide
      antidiabetic drug, reduces the risk for developing type-2 diabetes in persons at risk by over
      one-third with few adverse effects (e.g., gastrointestinal irritation). Metformin prevents
      type-2 diabetes primarily through decreasing hepatic glucose synthesis, as well as enhancing
      insulin sensitivity and increasing peripheral glucose uptake. The molecular mechanisms remain
      unclear, although a number of potential mechanism such as activation of AMP-activated protein
      kinase (AMPK) and inhibition of mitochondrial glycerophosphate dehydrogenase have been
      proposed. The fact that metformin treatment in persons with type-2 diabetes has been
      associated with reduced risk of other aging-related diseases and conditions, including
      cardiovascular disease, cancer and cognitive decline supports the possibility of the
      beneficial effects of metformin on healthy aging. It is imperative to capitalize on these
      leads to extend health span among older adults.

      To translate animal findings to human intervention trials, appropriate aging biomarkers are
      needed. Methylomic and transcriptomic profiles in relevant cells may reflect molecular
      features that mediate effects of both genetic and environmental factors on aging-related
      functional decline and disease. The roles of monocytes have been implicated in development of
      many aging-related diseases such as cardiovascular disease, cancer and neurodegenerative
      disease. In a cross-sectional association study of 1,200 monocyte samples, we identified
      1,794 age-associated methylation sites and 2,704 age-associated transcripts, which were
      over-represented in two networks (autophagy and oxidative phosphorylation) and suggestive of
      decline in those functions with age. Both autophagy and oxidative phosphorylation are
      considered as key contributors to the aging process, and their dysfunctions have been linked
      to aging-related diseases. Changes in these aging-related omic biomarkers may be early
      indicators of cellular damage or disruption that eventually leads to age-related
      dysfunctions. Assessment of these aging biomarkers in response to therapeutic intervention
      may also provide molecular insight for personalizing treatment. The investigators propose a
      pilot study to examine changes in aging-related omic profiles after 3 months of metformin
      treatment in 35 monocyte samples from older adults using a randomized, double-blind,
      placebo-controlled crossover study design.

      Our overarching goal of the pilot study is to evaluate the utility of using the aging-related
      omic biomarkers as an indicator of pharmacologic responses in the anti-aging therapeutic
      intervention trials through the following specific aims. Although this pilot study does not
      have sufficient power to definitively test all the aims, it will provide essential
      preliminary data for developing a full scale research program.

        -  Aim 1A: To test the effects of the metformin treatment on transcriptomic profiles and
           related functional changes in human monocytes,

        -  Aim 1B: To explore the effects of the metformin treatment on methylomic profiles in
           human monocytes,

        -  Aim 2: To investigate the longitudinal relationship between transcriptional and
           functional changes in human monocytes during the metformin treatment and

        -  Aim 3: To test the effects of the metformin treatment on frailty and other aging-related
           physical and cognitive measures and investigate the longitudinal relationship between
           these changes and transcriptional changes.

      A randomized, double-blind, placebo-controlled crossover trial in 30 participants using
      metformin and matching placebo will be used. In the absence of a treatment by sequence
      interaction effect, this design can increase study power for evaluating treatment effects by
      allowing each participant to be his/her own control. The period effect may be minimum because
      the primary outcomes, methylation and transcriptional measures, are relatively stable
      overtime.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Health Services Research
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change in eigengene scores
time frame: baseline, 12 weeks, 24 weeks
description: Individual methylation sites and transcripts, especially the eigengenes of autophage, oxidative phosphorylation and protein synthesis networks Methylomic and transcriptomic profiles in monocytes will be quantified using the Illumina HumanMethylation450 BeadChip and the Illumina HumanHT-12 v4 Expression BeadChips, respectively. All of these measures will be aggregated into one eigengene score.
arm group label: Metformin then Placebo
arm group type: Active Comparator
description: Metformin dosing at 425, 850 and 1700 mg with GLUCOPHAGE® (metformin hydrochloride) Tablets. Treatment with metformin will be initiated at a dose of 425 mg (half pill) taken orally once a day at night for 7 days. After the week, the participant will be called to assess tolerance and will be asked to increase dose to one pill at night at a dose of 850 mg for one week. At the end of the second week, participants will be called again and if they tolerated the second dose, they will be asked to take two 850 mg pills, one in the morning and one at night, for a total dose of 1700 mg which is within the range of the usual effective dose of 1500 to 2000 mg/day for the remainder of the 3 months. Will then cross over to 3 months on placebo.
arm group label: Placebo then Metormin
arm group type: Placebo Comparator
description: Dietary Supplement: Placebo with Methylcellulose capsules. Treatment with placebo will be initiated at a dose of a half pill taken orally once a day at night for 7 days. After the week, the participant will be called to assess tolerance and will be asked to increase dose to one pill at night for one week. At the end of the second week, participants will be called again and if they tolerated the second dose, they will be asked to take two pills, one in the morning and one at night for the remainder of the 3 months. After 3 months on placebo, participants will then cross over to 3 months of metformin as described in the other arm.
intervention type: Drug
intervention name: Metformin
arm group label: Metformin then Placebo
arm group label: Placebo then Metormin
intervention type: Drug
intervention name: Placebo
arm group label: Metformin then Placebo
arm group label: Placebo then Metormin
criteria: 
gender: All
minimum age: 65 Years
maximum age: 79 Years
healthy volunteers: No
last name: Jingzhong Ding, PhD
role: Principal Investigator
affiliation: Wake Forest University Health Sciences
facility: 
country: United States
responsible party type: Sponsor
mesh term: Coronary Artery Disease
mesh term: Obesity, Abdominal
mesh term: Cognitive Dysfunction
mesh term: Metformin
sharing ipd: No
submitted: April 29, 2022
submission canceled: May 2, 2022
submitted: May 3, 2022
returned: May 31, 2022
submitted: July 12, 2023
returned: August 1, 2023
submitted: September 8, 2023