<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/NCT02973477</url>
  </required_header>
  <id_info>
    <org_study_id>HUM00121107</org_study_id>
    <nct_id>NCT02973477</nct_id>
  </id_info>
  <brief_title>Dapagliflozin and Measures of Cardiovascular Autonomic Function in Patients With Type 2 Diabetes (T2D)</brief_title>
  <official_title>Dapagliflozin and Measures of Cardiovascular Autonomic Function in Patients With Type 2 Diabetes (T2D)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Michigan</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Michigan</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>
      The purpose of this study is to evaluate the effect of dapagliflozin, a FDA approved diabetes&#xD;
      medication, on measures of nervous system function of the heart in patients with type 2&#xD;
      diabetes. The investigators will compare the effect of dapagliflozin with an active&#xD;
      comparator, glimepiride (a different FDA approved diabetes medication) on measures of heart&#xD;
      rate variability and assess whether dapagliflozin has modulating effects on measures of&#xD;
      nervous system function of the heart. This is a crossover study design where all participants&#xD;
      will receive both study medications equally (12-week intervention periods) in a certain&#xD;
      order.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study rationale: Empagliflozin and dapagliflozin are sodium-glucose transporter-2 (SGLT-2)&#xD;
      inhibitors which prevent the reabsorption of glucose via proximal renal tubules, and are the&#xD;
      most recently approved class for treating hyperglycemia in type 2 diabetes. Besides effective&#xD;
      glucose lowering effects as documented by ~ 0.7-1.2% HbA1c reduction, these agents also&#xD;
      promote weight loss and reduce blood pressure (BP). Furthermore, recent data from the&#xD;
      Empagliflozin Cardiovascular Outcome Trial in type 2 diabetes (EMPA-REG OUTCOME) reported&#xD;
      significant reduction in main cardiovascular disease (CVD) outcomes and CVD death in patients&#xD;
      with type 2 diabetes (T2D). The exact mechanism of the beneficial effects on cardiovascular&#xD;
      outcomes is not yet understood, although their effects on body weight, glucose control and BP&#xD;
      reduction were suggested. However, other classes of drugs with similar effects such as GLP-1&#xD;
      receptor agonist, thiazolidinedione did not clearly show the beneficial effects in CVD&#xD;
      outcomes. The interesting observation is that improvement in BP with SGLT-2 inhibitors&#xD;
      occurred without a compensatory increase in HR and that most benefit was obtained also in&#xD;
      patients with some evidence of heart failure.&#xD;
&#xD;
      Thus, the investigators postulated the hypothesis that SGLT-2 may also have a modulatory&#xD;
      effect on the sympathetic/parasympathetic balance, and this may contribute to the potential&#xD;
      benefits on cardiovascular outcomes in patients with diabetes.&#xD;
&#xD;
      Study Design: The investigators plan to test this hypothesis in a randomized, double-blind,&#xD;
      2-period crossover clinical trial comparing 12-weeks of glycemic intervention with&#xD;
      dapagliflozin versus glimepiride. The investigators include an active comparator with&#xD;
      glimepiride which have a similar glucose lowering in patients with T2D, to account for the&#xD;
      effects of reductions in blood glucose on measures of CAN, and will evaluate whether changes&#xD;
      in measures of CAN are different among patients who are taking glimepiride or dapagliflozin.&#xD;
      The two crossover periods will be separated by a 2-week wash-out period.&#xD;
&#xD;
      All subjects will be allocated and randomized to each treatment sequence. Participants will&#xD;
      receive blindly either dapagliflozin 5 mg or glimepiride 2 mg 1 tablet daily initially for 4&#xD;
      weeks then titrating the dose based on blood glucose levels up to 2 tablets daily for 8 more&#xD;
      weeks (total 12 weeks) followed by 2-week washout period and then they will receive the study&#xD;
      drugs in reverse order to the first period during second crossover period for 12 weeks.&#xD;
&#xD;
      Study population: 45 patients with T2D on background metformin monotherapy who are not&#xD;
      meeting ADA recommended glycemic target.&#xD;
&#xD;
      Primary outcomes: changes in measures of cardiovascular autonomic neuropathy such as heart&#xD;
      rate variability (HRV) as defined by frequency domain measures of HRV: low frequency (LF)&#xD;
      power (ms2); high frequency (HF) power (ms2) as measured as LF:HF ratio.&#xD;
&#xD;
      Secondary outcomes: (i) changes in measures of HRV as defined by time domain measures of HRV:&#xD;
      standard deviation of the normal RR interval (SDNN) (msec) and root mean square of the&#xD;
      differences of successive RR intervals (rmsSD) (msec); (ii) changes in cardiovascular&#xD;
      autonomic reflex tests (CARTs) as defined by: expiration/inspiration (E/I) ratio, Valsalva&#xD;
      ratio, and 30:15 ratio; (iii) changes in measures of systolic and diastolic function will be&#xD;
      assessed by using stress echocardiogram and evaluate the following measures: i) LVEF, ii) LV&#xD;
      end diastolic volume, iii) LV end systolic volume, iv) LV mass, v) cardiac output.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 12, 2017</start_date>
  <completion_date type="Actual">August 22, 2019</completion_date>
  <primary_completion_date type="Actual">August 22, 2019</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>Treatment</primary_purpose>
    <masking>Single (Investigator)</masking>
    <masking_description>Randomization will be performed by the research Pharmacy. The study coordinator will not be blind to the randomization so that they can adequately discuss the medication with the participant. The study investigator will be blind to the randomization so as to not introduce bias in data qualification.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Changes in Measure of Heart Rate Variability Using Dapagliflozin vs Active Comparator Glimepiride.</measure>
    <time_frame>from first baseline to end of 12 weeks' treatment and from second baseline (following 2 weeks of washout) to end of 12 weeks' treatment</time_frame>
    <description>Heart Rate Variability, as shown by the difference of the LF:HF ratio from baseline to 12 weeks per arm (two 12-week periods with a 2-week washout period. The frequency domain measures [ low-frequency (LF) power (0.04-0.15 Hz), high-frequency (HF) power (0.15-0.4 Hz), and LF:HF ratio] are obtained by spectral analysis of R-R interval from continuous electrocardiogram recordings to evaluate for sympathetic/parasympathetic (autonomic nervous function) balance.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in Measures of Heart Rate Variability (HRV) Using Dapagliflozin vs Active Comparator Glimepiride.</measure>
    <time_frame>12 weeks on each intervention</time_frame>
    <description>Changes in measures of HRV as defined by: Time domain measures of HRV (continuous variables): (i) standard deviation of the normal RR interval (SDNN) (msec) and (ii) root mean square of the differences of successive RR intervals (rmsSD) (msec).&#xD;
Time domain (SDNN and rmsSD) measures of the normal R-R intervals are derived from HRV studies using a physiologic monitor (Nightingale PPM2; Zoe Medical Inc.) under paced breathing, reflecting parasympathetic activity.&#xD;
Time domain measures of the normal R-R intervals, basically reflecting parasympathetic activity, include: the difference between the longest and shortestR-R interval, standard deviation of 5-min average of normal R-R intervals (SDANN), root-mean square of the difference of successive R-R intervals (rMSSD).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs)</measure>
