<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/NCT02984644</url>
  </required_header>
  <id_info>
    <org_study_id>HSC20160586H</org_study_id>
    <nct_id>NCT02984644</nct_id>
  </id_info>
  <brief_title>Paradoxical Stimulation of Hepatic Glucose Production With Dapagliflozin</brief_title>
  <acronym>AZ11040</acronym>
  <official_title>Paradoxical Stimulation of Hepatic Glucose Production With Dapagliflozin (P2)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The University of Texas Health Science Center at San Antonio</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The University of Texas Health Science Center at San Antonio</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      To determine the role of plasma glucagon and insulin in the rise of endogenous glucose&#xD;
      production (EGP) following the SGLT2 inhibition.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The increase in plasma glucagon conc and/or decrease in plasma insulin conc in response to&#xD;
      glucosuria is (are) important signal(s) responsible, at least in part, for the increase in&#xD;
      EGP, which the investigators anticipate will be derived primarily from the liver. Insulin and&#xD;
      glucagon are powerful regulators of HGP. Therefore, the investigators anticipate that, at&#xD;
      least in part, an increase in HGP secondary to the rise in plasma glucagon concentration and&#xD;
      decrease in plasma insulin concentration in response to dapagliflozin-induced glucosuria will&#xD;
      account for the majority of increase in EGP in both NGT and T2DM subjects. This study will&#xD;
      define whether the increase in plasma glucagon and/or the decrease in plasma insulin are the&#xD;
      trigger to stimulate EGP. Eligible subjects will receive three 5-hour measurements of&#xD;
      endogenous glucose production (EGP), which is the biosynthesis of new glucose, with&#xD;
      administration of study drug after a 3-hour tracer equilibration period. Hepatic glucose&#xD;
      production (HGP), which is the net release of glucose from the liver, will be measured for 5&#xD;
      hours after drug administration to allow sufficient time for a significant increase in HGP&#xD;
      above baseline after dapagliflozin administration (10). In study 1, HGP will be measured for&#xD;
      5 hours after dapagliflozin (10 mg) or placebo administration. This is the control study. The&#xD;
      investigators expect to observe the &quot;paradoxical&quot; rise in EGP following dapagliflozin. Study&#xD;
      2 will be performed under glucose clamp conditions (i.e. maintaining the plasma glucose&#xD;
      concentration stable at each subject's fasting level). This study will define whether the&#xD;
      decline in plasma glucose concentration is the trigger to stimulate EGP. Study 3 will be&#xD;
      performed under pancreatic clamp conditions (maintaining the plasma glucagon and insulin&#xD;
      concentrations constant at the basal level). This study will define whether the increase in&#xD;
      plasma glucagon and/or the decrease in plasma insulin are the trigger to stimulate EGP.&#xD;
      Subjects will be randomized in a 2:1 ratio; 32 subjects will receive dapagliflozin and 16&#xD;
      subjects will receive placebo. Each study will be performed on a separate day, after a 10-12&#xD;
      hour overnight fast within 1-2 week period. Following studies 1-3, subjects will return for a&#xD;
      renal (kidney) MRI-measurement to record kidney size.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 6, 2017</start_date>
  <completion_date type="Actual">November 16, 2019</completion_date>
  <primary_completion_date type="Actual">November 16, 2018</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Measurement of the Change in Plasma Glucose (mg/dL): Study 1</measure>
    <time_frame>Baseline to 240-300 minutes</time_frame>
    <description>Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose concentration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Plasma Glucose Measurement Using a Glucose Clamp: Study 2</measure>
    <time_frame>Baseline to 240-300 minutes</time_frame>
    <description>Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose for study 2: EGP plus glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Plasma Glucose Using a Pancreatic Clamp: Study 3</measure>
    <time_frame>Baseline to 240-300 minutes</time_frame>
    <description>Change from Baseline to the last hour of the study (240-300 minutes) in plasma glucose using a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in EGP: Study 1</measure>
    <time_frame>Baseline to 240-300 minutes</time_frame>
    <description>Change from baseline to the last hour of the study (240-300 minutes) in EGP</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in EGP With Glucose Clamp: Study 2</measure>
    <time_frame>Baseline to 240-300 minutes</time_frame>
    <description>Change from baseline to the last hour of the study (240-300 minutes) in EGP using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in EGP With Pancreatic Clamp: Study 3</measure>
    <time_frame>Baseline to 240-300 minutes</time_frame>
    <description>Change from baseline to the last hour of the study (240-300 minutes) of EGP with a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.VIn this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Plasma Insulin Concentrations: Study 1</measure>
    <time_frame>Baseline to 240-300 minutes</time_frame>
    <description>Plasma insulin concentrations during measurement of EGP</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Insulin Concentrations During Measurement of EGP Plus Glucose Clamp: Study 2</measure>
    <time_frame>Baseline to 240-300 minutes</time_frame>
    <description>Plasma insulin concentration is measured from baseline to the last hour of the study while using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Plasma Insulin While Using Pancreatic Clamp: Study 3</measure>
