<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/NCT03782259</url>
  </required_header>
  <id_info>
    <org_study_id>STUDY00004982</org_study_id>
    <secondary_id>ESR 17-13124</secondary_id>
    <nct_id>NCT03782259</nct_id>
  </id_info>
  <brief_title>Effects of SGLT-2 Inhibition on Myocardial Fibrosis and Inflammation as Assessed by Cardiac MRI in Patients With DM2</brief_title>
  <official_title>Effects of SGLT-2 Inhibition With Dapagliflozin on Myocardial Fibrosis and Inflammation as Assessed by Cardiac MRI With T1- and T2-mapping in Patients With Type-2 Diabetes</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Washington</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Washington</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      There is an unmet need for Cardiovascular Disease (CVD) risk reduction in patients with Type&#xD;
      2 Diabetes. In recent trials there has been promising findings of more effective glucose&#xD;
      management and reductions in overall CVD events and hospitalization for heart failure with&#xD;
      SGLT-2 inhibition. Using the capability of cardiac MRI with T1- and T2-mapping in assessments&#xD;
      of myocardial fibrosis and inflammation, the investigators propose to conduct a clinical&#xD;
      trial to investigate the effects of SGLT-2 inhibition with dapagliflozin on myocardial&#xD;
      strain, fibrosis and inflammation as assessed by cardiac MRI with T1- and T2-mapping in&#xD;
      patients with type-2 diabetes.&#xD;
&#xD;
      Over approximately 12 months subjects will have 6 clinical visits at the investigators&#xD;
      research clinic. During this time subjects will be randomized to receive either active 10mg&#xD;
      dapagliflozin or a matching placebo. 2 MRI scans at one of the two University of Washington&#xD;
      research imaging centers will take place. One at randomization and the second scan will occur&#xD;
      approximately 12 months after the first scan.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Given the unmet needs for CVD risk reduction in patients with Type 2 Diabetes Mellitus&#xD;
      (T2DM), the promising findings of more effective glucose management and reductions in overall&#xD;
      CVD events and hospitalization for heart failure with SGLT-2 inhibition demonstrated in&#xD;
      recent trials, and the capability of cardiac MRI (CMRI) with T1- and T2-mapping in&#xD;
      assessments of myocardial fibrosis and inflammation, the investigators propose to conduct a&#xD;
      staged research program using adaptive study design to investigate the effects of SGLT-2&#xD;
      inhibition with dapagliflozin on myocardial strain, fibrosis and inflammation as assessed by&#xD;
      cardiac MRI with T1- and T2-mapping in patients with type-2 diabetes.&#xD;
&#xD;
      A total of 60 subjects with &gt;=18 years of age, type-2 diabetes history &gt;=5 years and HbA1C&#xD;
      7-10% will be randomized at 1:1 to Dapagliflozin 10mg or matching placebo once daily for 1&#xD;
      year. All subjects will be followed every 3 months for clinical and laboratory evaluations&#xD;
      and assessments. All subjects will undergo CMRI at baseline and 1 year.&#xD;
&#xD;
      The primary myocardial strain endpoint includes global myocardial longitudinal strain (GLS).&#xD;
      Myocardial fibrosis endpoint is change in extracellular volume fraction (ECV) as assessed by&#xD;
      T1-mapping over 12 months. ECV combines native and contrast-enhanced T1 mapping. The change&#xD;
      of the T1 relaxation rate (i.e., 1/T1) in blood between pre- and post-contrast imaging is&#xD;
      converted with the blood hematocrit into a reference for plasma T1, which serves as reference&#xD;
      for the T1 changes in tissue.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 26, 2019</start_date>
  <completion_date type="Actual">November 16, 2022</completion_date>
  <primary_completion_date type="Actual">November 16, 2022</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>Parallel Assignment</intervention_model>
    <intervention_model_description>Randomized, double-blind and placebo controlled cardiac MRI study</intervention_model_description>
    <primary_purpose>Screening</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Extracellular volume fraction (ECV)</measure>
    <time_frame>Approximately 12 Months</time_frame>
    <description>Extracellular volume fraction (ECV) measured from cardiac MRI with T1-mapping at two timepoints. MRI at Randomization and MRI at approximately 12 Months. ECV combines native and contrast-enhanced T1 mapping. Ancova test with adjusted for baseline ECV will be used to compare change in ECV over 12 months between 2 treatment groups.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Global myocardial longitudinal strain (GLS)</measure>
    <time_frame>Approximately 12 Months</time_frame>