    <time_frame>12 weeks on each intervention</time_frame>
    <description>Changes in CARTs as defined by: i) expiration/inspiration (E/I) ratio, ii) Valsalva ratio and iii) 30:15 ratio. Cardiovascular autonomic reflex tests assess the cardiovascular autonomic function using provocative physiological maneuvers under paced breathing [R-R response to breathing (E:I ratio), to Valsalva maneuver (Valsalva ratio) and to postural changes (30:15 ratio)] at baseline and at the end of each study drug period using a physiologic monitor (Nightingale PPM2; Zoe Medical Inc.).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in B-type Natriuretic Peptide With Each Intervention as a Measure of Left Ventricular Function</measure>
    <time_frame>12 weeks for each intervention</time_frame>
    <description>Changes in B-type Natriuretic Peptide (BNP) with each intervention as a measure of left ventricular function.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Glucose Variability</measure>
    <time_frame>2 weeks on each intervention</time_frame>
    <description>Measures of glucose variability via the continuous glucose monitoring system Libre Pro</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">45</enrollment>
  <condition>Type2 Diabetes</condition>
  <condition>Cardiovascular Diseases</condition>
  <arm_group>
    <arm_group_label>Group A: Dapagliflozin/Glimepiride</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will take open-label dapagliflozin 5 mg daily for 4 weeks and escalate the dose gradually up to dapagliflozin 10 mg daily as needed based on their glucose monitoring for a total of 12 weeks on dapagliflozin. Patients will then begin a 2 week washout period where they are not taking any study drugs. After the washout period, participants will receive open-label glimepiride 2 mg daily for 4 weeks and escalate the dose gradually up to glimepiride 4 mg daily (no more than 4 mg daily) as needed based on their glucose monitoring for a total of 12 weeks on glimepiride.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group B: Glimepiride/Dapagliflozin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will take open-label glimepiride 2 mg daily for 4 weeks and escalate the dose gradually up to glimepiride 4 mg daily (no more than 4 mg daily) as needed based on their glucose monitoring for a total of 12 weeks on glimepiride. Patients will then begin a 2 week washout period where they are not taking any study drugs. After the washout period, participants will receive open-label dapagliflozin 5 mg daily for 4 weeks and escalate the dose gradually up to dapagliflozin 10 mg daily as needed based on their glucose monitoring for a total of 12 weeks on dapagliflozin.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dapagliflozin</intervention_name>
    <description>Dapagliflozin is a sodium glucose transporter-2 (SGLT-2) inhibitor, a new class of glucose lowering agent that reduces hyperglycemia in patients with T2D by reducing renal glucose reabsorption.</description>
    <arm_group_label>Group A: Dapagliflozin/Glimepiride</arm_group_label>
    <arm_group_label>Group B: Glimepiride/Dapagliflozin</arm_group_label>
    <other_name>Study Drug</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Glimepiride</intervention_name>
    <description>Glimepiride is a sulfonylurea agent that reduces hyperglycemia in patients with T2D by stimulating insulin release from the pancreatic beta cells and reduction of glucose output from the liver.</description>
    <arm_group_label>Group A: Dapagliflozin/Glimepiride</arm_group_label>
    <arm_group_label>Group B: Glimepiride/Dapagliflozin</arm_group_label>
    <other_name>Active Comparator</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients with type 2 diabetes as defined on background metformin monotherapy who are&#xD;
             not meeting ADA standard of care recommended glucose target.&#xD;
&#xD;
          2. Age ≥18 years&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. History of multiple urinary tract infections&#xD;
&#xD;
          2. Patients with mycotic infections especially genital infections.&#xD;
&#xD;
          3. Patients at risk for volume depletion due to co-existing conditions or concomitant&#xD;
             medications, such as loop diuretics should have careful monitoring of their volume&#xD;
             status. This is listed as exclusion criteria but then it says that they just need&#xD;
             careful monitoring. Is it an exclusion or not?&#xD;
&#xD;
          4. Severely hypotensive patients&#xD;
&#xD;
          5. History of unexplained microscopic or gross hematuria, or microscopic hematuria at&#xD;
             visit 1, confirmed by a follow-up sample at next scheduled visit.&#xD;
&#xD;
          6. Presence of hypersensitivity to dapagliflozin or other SGLT2 inhibitors (e.g.&#xD;
             anaphylaxis, angioedema, exfoliative skin conditions&#xD;
&#xD;
          7. Inability or refusal to comply with protocol&#xD;
&#xD;
          8. Current participation or participation in an experimental drug study in the previous&#xD;
             three months&#xD;
&#xD;
          9. History of diabetic ketoacidosis&#xD;
&#xD;
         10. Planned cardiac surgery or angioplasty within 3 months&#xD;
&#xD;
         11. Recent history of acute CV events such as MI, stroke, PAD within 3 months prior to&#xD;
             enrollment&#xD;
&#xD;
         12. Patients with severe renal impairment or unstable or rapidly progressing renal disease&#xD;
             or end stage renal disease.&#xD;
&#xD;
         13. Clinical conditions that could interfere with the cardiovascular autonomic function&#xD;
             and heart rate variability (arrhythmias)&#xD;
&#xD;
         14. Severe hepatic insufficiency and/or significant abnormal liver function (defined as&#xD;
             aspartate aminotransferase &gt;3× upper limit of normal (ULN) and/or alanine&#xD;
             aminotransferase &gt;3× ULN) or creatinine kinase &gt;3× ULN.&#xD;
&#xD;
         15. History of cancer other than basal cell carcinoma and/or treatment for cancer within&#xD;
             the last 5 years&#xD;
&#xD;
         16. Women of child-bearing potential who may be pregnant or lactating.&#xD;
&#xD;
         17. History of pancreas, kidney or liver transplant&#xD;
&#xD;
         18. History of drug or alcohol abuse&#xD;
&#xD;
         19. History of allergy to sulfa drugs&#xD;
&#xD;
         20. Presence of any condition that, in the opinion of the investigator would make it&#xD;
             unlikely for the subject to complete the study&#xD;
&#xD;
         21. Congestive heart failure (CHF) defined as New York Heart Association class III and IV&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Rodica Pop-Busui, M.D. Ph.D</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Michigan Department of Internal Medicine Division of Metabolism, Endocrinology and Diabetes</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Lynn P Ang, M.D</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Michigan Department of Internal Medicine Division of Metabolism, Endocrinology and Diabetes</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Michigan</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>November 16, 2016</study_first_submitted>
  <study_first_submitted_qc>November 21, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 25, 2016</study_first_posted>
  <results_first_submitted>August 17, 2020</results_first_submitted>
  <results_first_submitted_qc>October 21, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">October 22, 2020</results_first_posted>
  <last_update_submitted>October 21, 2020</last_update_submitted>
  <last_update_submitted_qc>October 21, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 22, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Michigan</investigator_affiliation>
    <investigator_full_name>Rodica Pop-Busui</investigator_full_name>