    <time_frame>Baseline to last hour of the study</time_frame>
    <description>Plasma insulin concentration during measurement of EGP while using pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Glucagon: Study 1</measure>
    <time_frame>Baseline to 240-300 minutes</time_frame>
    <description>Change in glucagon concentrations during measurement of EGP</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Glucagon Using Glucose Clamp: Study 2</measure>
    <time_frame>Baseline to 240-300 minutes</time_frame>
    <description>Plasma glucagon concentration during measurement of EGP using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Glucagon Using Pancreatic Clamp: Study 3</measure>
    <time_frame>Baseline to 240-300 minutes</time_frame>
    <description>Measurement of change in plasma glucagon from baseline to one hour prior to end of study while using a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Type II; Diabetes</condition>
  <arm_group>
    <arm_group_label>Dapagliflozin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>32 subjects will receive dapagliflozin 10mg</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>16 subjects will receive placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dapagliflozin</intervention_name>
    <description>Three 5-hour measurements (after dapagliflozin 10mg administration) of endogenous glucose production (EGP) will be performed on separate days.</description>
    <arm_group_label>Dapagliflozin</arm_group_label>
    <other_name>Farxiga</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Three 5-hour measurements (after placebo administration) of endogenous glucose production (EGP) will be performed on separate days.</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Placebo for Dapagliflozin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  T2DM according to ADA criteria-HbA1C &lt; 8.0%&#xD;
&#xD;
          -  BMI = 25-35 kg/m2&#xD;
&#xD;
          -  Subjects must be in good general health as determined by physical exam, medical&#xD;
             history, blood chemistries, CBC, TSH, T4, EKG and urinanalysis&#xD;
&#xD;
          -  Body weight has been stable (± 3 lbs) over the preceding three months&#xD;
&#xD;
          -  Do not participate in an excessively heavy exercise program&#xD;
&#xD;
          -  Taking stable dose (more than 3 months) of monotherapy or combination therapy with&#xD;
             metformin and/or a sulfonylurea&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subjects taking drugs known to affect glucose metabolism (other than metformin and&#xD;
             sulfonylurea) will be excluded&#xD;
&#xD;
          -  Individuals with evidence of proliferative diabetic retinopathy, plasma creatinine&#xD;
             &gt;1.4 females or &gt;1.5 males, or 24-hour urine albumin excretion &gt; 300 mg will be&#xD;
             excluded&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Eugenio Cersosimo, MD,PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>The University of Texas Health Science Center at San Antonio</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Texas Health Science Center</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2019</verification_date>
  <study_first_submitted>November 30, 2016</study_first_submitted>
  <study_first_submitted_qc>December 2, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 7, 2016</study_first_posted>
  <results_first_submitted>November 8, 2019</results_first_submitted>
  <results_first_submitted_qc>December 2, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">December 18, 2019</results_first_posted>
  <last_update_submitted>December 2, 2019</last_update_submitted>
  <last_update_submitted_qc>December 2, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">December 18, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>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>
  </intervention_browse>
  <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>September 18, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/44/NCT02984644/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Dapagliflozin</title>
          <description>Subjects will receive dapagliflozin 10mg&#xD;
Dapagliflozin: Three 5-hour measurements (after dapagliflozin 10mg administration) of endogenous glucose production (EGP) will be performed on separate days.</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>Subjects will receive placebo&#xD;
Placebo: Three 5-hour measurements (after placebo administration) of endogenous glucose production (EGP) will be performed on separate days.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
                <participants group_id="P2" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
                <participants group_id="P2" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Dapagliflozin</title>
          <description>Subjects will receive dapagliflozin 10mg&#xD;
Dapagliflozin: Three 5-hour measurements (after dapagliflozin 10mg administration) of endogenous glucose production (EGP) will be performed on separate days.</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>Subjects will receive placebo&#xD;
Placebo: Three 5-hour measurements (after placebo administration) of endogenous glucose production (EGP) will be performed on separate days.</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="20"/>
            <count group_id="B2" value="10"/>
            <count group_id="B3" value="30"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="55" spread="2"/>
                    <measurement group_id="B2" value="53" spread="2"/>