    <description>Global myocardial longitudinal strain (GLS) measured from cardiac MRI with T1-mapping at two timepoints. MRI at Randomization and MRI at approximately 12 Months. Myocardial strain measurements with feature tracking will be performed to measure myocardial strain and strain rate from the bSSFP short-axis and long-axis cine images. Long-axis cine images will be further used to compute GLS. Ancova test with adjusted for baseline GLS will be used to compare change in GLS over 12 months between 2 treatment groups.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>T2 relaxation time</measure>
    <time_frame>Approximately 12 Months</time_frame>
    <description>Change from baseline in T2 relaxation time measured from cardiac MRI with T2-mapping at two timepoints. MRI at Randomization and MRI at approximately 12 Months</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Epicardial fat</measure>
    <time_frame>Approximately 12 Months</time_frame>
    <description>Change from baseline in Epicardial fat measured from cardiac MRI with T1-mapping at two timepoints. MRI at Randomization and MRI at approximately 12 Months&#xD;
Ancova test will be used for comparisons of epicardial fat between 2 different timepoints within each treatment group, at between 2 treatments at the same time point, and changes during the study.</description>
  </other_outcome>
  <other_outcome>
    <measure>Fasting glucose</measure>
    <time_frame>Approximately 12 Months</time_frame>
    <description>Fasting glucose will be measured every 3 months for approximately 12 months.</description>
  </other_outcome>
  <other_outcome>
    <measure>HbA1C</measure>
    <time_frame>Approximately 12 Months</time_frame>
    <description>Hemoglobin A1c (HbA1c) will be measured every 3 months for approximately 12 months.</description>
  </other_outcome>
  <other_outcome>
    <measure>LDL particle size</measure>
    <time_frame>Approximately 12 Months</time_frame>
    <description>LDL particle size measured from plasma samples at Randomization and at approximately 12 Months</description>
  </other_outcome>
  <other_outcome>
    <measure>hsCRP</measure>
    <time_frame>Approximately 12 Months</time_frame>
    <description>Inflammatory marker hsCRP at Screening, 6 months and at approximately 12 Months.</description>
  </other_outcome>
  <other_outcome>
    <measure>Tumor necrosis factor (TNF)-α</measure>
    <time_frame>Approximately 12 Months</time_frame>
    <description>Inflammatory marker TNF-α measured from plasma samples at Randomization and at approximately 12 Months</description>
  </other_outcome>
  <other_outcome>
    <measure>Iinterleukin (IL)-6</measure>
    <time_frame>Approximately 12 Months</time_frame>
    <description>Inflammatory marker IL-6 measured from plasma samples at Randomization and at approximately 12 Months</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>Type 2 Diabetes Mellitus</condition>
  <condition>Myocardial Fibrosis</condition>
  <condition>Myocardial Inflammation</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>10mg tabs placebo matching dapagliflozin.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Active</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>10mg tabs of dapagliflozin</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>dapagliflozin</intervention_name>
    <description>Subjects will either receive 10mg tabs of dapagliflozin or identical looking placebo - inactive medication. Subjects have an equal chance of receiving dapagliflozin or placebo. Which treatment subjects receive is decided at random by a computer (purely by chance, like the tossing of a coin). Neither subjects nor the Study Site personnel will know which treatment subjects are assigned to. The study drug must be taken daily. The subject's other medications will not be changed by the study.</description>
    <arm_group_label>Active</arm_group_label>
    <other_name>Forxiga</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Men and women at least 18 years of age&#xD;
&#xD;
          2. Subjects with type-2 diabetes history &gt;=5 years&#xD;
&#xD;
          3. HbA1C 7-10% with glucose control medications including insulin, metformin or&#xD;
             sulfonylurea&#xD;
&#xD;
          4. Medically stable&#xD;
&#xD;
          5. Willing to participate and sign informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Contraindication to MRI&#xD;
&#xD;
          2. Currently or within last three months treatment with a SGLT2 inhibitor&#xD;
&#xD;
          3. Currently taking glucagon-like peptide (GLP)-1 receptor antagonist&#xD;
&#xD;
          4. Glomerular filtration rate (GFR) &lt;60 mL/min/1.73 m2&#xD;
&#xD;
          5. Unstable or rapidly progressive renal disease&#xD;
&#xD;
          6. Hypotension with systolic blood pressure (SBP) &lt;100 mmHg&#xD;
&#xD;
          7. Hypersensitivity to dapagliflozin or any excipients&#xD;
&#xD;
          8. Patients with severe hepatic impairment (Child-Pugh class C)&#xD;
&#xD;