    <investigator_title>Professor of Internal Medicine</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cardiovascular Diseases</mesh_term>
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dapagliflozin</mesh_term>
    <mesh_term>Glimepiride</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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>March 10, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/77/NCT02973477/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>First Dapagliflozin Then Glimepiride</title>
          <description>Participants received open-label dapagliflozin 5 mg daily for 4 weeks and then the dose escalated gradually up to dapagliflozin 10 mg daily as needed based on their glucose monitoring for a total of 12 weeks on dapagliflozin. Patients then began a 2 week washout period where they did not take any study drugs. After the washout period, participants received open-label glimepiride 2 mg daily for 4 weeks and the dose escalated gradually up to glimepiride 4 mg daily (no more than 4 mg daily) as needed based on their glucose monitoring for a total of 12 weeks on glimepiride.</description>
        </group>
        <group group_id="P2">
          <title>First Glimepiride Then Dapagliflozin</title>
          <description>Participants received open-label glimepiride 2 mg daily for 4 weeks and the dose escalated gradually up to glimepiride 4 mg daily (no more than 4 mg daily) as needed based on their glucose monitoring for a total of 12 weeks on glimepiride. Patients then began a 2 week washout period where they did not take any study drugs. After the washout period, participants took open-label dapagliflozin 5 mg daily for 4 weeks and then the dose escalated gradually up to dapagliflozin 10 mg daily as needed based on their glucose monitoring for a total of 12 weeks on dapagliflozin.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>First Intervention</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="19"/>
                <participants group_id="P2" count="26"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="19"/>
                <participants group_id="P2" count="24"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Washout</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="19"/>
                <participants group_id="P2" count="24"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
                <participants group_id="P2" count="24"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Second Intervention</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
                <participants group_id="P2" count="24"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
                <participants group_id="P2" count="24"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>First Dapagliflozin Then Glimepiride</title>
          <description>Participants received open-label dapagliflozin 5 mg daily for 4 weeks and then the dose escalated gradually up to dapagliflozin 10 mg daily as needed based on their glucose monitoring for a total of 12 weeks on dapagliflozin. Patients then began a 2 week washout period where they did not take any study drugs. After the washout period, participants received open-label glimepiride 2 mg daily for 4 weeks and the dose escalated gradually up to glimepiride 4 mg daily (no more than 4 mg daily) as needed based on their glucose monitoring for a total of 12 weeks on glimepiride.</description>
        </group>
        <group group_id="B2">
          <title>First Glimepiride Then Dapagliflozin</title>
          <description>Participants received open-label glimepiride 2 mg daily for 4 weeks and the dose escalated gradually up to glimepiride 4 mg daily (no more than 4 mg daily) as needed based on their glucose monitoring for a total of 12 weeks on glimepiride. Patients then began a 2 week washout period where they did not take any study drugs. After the washout period, participants took open-label dapagliflozin 5 mg daily for 4 weeks and then the dose escalated gradually up to dapagliflozin 10 mg daily as needed based on their glucose monitoring for a total of 12 weeks on dapagliflozin.</description>
        </group>
        <group group_id="B3">
          <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="19"/>
            <count group_id="B2" value="26"/>
            <count group_id="B3" value="45"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="19"/>
                    <count group_id="B2" value="26"/>
                    <count group_id="B3" value="45"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="57" spread="9"/>
                    <measurement group_id="B2" value="56" spread="8"/>
                    <measurement group_id="B3" value="57" spread="8"/>
                  </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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="19"/>
                    <count group_id="B2" value="26"/>
                    <count group_id="B3" value="45"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="19"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="26"/>
                  </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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="19"/>
                    <count group_id="B2" value="26"/>
                    <count group_id="B3" value="45"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <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_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                  </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_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="18"/>
                    <measurement group_id="B3" value="30"/>
                  </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_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>LF:HF Ratio</title>
          <description>The frequency domain measures [ low-frequency (LF) power (0.04-0.15 Hz), high-frequency (HF) power (0.15-0.4 Hz), and LF:HF ratio] are obtained by spectral analysis of R-R interval from continuous electrocardiogram recordings to evaluate for sympathetic/parasympathetic (autonomic nervous function) balance.</description>
          <population>3 participants lost to follow up after baseline data collection.</population>
          <units>Ratio</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <title>Baseline before First Intervention</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="19"/>
                    <count group_id="B2" value="26"/>
                    <count group_id="B3" value="45"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1.00" spread="1.74"/>
                    <measurement group_id="B2" value="0.73" spread="1.31"/>
                    <measurement group_id="B3" value="0.84" spread="1.49"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Baseline before Second Intervention</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="18"/>
                    <count group_id="B2" value="24"/>
                    <count group_id="B3" value="42"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0.82" spread="1.32"/>
                    <measurement group_id="B2" value="0.35" spread="1.36"/>
                    <measurement group_id="B3" value="0.61" spread="1.46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Changes in Measure of Heart Rate Variability Using Dapagliflozin vs Active Comparator Glimepiride.</title>
        <description>Heart Rate Variability, as shown by the difference of the LF:HF ratio from baseline to 12 weeks per arm (two 12-week periods with a 2-week washout period. The frequency domain measures [ low-frequency (LF) power (0.04-0.15 Hz), high-frequency (HF) power (0.15-0.4 Hz), and LF:HF ratio] are obtained by spectral analysis of R-R interval from continuous electrocardiogram recordings to evaluate for sympathetic/parasympathetic (autonomic nervous function) balance.</description>