                    <measurement group_id="B3" value="54" spread="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <population>30 participants were randomized: 20 to the Dapagliflozin and 10 to the placebo arm of the study</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="18"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Hispanic</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Caucasian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>African American</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Measurement of the Change in Plasma Glucose (mg/dL): Study 1</title>
        <description>Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose concentration</description>
        <time_frame>Baseline to 240-300 minutes</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dapagliflozin 10mg</title>
            <description>Change in plasma glucose concentration to show effect of Dapagliflozin on EGP (endogenous glucose production)</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Change in plasma glucose concentration after placebo administration</description>
          </group>
        </group_list>
        <measure>
          <title>Measurement of the Change in Plasma Glucose (mg/dL): Study 1</title>
          <description>Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose concentration</description>
          <units>mg/dl</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-29" spread="4"/>
                    <measurement group_id="O2" value="-17" spread="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Change in Plasma Glucose Measurement Using a Glucose Clamp: Study 2</title>
        <description>Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose for study 2: EGP plus glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)</description>
        <time_frame>Baseline to 240-300 minutes</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dapagliflozin 10mg</title>
            <description>Change in plasma glucose concentration to show effect of Dapagliflozin on EGP (endogenous glucose production) using a glucose clamp</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Change in plasma glucose concentration after placebo administration using a glucose clamp</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Plasma Glucose Measurement Using a Glucose Clamp: Study 2</title>
          <description>Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose for study 2: EGP plus glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)</description>
          <units>mg/dl</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3" spread="1"/>
                    <measurement group_id="O2" value="1" spread="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Change in Plasma Glucose Using a Pancreatic Clamp: Study 3</title>
        <description>Change from Baseline to the last hour of the study (240-300 minutes) in plasma glucose using a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.</description>
        <time_frame>Baseline to 240-300 minutes</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dapagliflozin 10mg</title>
            <description>Change in plasma glucose concentration to show effect of Dapagliflozin on plasma glucose concentration</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Change in plasma glucose concentration after placebo administration</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Plasma Glucose Using a Pancreatic Clamp: Study 3</title>
          <description>Change from Baseline to the last hour of the study (240-300 minutes) in plasma glucose using a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.</description>
          <units>mg/dl</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-30" spread="4"/>
                    <measurement group_id="O2" value="-7" spread="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Change in EGP: Study 1</title>
        <description>Change from baseline to the last hour of the study (240-300 minutes) in EGP</description>
        <time_frame>Baseline to 240-300 minutes</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dapagliflozin</title>
            <description>Subjects will receive dapagliflozin 10mg&#xD;
Dapagliflozin: Three 5-hour measurements (after dapagliflozin 10mg administration) of endogenous glucose production (EGP) will be performed on separate days.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Subjects will receive placebo&#xD;
Placebo: Three 5-hour measurements (after placebo administration) of endogenous glucose production (EGP) will be performed on separate days.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in EGP: Study 1</title>
          <description>Change from baseline to the last hour of the study (240-300 minutes) in EGP</description>
          <units>mg/kg.min</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.10" spread="0.1"/>
                    <measurement group_id="O2" value="-0.56" spread="0.11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Change in EGP With Glucose Clamp: Study 2</title>
        <description>Change from baseline to the last hour of the study (240-300 minutes) in EGP using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)</description>
        <time_frame>Baseline to 240-300 minutes</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dapagliflozin 10mg</title>
            <description>Change in EGP (endogenous glucose production) after dapagliflozin administration</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Change in EGP concentration after placebo administration</description>
          </group>
        </group_list>
        <measure>
          <title>Change in EGP With Glucose Clamp: Study 2</title>
          <description>Change from baseline to the last hour of the study (240-300 minutes) in EGP using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)</description>
          <units>mg/kg.min</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.57" spread="0.12"/>
                    <measurement group_id="O2" value="-1.28" spread="0.172"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Change in EGP With Pancreatic Clamp: Study 3</title>