          9. Patients with active hepatitis B or C infection&#xD;
&#xD;
         10. Any of the following CV/Vascular Diseases within 3 months prior to signing the consent&#xD;
             at enrollment, as assessed by the investigator:&#xD;
&#xD;
               1. Myocardial infarction&#xD;
&#xD;
               2. Cardiac surgery or revascularization (CABG/PTCA)&#xD;
&#xD;
               3. Unstable angina&#xD;
&#xD;
               4. Heart Failure - New York Heart Association (NYHA) Class IV&#xD;
&#xD;
               5. Transient ischemic attack (TIA) or significant cerebrovascular disease&#xD;
&#xD;
               6. Unstable or previously undiagnosed arrhythmia&#xD;
&#xD;
               7. Established peripheral artery disease (PAD)&#xD;
&#xD;
        (18) Active bladder cancer (19) Recent episode of Diabetic ketoacidosis (DKA), frequent&#xD;
        episodes of DKA (20) High risk of fractures, amputations and fibrosis (21) Women of&#xD;
        child-bearing potential (ie, those who are not chemically or surgically sterilized or who&#xD;
        are not post-menopausal) who have a positive pregnancy test at enrollment or randomization,&#xD;
        OR women who are not willing to use a medically accepted method of contraception that is&#xD;
        considered reliable in the judgment of the investigator, from the time of signing the&#xD;
        informed consent until two weeks after the last dose of study drug, OR women who are&#xD;
        breast-feeding.&#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>Xue-Qiao Zhao, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Washington</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Washington</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>October 24, 2018</study_first_submitted>
  <study_first_submitted_qc>December 18, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 20, 2018</study_first_posted>
  <last_update_submitted>January 9, 2023</last_update_submitted>
  <last_update_submitted_qc>January 9, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 11, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Washington</investigator_affiliation>
    <investigator_full_name>Xue-Qiao Zhao</investigator_full_name>
    <investigator_title>Research Professor, Department of Medicine - Cardiology</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Myocarditis</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
    <mesh_term>Fibrosis</mesh_term>
    <mesh_term>Inflammation</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dapagliflozin</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03782259
org study id: STUDY00004982
secondary id: ESR 17-13124
nct id: NCT03782259
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
There is an unmet need for Cardiovascular Disease (CVD) risk reduction in patients with Type
      2 Diabetes. In recent trials there has been promising findings of more effective glucose
      management and reductions in overall CVD events and hospitalization for heart failure with
      SGLT-2 inhibition. Using the capability of cardiac MRI with T1- and T2-mapping in assessments
      of myocardial fibrosis and inflammation, the investigators propose to conduct a clinical
      trial to investigate the effects of SGLT-2 inhibition with dapagliflozin on myocardial
      strain, fibrosis and inflammation as assessed by cardiac MRI with T1- and T2-mapping in
      patients with type-2 diabetes.

      Over approximately 12 months subjects will have 6 clinical visits at the investigators
      research clinic. During this time subjects will be randomized to receive either active 10mg
      dapagliflozin or a matching placebo. 2 MRI scans at one of the two University of Washington
      research imaging centers will take place. One at randomization and the second scan will occur
      approximately 12 months after the first scan.
Given the unmet needs for CVD risk reduction in patients with Type 2 Diabetes Mellitus
      (T2DM), the promising findings of more effective glucose management and reductions in overall
      CVD events and hospitalization for heart failure with SGLT-2 inhibition demonstrated in
      recent trials, and the capability of cardiac MRI (CMRI) with T1- and T2-mapping in
      assessments of myocardial fibrosis and inflammation, the investigators propose to conduct a
      staged research program using adaptive study design to investigate the effects of SGLT-2
      inhibition with dapagliflozin on myocardial strain, fibrosis and inflammation as assessed by
      cardiac MRI with T1- and T2-mapping in patients with type-2 diabetes.

      A total of 60 subjects with >=18 years of age, type-2 diabetes history >=5 years and HbA1C
      7-10% will be randomized at 1:1 to Dapagliflozin 10mg or matching placebo once daily for 1
      year. All subjects will be followed every 3 months for clinical and laboratory evaluations
      and assessments. All subjects will undergo CMRI at baseline and 1 year.