        <time_frame>from first baseline to end of 12 weeks' treatment and from second baseline (following 2 weeks of washout) to end of 12 weeks' treatment</time_frame>
        <population>All participants who completed both interventions were included in the analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>First Dapagliflozin Then Glimepiride</title>
            <description>Participants took open-label dapagliflozin 5 mg daily for 4 weeks and then the dose escalated gradually up to dapagliflozin 10 mg daily as needed based on their glucose monitoring for a total of 12 weeks on dapagliflozin. Patients then began a 2 week washout period where they did not take any study drugs. After the washout period, participants received open-label glimepiride 2 mg daily for 4 weeks and the dose escalated gradually up to glimepiride 4 mg daily (no more than 4 mg daily) as needed based on their glucose monitoring for a total of 12 weeks on glimepiride.</description>
          </group>
          <group group_id="O2">
            <title>First Glimepiride Then Dapagliflozin</title>
            <description>Participants received open-label glimepiride 2 mg daily for 4 weeks and the dose escalated gradually up to glimepiride 4 mg daily (no more than 4 mg daily) as needed based on their glucose monitoring for a total of 12 weeks on glimepiride. Patients then began a 2 week washout period where they did not take any study drugs. After the washout period, participants took open-label dapagliflozin 5 mg daily for 4 weeks and then the dose escalated gradually up to dapagliflozin 10 mg daily as needed based on their glucose monitoring for a total of 12 weeks on dapagliflozin.</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Measure of Heart Rate Variability Using Dapagliflozin vs Active Comparator Glimepiride.</title>
          <description>Heart Rate Variability, as shown by the difference of the LF:HF ratio from baseline to 12 weeks per arm (two 12-week periods with a 2-week washout period. The frequency domain measures [ low-frequency (LF) power (0.04-0.15 Hz), high-frequency (HF) power (0.15-0.4 Hz), and LF:HF ratio] are obtained by spectral analysis of R-R interval from continuous electrocardiogram recordings to evaluate for sympathetic/parasympathetic (autonomic nervous function) balance.</description>
          <population>All participants who completed both interventions were included in the analysis.</population>
          <units>LF:HF ratio</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>value at 12 weeks minus value at 1st baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.18" spread="1.51"/>
                    <measurement group_id="O2" value="-0.34" spread="1.54"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>value at 26 weeks minus value at 2nd baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.26" spread="1.85"/>
                    <measurement group_id="O2" value="0.26" spread="1.92"/>
                  </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_list>
            <groups_desc>This is the adjusted mixed models analysis for both periods, both arms, comparing each treatment's change.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Mixed effects model</non_inferiority_desc>
            <p_value>0.28</p_value>
            <p_value_desc>Adjusted analysis used a linear mixed effects model with unstructured covariance matrix controlled for possible period and sequence (carryover) effects for the outcome.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>Coefficient</param_type>
            <param_value>0.28</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.24</ci_lower_limit>
            <ci_upper_limit>0.8</ci_upper_limit>
            <estimate_desc>The outcome was logged in the model. The outcome was the natural log of that variable and the coefficient and CI are for the relationship with the log of the outcome.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Measures of Heart Rate Variability (HRV) Using Dapagliflozin vs Active Comparator Glimepiride.</title>
        <description>Changes in measures of HRV as defined by: Time domain measures of HRV (continuous variables): (i) standard deviation of the normal RR interval (SDNN) (msec) and (ii) root mean square of the differences of successive RR intervals (rmsSD) (msec).&#xD;
Time domain (SDNN and rmsSD) measures of the normal R-R intervals are derived from HRV studies using a physiologic monitor (Nightingale PPM2; Zoe Medical Inc.) under paced breathing, reflecting parasympathetic activity.&#xD;
Time domain measures of the normal R-R intervals, basically reflecting parasympathetic activity, include: the difference between the longest and shortestR-R interval, standard deviation of 5-min average of normal R-R intervals (SDANN), root-mean square of the difference of successive R-R intervals (rMSSD).</description>
        <time_frame>12 weeks on each intervention</time_frame>
        <population>All who started an intervention were included in analysis for Before treatment. Only those who completed it are included in After treatment. Changes in numbers represent participants from an arm leaving before completing an intervention. Since 3 people who began Glimepiride did not complete it, the 44 shown in &quot;Before&quot; reduces to 41 &quot;After&quot;.</population>
        <group_list>
          <group group_id="O1">
            <title>Participants Who Received Dapagliflozin Intervention</title>
            <description>Participants received open-label dapagliflozin 5 mg daily for 4 weeks and then the dose escalated gradually up to dapagliflozin 10 mg daily as needed based on their glucose monitoring for a total of 12 weeks on dapagliflozin, whether before or after washout.</description>
          </group>
          <group group_id="O2">
            <title>Participants Who Received Glimepiride Intervention</title>
            <description>Participants received open-label glimepiride 2 mg daily for 4 weeks and the dose escalated gradually up to glimepiride 4 mg daily (no more than 4 mg daily) as needed based on their glucose monitoring for a total of 12 weeks on glimepiride whether before or after washout.</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Measures of Heart Rate Variability (HRV) Using Dapagliflozin vs Active Comparator Glimepiride.</title>
          <description>Changes in measures of HRV as defined by: Time domain measures of HRV (continuous variables): (i) standard deviation of the normal RR interval (SDNN) (msec) and (ii) root mean square of the differences of successive RR intervals (rmsSD) (msec).&#xD;
Time domain (SDNN and rmsSD) measures of the normal R-R intervals are derived from HRV studies using a physiologic monitor (Nightingale PPM2; Zoe Medical Inc.) under paced breathing, reflecting parasympathetic activity.&#xD;
Time domain measures of the normal R-R intervals, basically reflecting parasympathetic activity, include: the difference between the longest and shortestR-R interval, standard deviation of 5-min average of normal R-R intervals (SDANN), root-mean square of the difference of successive R-R intervals (rMSSD).</description>
          <population>All who started an intervention were included in analysis for Before treatment. Only those who completed it are included in After treatment. Changes in numbers represent participants from an arm leaving before completing an intervention. Since 3 people who began Glimepiride did not complete it, the 44 shown in &quot;Before&quot; reduces to 41 &quot;After&quot;.</population>
          <units>msec</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="43"/>
                <count group_id="O2" value="44"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>SDNN before treatment</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="43"/>
                    <count group_id="O2" value="44"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="40.72" spread="16.63"/>