        <description>Change from baseline to the last hour of the study (240-300 minutes) of EGP with a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.VIn this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.</description>
        <time_frame>Baseline to 240-300 minutes</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dapagliflozin 10mg</title>
            <description>Change in EGP (endogenous glucose production) after dapagliflozin administration using a pancreatic clamp</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Change in EGP concentration after placebo administration using a pancreatic clamp</description>
          </group>
        </group_list>
        <measure>
          <title>Change in EGP With Pancreatic Clamp: Study 3</title>
          <description>Change from baseline to the last hour of the study (240-300 minutes) of EGP with a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.VIn this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.</description>
          <units>mg/kg.min</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.23" spread="0.09"/>
                    <measurement group_id="O2" value="-0.48" spread="0.05"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Plasma Insulin Concentrations: Study 1</title>
        <description>Plasma insulin concentrations during measurement of EGP</description>
        <time_frame>Baseline to 240-300 minutes</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dapagliflozin</title>
            <description>Subjects will receive dapagliflozin 10mg. Change in plasma insulin level is measured at baseline minus the last hour of the study.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Subjects will receive placebo. Change in plasma insulin level is measured at baseline minus the last hour of the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Plasma Insulin Concentrations: Study 1</title>
          <description>Plasma insulin concentrations during measurement of EGP</description>
          <units>microUnits/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="20"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5" spread="1"/>
                    <measurement group_id="O2" value="3" spread="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Plasma Insulin Concentrations During Measurement of EGP Plus Glucose Clamp: Study 2</title>
        <description>Plasma insulin concentration is measured from baseline to the last hour of the study while using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)</description>
        <time_frame>Baseline to 240-300 minutes</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dapagliflozin</title>
            <description>Subjects will receive dapagliflozin 10mg. Change in plasma insulin level is measured at baseline minus the last hour of the study while using glucose clamp.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Subjects will receive placebo. Change in plasma insulin level is measured at baseline minus the last hour of the study while using glucose clamp.</description>
          </group>
        </group_list>
        <measure>
          <title>Plasma Insulin Concentrations During Measurement of EGP Plus Glucose Clamp: Study 2</title>
          <description>Plasma insulin concentration is measured from baseline to the last hour of the study while using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)</description>
          <units>microUnits/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="20"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0" spread="1"/>
                    <measurement group_id="O2" value="0" spread="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Plasma Insulin While Using Pancreatic Clamp: Study 3</title>
        <description>Plasma insulin concentration during measurement of EGP while using pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.</description>
        <time_frame>Baseline to last hour of the study</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dapagliflozin</title>
            <description>Subjects will receive dapagliflozin 10mg. Change in plasma insulin level is measured at baseline minus the last hour of the study while using pancreatic clamp.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Subjects will receive placebo. Change in plasma insulin level is measured at baseline minus the last hour of the study while using pancreatic clamp.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Plasma Insulin While Using Pancreatic Clamp: Study 3</title>
          <description>Plasma insulin concentration during measurement of EGP while using pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.</description>
          <units>microUnits/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="20"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2" spread="1"/>
                    <measurement group_id="O2" value="0" spread="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Glucagon: Study 1</title>
        <description>Change in glucagon concentrations during measurement of EGP</description>
        <time_frame>Baseline to 240-300 minutes</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dapagliflozin</title>
            <description>Subjects will receive dapagliflozin 10mg. Change in plasma glucagon level is measured at baseline minus the last hour of the study.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Subjects will receive placebo. Change in plasma glucagon level is measured at baseline minus the last hour of the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Glucagon: Study 1</title>
          <description>Change in glucagon concentrations during measurement of EGP</description>
          <units>ng/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="20"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5" spread="2"/>
