<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/NCT04461041</url>
  </required_header>
  <id_info>
    <org_study_id>1245-0206</org_study_id>
    <nct_id>NCT04461041</nct_id>
  </id_info>
  <brief_title>Empagliflozin and Cardiac Remodelling in People Without Diabetes</brief_title>
  <acronym>EMPA-HEART 2</acronym>
  <official_title>Empagliflozin and Cardiac Remodelling in People Without Diabetes</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Unity Health Toronto</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Canadian Medical and Surgical Knowledge Translation Research Group</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Applied Health Research Centre</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Unity Health Toronto</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the effects of empagliflozin on cardiac structure,&#xD;
      function and circulating biomarkers in patients with cardiovascular risk factors, but without&#xD;
      diabetes. Empagliflozin is an antihyperglycemic agent approved by Health Canada and the FDA&#xD;
      for the treatment of type 2 diabetes. Previous post-marketing clinical trials demonstrated a&#xD;
      reduction in cardiovascular deaths and heart failure in patients with type 2 diabetes treated&#xD;
      with empagliflozin. In the first EMPA-HEART trial, we demonstrated that empagliflozin reduces&#xD;
      cardiac mass in patients with type 2 diabetes, as seen through cardiac magnetic resonance&#xD;
      imaging (cMRI). Therefore, the aim of this study, EMPA-HEART 2, is to determine whether&#xD;
      empagliflozin can similarly impact cardiac structure in patients without diabetes, but with&#xD;
      various cardiovascular risk factors.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Sodium-glucose cotransporter 2 (SGLT2) inhibitors (empagliflozin, canagliflozin and&#xD;
      dapagliflozin) are approved medications to improve glycemic control in adult patients with&#xD;
      type 2 diabetes. When added to current standard-of-care diabetes treatment, SGLT2 inhibitors&#xD;
      are associated with clinically meaningful reductions in major adverse cardiovascular events,&#xD;
      reduced rates of hospitalization for heart failure and a decrease in major adverse kidney&#xD;
      outcomes. Importantly, these benefits were observed consistently in people with and without&#xD;
      type 2 diabetes and across all levels of baseline glycemic control. These data point towards&#xD;
      a glucose-independent, cardioprotective effect of SGLT2 inhibition. How SGLT2 inhibition&#xD;
      might reduce cardiac outcomes in people without diabetes remains unclear, and this is the&#xD;
      specific objective of EMPA-HEART 2.&#xD;
&#xD;
      The study drug, empagliflozin (marketed as Jardiance), belongs to a class of medications that&#xD;
      lowers blood glucose (sugar) by preventing glucose from entering back into blood circulation&#xD;
      and ensures it is eliminated in urine. Empagliflozin is approved by the FDA and Health Canada&#xD;
      for the treatment of type 2 diabetes.&#xD;
&#xD;
      This is a double-blind, randomized, placebo-controlled, parallel-group study of empagliflozin&#xD;
      vs. placebo in patients without diabetes but with various cardiovascular risk factors. The&#xD;
      purpose is to determine the effects of empagliflozin on cardiac structure by using cMRI.&#xD;
      Patients who have given informed consent will undergo a baseline cMRI and will then be&#xD;
      randomly assigned in a 1:1 basis to either empagliflozin 10 mg once daily or matching&#xD;
      placebo. An end of study cMRI will be performed at 26 weeks (6 months after starting the&#xD;
      study drug).&#xD;
&#xD;
      The study subjects will be followed for 6 months. The patients will be assessed using cMRI,&#xD;
      which is considered the &quot;gold standard&quot; for measuring left ventricular (LV) volume, mass, and&#xD;
      ejection fraction. The investigators will assess changes from baseline in LV mass, LV&#xD;
      end-diastolic volume, end-systolic volume, LV ejection fraction, LV diastolic and systolic&#xD;
      function, and LV wall stress via cMRI in enrolled patients treated with empagliflozin&#xD;
      compared to those who receive placebo. