<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/NCT04401904</url>
  </required_header>
  <id_info>
    <org_study_id>HSC20190766H</org_study_id>
    <secondary_id>2P30AG044271</secondary_id>
    <nct_id>NCT04401904</nct_id>
  </id_info>
  <brief_title>SGLT2 Inhibition in Older Obese Adults With Pre-diabetes</brief_title>
  <acronym>SGLT2i</acronym>
  <official_title>Effect of SGLT2 Inhibition on Aging-related Biomarkers in Older Obese Adults With Pre-diabetes</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The University of Texas Health Science Center at San Antonio</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute on Aging (NIA)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>The University of Texas Health Science Center at San Antonio</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Inhibitors of the sodium-glucose co-transporter (SGLT2) are FDA-approved for the treatment of&#xD;
      type 2 diabetes (T2DM). Their mechanism of action involves lowering of blood glucose&#xD;
      concentration secondary to increased glucose excretion of glucose by the kidney. These drugs&#xD;
      also improve body weight, blood pressure, and cardiac function. Based on these pleiotropic&#xD;
      effects, including its calorie restriction-mimetic properties, the study team hypothesize&#xD;
      that SGLT2 drugs will impact several basic aging-related processes, including reductions in&#xD;
      oxidative damage to DNA and proteins, advanced glycation end products (AGE) and receptor for&#xD;
      AGE (RAGE), cellular senescence, and mitochondrial function.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Investigations into the aging process have identified major cellular dysfunctions that&#xD;
      contribute to aging, including but not limited to increased burden of damaged DNA and&#xD;
      protein, reduction in mitochondrial respiration, and the development of pro-inflammatory&#xD;
      senescent cells. Developing and testing interventions that interact with multiple points of&#xD;
      this spectrum may delay the aging process. Based on prior investigations, the study team&#xD;
      believe the SGLT2 inhibitor class of drugs may target these basic mechanisms involved in the&#xD;
      aging process and propose testing in a high-risk human population to evaluate their&#xD;
      effectiveness in ameliorating aging-associated dysfunctions. Specifically, the investigators&#xD;
      hypothesize that SGLT2i drugs will lead to reductions in oxidative damage to DNA and&#xD;
      proteins, AGE-RAGE, and cellular senescence, which will be accompanied by improvements in&#xD;
      mitochondrial function. If the hypothesis is correct, these findings could lead to the&#xD;
      development of new approaches to increase both health-span and lifespan.&#xD;
&#xD;
      This is a single center, open-label, randomized controlled trial. The target enrollment for&#xD;
      this pilot study is 20 completed subjects, split evenly between experimental and control&#xD;
      groups. Each subject will be randomized to either the experimental group of dapagliflozin&#xD;
      10mg daily for 12 weeks or the control group of nutritional counseling for weight loss.&#xD;
      Health-span and clinical evaluations will be taken at baseline and at weeks 10-12 of the&#xD;
      study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">June 25, 2020</start_date>
  <completion_date type="Anticipated">August 31, 2023</completion_date>
  <primary_completion_date type="Actual">September 14, 2022</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>20 completed subjects are planned. Each subject will be randomized to either the experimental group of dapagliflozin 10mg daily for 12 weeks or the control group of nutritional counseling for weight loss.</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>AGE-RAGE measurement in urine</measure>
    <time_frame>Baseline to 12 weeks</time_frame>
    <description>Change in AGE-RAGE measured by enzyme-linked immunosorbent assay (ELISA).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Mitochondrial Function</measure>
    <time_frame>Baseline to 12 weeks</time_frame>
    <description>Change % on muscle mitochondrial respiration measured in muscle tissue with Oroboros in O2 Flux per mg tissue.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Insulin Sensitivity</measure>
    <time_frame>Baseline to 12 weeks</time_frame>
    <description>Percentage of change in insulin sensitivity using the Matsuda index derived from the Oral GlucoseTolerance test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Oxidative Stress</measure>
    <time_frame>Baseline to 12 weeks</time_frame>
    <description>Change in reactive oxygen species (ROS) production using the Oxygraph instrument.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cellular Senescence</measure>
    <time_frame>Baseline to 12 weeks</time_frame>
    <description>Change in senescence cell markers (p16, p21, beta gal) measure by Reverse transcription polymerase chain reaction (RT PCR) (Australia (AU)).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DNA methylation</measure>
    <time_frame>Baseline to 12 weeks</time_frame>
    <description>Change in DNA methylation and epigenetic clock.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Grip Strength</measure>
    <time_frame>Baseline to 12 weeks</time_frame>
    <description>Change in grip strength measured using a hand-held dynamometer in Newton meters (Nm)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Isometric knee extension</measure>
    <time_frame>Baseline to 12 weeks</time_frame>
    <description>Change in isometric torque using a Biodex dynamometer (Nm)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>6 minute walking distance</measure>
    <time_frame>Baseline to 12 weeks</time_frame>
    <description>Change in walking distance in the 6 minute walking test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Volumes of maximal oxygen uptake (VO2 max)</measure>
    <time_frame>Baseline to 12 weeks</time_frame>
    <description>Change % in VO2 max measured by cardiopulmonary exercise testing (CPET)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Aging</condition>
  <arm_group>