                    <measurement group_id="O2" value="-1" spread="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Glucagon Using Glucose Clamp: Study 2</title>
        <description>Plasma glucagon concentration during measurement of EGP using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism.</description>
        <time_frame>Baseline to 240-300 minutes</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dapagliflozin</title>
            <description>Subjects will receive dapagliflozin 10mg. Change in plasma glucagon level is measured at baseline minus the last hour of the study while using a glucose clamp.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Subjects will receive placebo. Change in plasma glucagon level is measured at baseline minus the last hour of the study while using a glucose clamp.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Glucagon Using Glucose Clamp: Study 2</title>
          <description>Plasma glucagon concentration during measurement of EGP using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism.</description>
          <units>ng/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="20"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-6" spread="2"/>
                    <measurement group_id="O2" value="-7" spread="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Glucagon Using Pancreatic Clamp: Study 3</title>
        <description>Measurement of change in plasma glucagon from baseline to one hour prior to end of study while using a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.</description>
        <time_frame>Baseline to 240-300 minutes</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dapagliflozin</title>
            <description>Subjects will receive dapagliflozin 10mg. Change in plasma glucagon level is measured at baseline minus the last hour of the study while using a pancreatic clamp.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Subjects will receive placebo. Change in plasma glucagon level is measured at baseline minus the last hour of the study while using a pancreatic clamp.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Glucagon Using Pancreatic Clamp: Study 3</title>
          <description>Measurement of change in plasma glucagon from baseline to one hour prior to end of study while using a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.</description>
          <units>ng/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="20"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1" spread="1"/>
                    <measurement group_id="O2" value="-2" spread="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>On each study day: Study start at 6am until study ends at 2pm.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Dapagliflozin</title>
          <description>20 subjects will receive dapagliflozin 10mg&#xD;
Dapagliflozin: Three 5-hour measurements (after dapagliflozin 10mg administration) of endogenous glucose production (EGP) will be performed on separate days.</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>10 subjects will receive placebo&#xD;
Placebo: Three 5-hour measurements (after placebo administration) of endogenous glucose production (EGP) will be performed on separate days.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Eugenio Cersosimo</name_or_title>
      <organization>University of Texas Health Science Center at San Antonio</organization>
      <phone>210-358-7200</phone>
      <email>cersosimo@uthscsa.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/NCT02984644
org study id: HSC20160586H
nct id: NCT02984644
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
To determine the role of plasma glucagon and insulin in the rise of endogenous glucose
      production (EGP) following the SGLT2 inhibition.
The increase in plasma glucagon conc and/or decrease in plasma insulin conc in response to
      glucosuria is (are) important signal(s) responsible, at least in part, for the increase in
      EGP, which the investigators anticipate will be derived primarily from the liver. Insulin and
      glucagon are powerful regulators of HGP. Therefore, the investigators anticipate that, at
      least in part, an increase in HGP secondary to the rise in plasma glucagon concentration and
      decrease in plasma insulin concentration in response to dapagliflozin-induced glucosuria will
      account for the majority of increase in EGP in both NGT and T2DM subjects. This study will
      define whether the increase in plasma glucagon and/or the decrease in plasma insulin are the
      trigger to stimulate EGP. Eligible subjects will receive three 5-hour measurements of
      endogenous glucose production (EGP), which is the biosynthesis of new glucose, with
      administration of study drug after a 3-hour tracer equilibration period. Hepatic glucose
      production (HGP), which is the net release of glucose from the liver, will be measured for 5
      hours after drug administration to allow sufficient time for a significant increase in HGP
      above baseline after dapagliflozin administration (10). In study 1, HGP will be measured for
      5 hours after dapagliflozin (10 mg) or placebo administration. This is the control study. The
      investigators expect to observe the "paradoxical" rise in EGP following dapagliflozin. Study
      2 will be performed under glucose clamp conditions (i.e. maintaining the plasma glucose
      concentration stable at each subject's fasting level). This study will define whether the
      decline in plasma glucose concentration is the trigger to stimulate EGP. Study 3 will be
      performed under pancreatic clamp conditions (maintaining the plasma glucagon and insulin
      concentrations constant at the basal level). This study will define whether the increase in
      plasma glucagon and/or the decrease in plasma insulin are the trigger to stimulate EGP.