                    <measurement group_id="O2" value="39.75" spread="16.15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SDNN after treatment</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="43"/>
                    <count group_id="O2" value="41"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="37.74" spread="16.04"/>
                    <measurement group_id="O2" value="36.46" spread="17.68"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>rmsSD before treatment</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="43"/>
                    <count group_id="O2" value="44"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="26.91" spread="17.81"/>
                    <measurement group_id="O2" value="25.14" spread="13.06"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>rmsSD after treatment</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="43"/>
                    <count group_id="O2" value="41"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="24.30" spread="16.44"/>
                    <measurement group_id="O2" value="24.63" spread="17.38"/>
                  </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_list>
            <groups_desc>This is the adjusted analysis to compare the difference between the values from baseline to 12 weeks between each intervention for SDNN.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.97</p_value>
            <p_value_desc>Adjusted analysis used a linear mixed effects model with unstructured covariance matrix controlled for possible period and sequence (carryover) effects for the outcome.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>Coefficient</param_type>
            <param_value>-0.003</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.16</ci_lower_limit>
            <ci_upper_limit>0.15</ci_upper_limit>
            <estimate_desc>The outcome was logged in the model. The outcome was the natural log of that variable and the coefficient and CI are for the relationship with the log of the outcome.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>This is the adjusted analysis to compare the difference between the values from baseline to 12 weeks between each intervention for rmsSD.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.79</p_value>
            <p_value_desc>Adjusted analysis used a linear mixed effects model with unstructured covariance matrix controlled for possible period and sequence (carryover) effects for the outcome.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>Coefficient</param_type>
            <param_value>-0.02</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.21</ci_lower_limit>
            <ci_upper_limit>0.16</ci_upper_limit>
            <estimate_desc>The outcome was logged in the model. The outcome was the natural log of that variable and the coefficient and CI are for the relationship with the log of the outcome.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs)</title>
        <description>Changes in CARTs as defined by: i) expiration/inspiration (E/I) ratio, ii) Valsalva ratio and iii) 30:15 ratio. Cardiovascular autonomic reflex tests assess the cardiovascular autonomic function using provocative physiological maneuvers under paced breathing [R-R response to breathing (E:I ratio), to Valsalva maneuver (Valsalva ratio) and to postural changes (30:15 ratio)] at baseline and at the end of each study drug period using a physiologic monitor (Nightingale PPM2; Zoe Medical Inc.).</description>
        <time_frame>12 weeks on each intervention</time_frame>
        <population>All who started an intervention were included in Before rows if data was present. Only those who completed it are included in After treatment. Changes in numbers represent participants from an arm leaving before completing an intervention. Since 3 people who began Glimepiride did not complete it, the 44 shown in &quot;Before&quot; reduces to 41 &quot;After&quot;.</population>
        <group_list>
          <group group_id="O1">
            <title>All Participants Who Received Dapagliflozin</title>
            <description>Participants received open-label dapagliflozin 5 mg daily for 4 weeks and then the dose escalated gradually up to dapagliflozin 10 mg daily as needed based on their glucose monitoring for a total of 12 weeks on dapagliflozin, whether before or after washout.</description>
          </group>
          <group group_id="O2">
            <title>All Participants Who Received Glimiperide</title>
            <description>Participants received open-label glimepiride 2 mg daily for 4 weeks and the dose escalated gradually up to glimepiride 4 mg daily (no more than 4 mg daily) as needed based on their glucose monitoring for a total of 12 weeks on glimepiride.</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs)</title>
          <description>Changes in CARTs as defined by: i) expiration/inspiration (E/I) ratio, ii) Valsalva ratio and iii) 30:15 ratio. Cardiovascular autonomic reflex tests assess the cardiovascular autonomic function using provocative physiological maneuvers under paced breathing [R-R response to breathing (E:I ratio), to Valsalva maneuver (Valsalva ratio) and to postural changes (30:15 ratio)] at baseline and at the end of each study drug period using a physiologic monitor (Nightingale PPM2; Zoe Medical Inc.).</description>
          <population>All who started an intervention were included in Before rows if data was present. Only those who completed it are included in After treatment. Changes in numbers represent participants from an arm leaving before completing an intervention. Since 3 people who began Glimepiride did not complete it, the 44 shown in &quot;Before&quot; reduces to 41 &quot;After&quot;.</population>
          <units>ratio</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="43"/>
                <count group_id="O2" value="44"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>E/I ratio before treatment</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="43"/>
                    <count group_id="O2" value="44"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.13" spread="0.07"/>
                    <measurement group_id="O2" value="1.14" spread="0.08"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>EI ratio after treatment</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="43"/>
                    <count group_id="O2" value="41"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.14" spread="0.11"/>
                    <measurement group_id="O2" value="1.14" spread="0.13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Valsalva ratio before treatment</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="42"/>
                    <count group_id="O2" value="44"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.50" spread="0.36"/>
                    <measurement group_id="O2" value="1.44" spread="0.29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Valsalva ratio after treatment</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="43"/>
                    <count group_id="O2" value="41"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.60" spread="0.66"/>
                    <measurement group_id="O2" value="1.58" spread="0.85"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>30:15 ratio before treatment</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="42"/>
                    <count group_id="O2" value="44"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.17" spread="0.15"/>
                    <measurement group_id="O2" value="1.14" spread="0.09"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>30:15 ratio after treatment</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="43"/>
                    <count group_id="O2" value="41"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.14" spread="0.11"/>