    <arm_group_label>Dapagliflozin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>10 participants with pre-diabetes will be randomized to the experimental group to receive dapagliflozin 10mg by mouth daily for 12 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Nutritional Counseling</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>10 participants with pre-diabetes will be randomized to receive nutritional counseling weekly for 12 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dapagliflozin 10 mg</intervention_name>
    <description>10 participants randomized to receive 12 weeks of daily dapagliflozin 10mg by mouth</description>
    <arm_group_label>Dapagliflozin</arm_group_label>
    <other_name>Farxiga</other_name>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Nutritional counseling</intervention_name>
    <description>10 participants randomized to receive 12 weeks of weekly counseling on nutrition</description>
    <arm_group_label>Nutritional Counseling</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Men or post-menopausal women.&#xD;
&#xD;
          2. Age= 60+ years.&#xD;
&#xD;
          3. All ethnic groups.&#xD;
&#xD;
          4. Body Mass index (BMI) between 30-38 kg/m2.&#xD;
&#xD;
          5. Diagnosis of pre-diabetes (HbA1c 5.7-6.4% and 2 hr. Oral Glucose Tolerance Test (OGTT)&#xD;
             glucose between 140-199 mg/dL, evaluated at Visit 1 and 2).&#xD;
&#xD;
          6. Stable body weight (±3% for ≥3 months).&#xD;
&#xD;
          7. Willing to adhere to medication regimen for three months.&#xD;
&#xD;
          8. Montreal Cognitive Assessment score ≥21&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Diagnosis of diabetes based on American Diabetes Association (ADA) criteria&#xD;
&#xD;
          2. Impaired renal function with estimated Glomerular Filtration Rate (eGFR) &lt; 45&#xD;
             mL/min/1.73m2 .&#xD;
&#xD;
          3. Impaired liver function with labs ≥3 times upper limits of normal range&#xD;
&#xD;
          4. Abnormal hematocrit with lower limits of ≤30%&#xD;
&#xD;
          5. Abnormal triglycerides with upper limits ≥600 mg/dL&#xD;
&#xD;
          6. Abnormal Thyroid stimulating hormone (TSH) values ≤0.3 and ≥10&#xD;
&#xD;
          7. Urinalysis results with ˃ 5-10 white blood cell count&#xD;
&#xD;
          8. Concomitant medications known to affect glucose and lipid homeostasis (anti-diabetes&#xD;
             medications, glucocorticoids, atypical antipsychotics, anti-transplant rejection&#xD;
             medications, anti-retrovirals).&#xD;
&#xD;
          9. Current treatment with anticoagulants (warfarin). Aspirin (up to 325 mg) and&#xD;
             clopidogrel will be permitted if these can be held for seven days prior to the&#xD;
             biopsies.&#xD;
&#xD;
         10. History of recent cardiovascular event in the last 6 months or Heart Failure (New York&#xD;
             Heart Classification greater than class III-IV; recent EKG changes that suggest active&#xD;
             heart disease&#xD;
&#xD;
         11. Poorly controlled blood pressure (systolic BP&gt;180, diastolic BP&gt;100 mmHg).&#xD;
&#xD;
         12. Active inflammatory, autoimmune, infectious, hepatic, gastrointestinal, malignant, and&#xD;
             uncontrolled psychiatric disease (Subjects with depression, anxiety, PTSD, etc. can&#xD;
             enroll if controlled and on stable medication)&#xD;
&#xD;
         13. Blood donation within 2 months prior to enrollment&#xD;
&#xD;
         14. History of frequent UTI&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>60 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Carolina Solis-Herrera</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Texas Health at San Antonio</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Texas Diabetes Institute - University Health System</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78207</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Texas Health Science Center at San Antonio</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>April 22, 2020</study_first_submitted>
  <study_first_submitted_qc>May 20, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 26, 2020</study_first_posted>
  <last_update_submitted>July 25, 2023</last_update_submitted>
  <last_update_submitted_qc>July 25, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 28, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>pre-diabetes</keyword>
  <keyword>aging</keyword>
  <keyword>glucose metabolism</keyword>
  <keyword>borderline diabetes</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prediabetic State</mesh_term>
    <mesh_term>Glucose Intolerance</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dapagliflozin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Protocol, Statistical Analysis Plan, Published data</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_time_frame>After study completion, upon publication of data and on ClinicalTrials.gov 1 year after primary completion date of study.</ipd_time_frame>
    <ipd_access_criteria>Data will be analysed by a statistician for publication and by direct communication with the principal investigator</ipd_access_criteria>
  </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>October 30, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/04/NCT04401904/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>September 2, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/04/NCT04401904/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT04401904
org study id: HSC20190766H
secondary id: 2P30AG044271
nct id: NCT04401904
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Inhibitors of the sodium-glucose co-transporter (SGLT2) are FDA-approved for the treatment of
      type 2 diabetes (T2DM). Their mechanism of action involves lowering of blood glucose
      concentration secondary to increased glucose excretion of glucose by the kidney. These drugs
      also improve body weight, blood pressure, and cardiac function. Based on these pleiotropic
      effects, including its calorie restriction-mimetic properties, the study team hypothesize
      that SGLT2 drugs will impact several basic aging-related processes, including reductions in
      oxidative damage to DNA and proteins, advanced glycation end products (AGE) and receptor for
      AGE (RAGE), cellular senescence, and mitochondrial function.