      Subjects will be randomized in a 2:1 ratio; 32 subjects will receive dapagliflozin and 16
      subjects will receive placebo. Each study will be performed on a separate day, after a 10-12
      hour overnight fast within 1-2 week period. Following studies 1-3, subjects will return for a
      renal (kidney) MRI-measurement to record kidney size.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Participant)
measure: Measurement of the Change in Plasma Glucose (mg/dL): Study 1
time frame: Baseline to 240-300 minutes
description: Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose concentration
measure: Change in Plasma Glucose Measurement Using a Glucose Clamp: Study 2
time frame: Baseline to 240-300 minutes
description: Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose for study 2: EGP plus glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)
measure: Change in Plasma Glucose Using a Pancreatic Clamp: Study 3
time frame: Baseline to 240-300 minutes
description: Change from Baseline to the last hour of the study (240-300 minutes) in plasma glucose using a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.
measure: Change in EGP: Study 1
time frame: Baseline to 240-300 minutes
description: Change from baseline to the last hour of the study (240-300 minutes) in EGP
measure: Change in EGP With Glucose Clamp: Study 2
time frame: Baseline to 240-300 minutes
description: Change from baseline to the last hour of the study (240-300 minutes) in EGP using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)
measure: Change in EGP With Pancreatic Clamp: Study 3
time frame: Baseline to 240-300 minutes
description: Change from baseline to the last hour of the study (240-300 minutes) of EGP with a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.VIn this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.
measure: Change in Plasma Insulin Concentrations: Study 1
time frame: Baseline to 240-300 minutes
description: Plasma insulin concentrations during measurement of EGP
measure: Plasma Insulin Concentrations During Measurement of EGP Plus Glucose Clamp: Study 2
time frame: Baseline to 240-300 minutes
description: Plasma insulin concentration is measured from baseline to the last hour of the study while using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism. The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)
measure: Change in Plasma Insulin While Using Pancreatic Clamp: Study 3
time frame: Baseline to last hour of the study
description: Plasma insulin concentration during measurement of EGP while using pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.
measure: Change in Glucagon: Study 1
time frame: Baseline to 240-300 minutes
description: Change in glucagon concentrations during measurement of EGP
measure: Change in Glucagon Using Glucose Clamp: Study 2
time frame: Baseline to 240-300 minutes
description: Plasma glucagon concentration during measurement of EGP using a glucose clamp. The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose. This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism.
measure: Change in Glucagon Using Pancreatic Clamp: Study 3
time frame: Baseline to 240-300 minutes
description: Measurement of change in plasma glucagon from baseline to one hour prior to end of study while using a pancreatic clamp. In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique. Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration. Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.
arm group label: Dapagliflozin
arm group type: Active Comparator
description: 32 subjects will receive dapagliflozin 10mg
arm group label: Placebo
arm group type: Placebo Comparator
description: 16 subjects will receive placebo
intervention type: Drug
intervention name: Dapagliflozin
description: Three 5-hour measurements (after dapagliflozin 10mg administration) of endogenous glucose production (EGP) will be performed on separate days.
arm group label: Dapagliflozin
other name: Farxiga
intervention type: Drug
intervention name: Placebo
description: Three 5-hour measurements (after placebo administration) of endogenous glucose production (EGP) will be performed on separate days.
arm group label: Placebo
other name: Placebo for Dapagliflozin
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Eugenio Cersosimo, MD,PhD
role: Principal Investigator
affiliation: The University of Texas Health Science Center at San Antonio
facility: 
country: United States
responsible party type: Sponsor
mesh term: Diabetes Mellitus, Type 2
mesh term: Dapagliflozin
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 