                    <measurement group_id="O2" value="1.14" spread="0.10"/>
                  </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_list>
            <groups_desc>This is the adjusted analysis for both periods, both arms, comparing each treatment's change of EI ratio.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.58</p_value>
            <p_value_desc>Adjusted analysis used a linear mixed effects model with unstructured covariance matrix controlled for possible period and sequence (carryover) effects for the outcome.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>Coefficient</param_type>
            <param_value>0.01</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.02</ci_lower_limit>
            <ci_upper_limit>0.04</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>This is the adjusted analysis for both periods, both arms, comparing each treatment's change of Valsalva ratio.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.58</p_value>
            <p_value_desc>Adjusted analysis used a linear mixed effects model with unstructured covariance matrix controlled for possible period and sequence (carryover) effects for the outcome. Coefficient provided for Valsalva ratio.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>Coefficient</param_type>
            <param_value>0.02</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.05</ci_lower_limit>
            <ci_upper_limit>0.09</ci_upper_limit>
            <estimate_desc>The outcome was logged in the model. The outcome was the natural log of that variable and the coefficient and CI are for the relationship with the log of the outcome.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>This is the adjusted analysis for both periods, both arms, comparing each treatment's change of 30:15 ratio.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.56</p_value>
            <p_value_desc>Adjusted analysis used a linear mixed effects model with unstructured covariance matrix controlled for possible period and sequence (carryover) effects for the outcome. Coefficient provided for 30:15 ratio.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>Coefficient</param_type>
            <param_value>-0.01</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.05</ci_lower_limit>
            <ci_upper_limit>0.03</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in B-type Natriuretic Peptide With Each Intervention as a Measure of Left Ventricular Function</title>
        <description>Changes in B-type Natriuretic Peptide (BNP) with each intervention as a measure of left ventricular function.</description>
        <time_frame>12 weeks for each intervention</time_frame>
        <population>1 Glimiperide-first person's BNP measurement for Before treatment was missing. Only those who completed it are included in After treatment. Changes in numbers represent participants from an arm leaving before completing an intervention. Since 2 others who began Glimepiride did not complete it, the 43 shown in &quot;Before&quot; reduces to 41 &quot;After&quot;.</population>
        <group_list>
          <group group_id="O1">
            <title>All Participants Who Received Dapagliflozin</title>
            <description>Participants received open-label dapagliflozin 5 mg daily for 4 weeks and then the dose escalated gradually up to dapagliflozin 10 mg daily as needed based on their glucose monitoring for a total of 12 weeks on dapagliflozin, whether before or after washout.</description>
          </group>
          <group group_id="O2">
            <title>All Participants Who Received Glimepiride</title>
            <description>Participants received open-label glimepiride 2 mg daily for 4 weeks and the dose escalated gradually up to glimepiride 4 mg daily (no more than 4 mg daily) as needed based on their glucose monitoring for a total of 12 weeks on glimepiride.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in B-type Natriuretic Peptide With Each Intervention as a Measure of Left Ventricular Function</title>
          <description>Changes in B-type Natriuretic Peptide (BNP) with each intervention as a measure of left ventricular function.</description>
          <population>1 Glimiperide-first person's BNP measurement for Before treatment was missing. Only those who completed it are included in After treatment. Changes in numbers represent participants from an arm leaving before completing an intervention. Since 2 others who began Glimepiride did not complete it, the 43 shown in &quot;Before&quot; reduces to 41 &quot;After&quot;.</population>
          <units>pg/ml</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="43"/>
                <count group_id="O2" value="43"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>BNP before treatment</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="43"/>
                    <count group_id="O2" value="43"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12.72" spread="9.76"/>
                    <measurement group_id="O2" value="16.93" spread="13.69"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>BNP after treatment</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="43"/>
                    <count group_id="O2" value="41"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14.76" spread="13.41"/>
                    <measurement group_id="O2" value="15.49" spread="11.58"/>
                  </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_list>
            <groups_desc>This is the adjusted analysis for both periods, both arms, comparing each treatment's change of BNP.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.92</p_value>
            <p_value_desc>Adjusted analysis used a linear mixed effects model with unstructured covariance matrix controlled for possible period and sequence (carryover) effects for the outcome.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>Coefficient</param_type>
            <param_value>0.01</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.23</ci_lower_limit>
            <ci_upper_limit>0.25</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Glucose Variability</title>
        <description>Measures of glucose variability via the continuous glucose monitoring system Libre Pro</description>
        <time_frame>2 weeks on each intervention</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>26 weeks</time_frame>
      <desc>At each study visit, patients were asked about any change in medical history or status as well as adverse events, effects, or reactions. Patients also called the study team when they experienced issues. Patients were encouraged to inform the study team if any adverse events were experienced, regardless of relatedness.</desc>
      <group_list>
        <group group_id="E1">
          <title>Dapagliflozin</title>
          <description>Participants will take open-label dapagliflozin 5 mg daily for 4 weeks and escalate the dose gradually up to dapagliflozin 10 mg daily as needed based on their glucose monitoring for a total of 12 weeks on dapagliflozin.</description>
        </group>
        <group group_id="E2">
          <title>Glimepiride</title>
          <description>Participants will take open-label glimepiride 2 mg daily for 4 weeks and escalate the dose gradually up to glimepiride 4 mg daily (no more than 4 mg daily) as needed based on their glucose monitoring for a total of 12 weeks on glimepiride.</description>
        </group>
        <group group_id="E3">
          <title>Not on Drug</title>
          <description>Participants who were not on study drug, either prior to drug assignment, during washout or after ceasing taking drug prior to categorization as lost to follow up. Since all participants were definitionally present in the prior to drug assignment period, all are included here.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <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="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Pulmonary Embolism</sub_title>