Investigations into the aging process have identified major cellular dysfunctions that
      contribute to aging, including but not limited to increased burden of damaged DNA and
      protein, reduction in mitochondrial respiration, and the development of pro-inflammatory
      senescent cells. Developing and testing interventions that interact with multiple points of
      this spectrum may delay the aging process. Based on prior investigations, the study team
      believe the SGLT2 inhibitor class of drugs may target these basic mechanisms involved in the
      aging process and propose testing in a high-risk human population to evaluate their
      effectiveness in ameliorating aging-associated dysfunctions. Specifically, the investigators
      hypothesize that SGLT2i drugs will lead to reductions in oxidative damage to DNA and
      proteins, AGE-RAGE, and cellular senescence, which will be accompanied by improvements in
      mitochondrial function. If the hypothesis is correct, these findings could lead to the
      development of new approaches to increase both health-span and lifespan.

      This is a single center, open-label, randomized controlled trial. The target enrollment for
      this pilot study is 20 completed subjects, split evenly between experimental and control
      groups. Each subject will be randomized to either the experimental group of dapagliflozin
      10mg daily for 12 weeks or the control group of nutritional counseling for weight loss.
      Health-span and clinical evaluations will be taken at baseline and at weeks 10-12 of the
      study.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: 20 completed subjects are planned. Each subject will be randomized to either the experimental group of dapagliflozin 10mg daily for 12 weeks or the control group of nutritional counseling for weight loss.
primary purpose: Basic Science
masking: None (Open Label)
measure: AGE-RAGE measurement in urine
time frame: Baseline to 12 weeks
description: Change in AGE-RAGE measured by enzyme-linked immunosorbent assay (ELISA).
measure: Mitochondrial Function
time frame: Baseline to 12 weeks
description: Change % on muscle mitochondrial respiration measured in muscle tissue with Oroboros in O2 Flux per mg tissue.
measure: Insulin Sensitivity
time frame: Baseline to 12 weeks
description: Percentage of change in insulin sensitivity using the Matsuda index derived from the Oral GlucoseTolerance test.
measure: Oxidative Stress
time frame: Baseline to 12 weeks
description: Change in reactive oxygen species (ROS) production using the Oxygraph instrument.
measure: Cellular Senescence
time frame: Baseline to 12 weeks
description: Change in senescence cell markers (p16, p21, beta gal) measure by Reverse transcription polymerase chain reaction (RT PCR) (Australia (AU)).
measure: DNA methylation
time frame: Baseline to 12 weeks
description: Change in DNA methylation and epigenetic clock.
measure: Grip Strength
time frame: Baseline to 12 weeks
description: Change in grip strength measured using a hand-held dynamometer in Newton meters (Nm)
measure: Isometric knee extension
time frame: Baseline to 12 weeks
description: Change in isometric torque using a Biodex dynamometer (Nm)
measure: 6 minute walking distance
time frame: Baseline to 12 weeks
description: Change in walking distance in the 6 minute walking test.
measure: Volumes of maximal oxygen uptake (VO2 max)
time frame: Baseline to 12 weeks
description: Change % in VO2 max measured by cardiopulmonary exercise testing (CPET)
arm group label: Dapagliflozin
arm group type: Experimental
description: 10 participants with pre-diabetes will be randomized to the experimental group to receive dapagliflozin 10mg by mouth daily for 12 weeks.
arm group label: Nutritional Counseling
arm group type: Other
description: 10 participants with pre-diabetes will be randomized to receive nutritional counseling weekly for 12 weeks
intervention type: Drug
intervention name: Dapagliflozin 10 mg
description: 10 participants randomized to receive 12 weeks of daily dapagliflozin 10mg by mouth
arm group label: Dapagliflozin
other name: Farxiga
intervention type: Behavioral
intervention name: Nutritional counseling
description: 10 participants randomized to receive 12 weeks of weekly counseling on nutrition
arm group label: Nutritional Counseling
criteria: 
gender: All
minimum age: 60 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Carolina Solis-Herrera
role: Principal Investigator
affiliation: University of Texas Health at San Antonio
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Prediabetic State
mesh term: Glucose Intolerance
mesh term: Dapagliflozin
sharing ipd: Yes
ipd description: Protocol, Statistical Analysis Plan, Published data
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd time frame: After study completion, upon publication of data and on ClinicalTrials.gov 1 year after primary completion date of study.
ipd access criteria: Data will be analysed by a statistician for publication and by direct communication with the principal investigator
provided document: 
provided document: 