      The primary myocardial strain endpoint includes global myocardial longitudinal strain (GLS).
      Myocardial fibrosis endpoint is change in extracellular volume fraction (ECV) as assessed by
      T1-mapping over 12 months. ECV combines native and contrast-enhanced T1 mapping. The change
      of the T1 relaxation rate (i.e., 1/T1) in blood between pre- and post-contrast imaging is
      converted with the blood hematocrit into a reference for plasma T1, which serves as reference
      for the T1 changes in tissue.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Randomized, double-blind and placebo controlled cardiac MRI study
primary purpose: Screening
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Extracellular volume fraction (ECV)
time frame: Approximately 12 Months
description: Extracellular volume fraction (ECV) measured from cardiac MRI with T1-mapping at two timepoints. MRI at Randomization and MRI at approximately 12 Months. ECV combines native and contrast-enhanced T1 mapping. Ancova test with adjusted for baseline ECV will be used to compare change in ECV over 12 months between 2 treatment groups.
measure: Global myocardial longitudinal strain (GLS)
time frame: Approximately 12 Months
description: Global myocardial longitudinal strain (GLS) measured from cardiac MRI with T1-mapping at two timepoints. MRI at Randomization and MRI at approximately 12 Months. Myocardial strain measurements with feature tracking will be performed to measure myocardial strain and strain rate from the bSSFP short-axis and long-axis cine images. Long-axis cine images will be further used to compute GLS. Ancova test with adjusted for baseline GLS will be used to compare change in GLS over 12 months between 2 treatment groups.
measure: T2 relaxation time
time frame: Approximately 12 Months
description: Change from baseline in T2 relaxation time measured from cardiac MRI with T2-mapping at two timepoints. MRI at Randomization and MRI at approximately 12 Months
measure: Epicardial fat
time frame: Approximately 12 Months
description: Change from baseline in Epicardial fat measured from cardiac MRI with T1-mapping at two timepoints. MRI at Randomization and MRI at approximately 12 Months
Ancova test will be used for comparisons of epicardial fat between 2 different timepoints within each treatment group, at between 2 treatments at the same time point, and changes during the study.
measure: Fasting glucose
time frame: Approximately 12 Months
description: Fasting glucose will be measured every 3 months for approximately 12 months.
measure: HbA1C
time frame: Approximately 12 Months
description: Hemoglobin A1c (HbA1c) will be measured every 3 months for approximately 12 months.
measure: LDL particle size
time frame: Approximately 12 Months
description: LDL particle size measured from plasma samples at Randomization and at approximately 12 Months
measure: hsCRP
time frame: Approximately 12 Months
description: Inflammatory marker hsCRP at Screening, 6 months and at approximately 12 Months.
measure: Tumor necrosis factor (TNF)-α
time frame: Approximately 12 Months
description: Inflammatory marker TNF-α measured from plasma samples at Randomization and at approximately 12 Months
measure: Iinterleukin (IL)-6
time frame: Approximately 12 Months
description: Inflammatory marker IL-6 measured from plasma samples at Randomization and at approximately 12 Months
arm group label: Placebo
arm group type: Placebo Comparator
description: 10mg tabs placebo matching dapagliflozin.
arm group label: Active
arm group type: Active Comparator
description: 10mg tabs of dapagliflozin
intervention type: Drug
intervention name: dapagliflozin
description: Subjects will either receive 10mg tabs of dapagliflozin or identical looking placebo - inactive medication. Subjects have an equal chance of receiving dapagliflozin or placebo. Which treatment subjects receive is decided at random by a computer (purely by chance, like the tossing of a coin). Neither subjects nor the Study Site personnel will know which treatment subjects are assigned to. The study drug must be taken daily. The subject's other medications will not be changed by the study.
arm group label: Active
other name: Forxiga
intervention type: Other
intervention name: Placebo
description: Placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Xue-Qiao Zhao, MD
role: Principal Investigator
affiliation: University of Washington
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Washington
investigator full name: Xue-Qiao Zhao
investigator title: Research Professor, Department of Medicine - Cardiology
mesh term: Myocarditis
mesh term: Diabetes Mellitus, Type 2
mesh term: Fibrosis
mesh term: Inflammation
mesh term: Dapagliflozin