                <description>Patient has a history of long airline travel</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</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="11" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="14" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial Fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Chest Pain</sub_title>
                <description>Nonspecific T-Wave changes on EKG - Possible relation to GERD - ED dx excluded cardiac ischemia</description>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Dizziness, Shakiness, Weakness and Sweaty</sub_title>
                <description>Not Hypoglycemic. Documented lowest glucose value was 92mg/dL.</description>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea, Vomiting and Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Abdominal Pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Genital Yeast Infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Cold Like Symptoms</sub_title>
                <description>In Not on Drug arm, participant experienced symptoms prior to randomization</description>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Stomach Virus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Urinary Tract Infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Strep Throat / Tonsillitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Food Poisoning</sub_title>
                <description>Vomiting and Diarrhea</description>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Ear and Sinus Infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Torn Left Hamstring</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Cut on Foot</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Abrasion of Left Cornea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Motor Vehicle Accident</sub_title>
                <description>Off Glimiperide due to prior Physician decision per protocol</description>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Right Leg Pain and Swelling</sub_title>
                <description>Right Leg Pain and Swelling - DVT was ruled out</description>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Diagnosis of Osteoporosis</sub_title>
                <description>Right First Metasophalangeal</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Left Shoulder Pain</sub_title>
                <description>Patient dispensed Glimepiride. Patient lost to follow up. Adverse event occurred between loss of contact and patient marked as lost to follow up</description>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Basal Cell Carcinoma</sub_title>
                <description>Removal of basal cell carcinoma completed</description>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Vasovagal Episode</sub_title>
                <description>Vasovagal episode resulting in vomiting due to blood draw</description>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Pins and Needles Sensation of Lower Extremities</sub_title>
                <description>Washout post-Dapagliflozin</description>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <description>Washout post-Glimepiride</description>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Worsening Depression and Mental Fogginess</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary Frequency and Discomfort - UTI Ruled Out</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Foot Ulcer</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Gull Bladder Removal</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Cataract Surgery</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="43"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE 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>Lynn Ang</name_or_title>
      <organization>University of Michigan</organization>
      <phone>734-232-8058</phone>
      <email>angly@med.umich.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/NCT02973477
org study id: HUM00121107
nct id: NCT02973477
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
The purpose of this study is to evaluate the effect of dapagliflozin, a FDA approved diabetes
      medication, on measures of nervous system function of the heart in patients with type 2
      diabetes. The investigators will compare the effect of dapagliflozin with an active
      comparator, glimepiride (a different FDA approved diabetes medication) on measures of heart
      rate variability and assess whether dapagliflozin has modulating effects on measures of
      nervous system function of the heart. This is a crossover study design where all participants
      will receive both study medications equally (12-week intervention periods) in a certain
      order.
Study rationale: Empagliflozin and dapagliflozin are sodium-glucose transporter-2 (SGLT-2)
      inhibitors which prevent the reabsorption of glucose via proximal renal tubules, and are the
      most recently approved class for treating hyperglycemia in type 2 diabetes. Besides effective
      glucose lowering effects as documented by ~ 0.7-1.2% HbA1c reduction, these agents also
      promote weight loss and reduce blood pressure (BP). Furthermore, recent data from the
      Empagliflozin Cardiovascular Outcome Trial in type 2 diabetes (EMPA-REG OUTCOME) reported
      significant reduction in main cardiovascular disease (CVD) outcomes and CVD death in patients
      with type 2 diabetes (T2D). The exact mechanism of the beneficial effects on cardiovascular
      outcomes is not yet understood, although their effects on body weight, glucose control and BP
      reduction were suggested. However, other classes of drugs with similar effects such as GLP-1
      receptor agonist, thiazolidinedione did not clearly show the beneficial effects in CVD
      outcomes. The interesting observation is that improvement in BP with SGLT-2 inhibitors
      occurred without a compensatory increase in HR and that most benefit was obtained also in
      patients with some evidence of heart failure.

      Thus, the investigators postulated the hypothesis that SGLT-2 may also have a modulatory
      effect on the sympathetic/parasympathetic balance, and this may contribute to the potential
      benefits on cardiovascular outcomes in patients with diabetes.

      Study Design: The investigators plan to test this hypothesis in a randomized, double-blind,
      2-period crossover clinical trial comparing 12-weeks of glycemic intervention with
      dapagliflozin versus glimepiride. The investigators include an active comparator with
      glimepiride which have a similar glucose lowering in patients with T2D, to account for the
      effects of reductions in blood glucose on measures of CAN, and will evaluate whether changes
      in measures of CAN are different among patients who are taking glimepiride or dapagliflozin.
      The two crossover periods will be separated by a 2-week wash-out period.

      All subjects will be allocated and randomized to each treatment sequence. Participants will
      receive blindly either dapagliflozin 5 mg or glimepiride 2 mg 1 tablet daily initially for 4
      weeks then titrating the dose based on blood glucose levels up to 2 tablets daily for 8 more
      weeks (total 12 weeks) followed by 2-week washout period and then they will receive the study
      drugs in reverse order to the first period during second crossover period for 12 weeks.

      Study population: 45 patients with T2D on background metformin monotherapy who are not
      meeting ADA recommended glycemic target.

      Primary outcomes: changes in measures of cardiovascular autonomic neuropathy such as heart
      rate variability (HRV) as defined by frequency domain measures of HRV: low frequency (LF)
      power (ms2); high frequency (HF) power (ms2) as measured as LF:HF ratio.

      Secondary outcomes: (i) changes in measures of HRV as defined by time domain measures of HRV:
      standard deviation of the normal RR interval (SDNN) (msec) and root mean square of the
      differences of successive RR intervals (rmsSD) (msec); (ii) changes in cardiovascular
      autonomic reflex tests (CARTs) as defined by: expiration/inspiration (E/I) ratio, Valsalva
      ratio, and 30:15 ratio; (iii) changes in measures of systolic and diastolic function will be
      assessed by using stress echocardiogram and evaluate the following measures: i) LVEF, ii) LV
      end diastolic volume, iii) LV end systolic volume, iv) LV mass, v) cardiac output.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Single (Investigator)
masking description: Randomization will be performed by the research Pharmacy. The study coordinator will not be blind to the randomization so that they can adequately discuss the medication with the participant. The study investigator will be blind to the randomization so as to not introduce bias in data qualification.
measure: Changes in Measure of Heart Rate Variability Using Dapagliflozin vs Active Comparator Glimepiride.
time frame: from first baseline to end of 12 weeks' treatment and from second baseline (following 2 weeks of washout) to end of 12 weeks' treatment
description: Heart Rate Variability, as shown by the difference of the LF:HF ratio from baseline to 12 weeks per arm (two 12-week periods with a 2-week washout period. The frequency domain measures [ low-frequency (LF) power (0.04-0.15 Hz), high-frequency (HF) power (0.15-0.4 Hz), and LF:HF ratio] are obtained by spectral analysis of R-R interval from continuous electrocardiogram recordings to evaluate for sympathetic/parasympathetic (autonomic nervous function) balance.
measure: Changes in Measures of Heart Rate Variability (HRV) Using Dapagliflozin vs Active Comparator Glimepiride.
time frame: 12 weeks on each intervention
description: Changes in measures of HRV as defined by: Time domain measures of HRV (continuous variables): (i) standard deviation of the normal RR interval (SDNN) (msec) and (ii) root mean square of the differences of successive RR intervals (rmsSD) (msec).
Time domain (SDNN and rmsSD) measures of the normal R-R intervals are derived from HRV studies using a physiologic monitor (Nightingale PPM2; Zoe Medical Inc.) under paced breathing, reflecting parasympathetic activity.
Time domain measures of the normal R-R intervals, basically reflecting parasympathetic activity, include: the difference between the longest and shortestR-R interval, standard deviation of 5-min average of normal R-R intervals (SDANN), root-mean square of the difference of successive R-R intervals (rMSSD).
measure: Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs)
time frame: 12 weeks on each intervention
description: Changes in CARTs as defined by: i) expiration/inspiration (E/I) ratio, ii) Valsalva ratio and iii) 30:15 ratio. Cardiovascular autonomic reflex tests assess the cardiovascular autonomic function using provocative physiological maneuvers under paced breathing [R-R response to breathing (E:I ratio), to Valsalva maneuver (Valsalva ratio) and to postural changes (30:15 ratio)] at baseline and at the end of each study drug period using a physiologic monitor (Nightingale PPM2; Zoe Medical Inc.).
measure: Change in B-type Natriuretic Peptide With Each Intervention as a Measure of Left Ventricular Function
time frame: 12 weeks for each intervention
description: Changes in B-type Natriuretic Peptide (BNP) with each intervention as a measure of left ventricular function.
measure: Glucose Variability
time frame: 2 weeks on each intervention
description: Measures of glucose variability via the continuous glucose monitoring system Libre Pro
arm group label: Group A: Dapagliflozin/Glimepiride
arm group type: Experimental
description: Participants will take open-label dapagliflozin 5 mg daily for 4 weeks and escalate the dose gradually up to dapagliflozin 10 mg daily as needed based on their glucose monitoring for a total of 12 weeks on dapagliflozin. Patients will then begin a 2 week washout period where they are not taking any study drugs. After the washout period, participants will receive open-label glimepiride 2 mg daily for 4 weeks and escalate the dose gradually up to glimepiride 4 mg daily (no more than 4 mg daily) as needed based on their glucose monitoring for a total of 12 weeks on glimepiride.
arm group label: Group B: Glimepiride/Dapagliflozin
arm group type: Experimental
description: Participants will take open-label glimepiride 2 mg daily for 4 weeks and escalate the dose gradually up to glimepiride 4 mg daily (no more than 4 mg daily) as needed based on their glucose monitoring for a total of 12 weeks on glimepiride. Patients will then begin a 2 week washout period where they are not taking any study drugs. After the washout period, participants will receive open-label dapagliflozin 5 mg daily for 4 weeks and escalate the dose gradually up to dapagliflozin 10 mg daily as needed based on their glucose monitoring for a total of 12 weeks on dapagliflozin.
intervention type: Drug
intervention name: Dapagliflozin
description: Dapagliflozin is a sodium glucose transporter-2 (SGLT-2) inhibitor, a new class of glucose lowering agent that reduces hyperglycemia in patients with T2D by reducing renal glucose reabsorption.
arm group label: Group A: Dapagliflozin/Glimepiride
arm group label: Group B: Glimepiride/Dapagliflozin
other name: Study Drug
intervention type: Drug
intervention name: Glimepiride
description: Glimepiride is a sulfonylurea agent that reduces hyperglycemia in patients with T2D by stimulating insulin release from the pancreatic beta cells and reduction of glucose output from the liver.
arm group label: Group A: Dapagliflozin/Glimepiride
arm group label: Group B: Glimepiride/Dapagliflozin
other name: Active Comparator
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Rodica Pop-Busui, M.D. Ph.D
role: Principal Investigator
affiliation: University of Michigan Department of Internal Medicine Division of Metabolism, Endocrinology and Diabetes
last name: Lynn P Ang, M.D
role: Principal Investigator
affiliation: University of Michigan Department of Internal Medicine Division of Metabolism, Endocrinology and Diabetes
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Michigan
investigator full name: Rodica Pop-Busui
investigator title: Professor of Internal Medicine
mesh term: Cardiovascular Diseases
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 2
mesh term: Dapagliflozin
mesh term: Glimepiride
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 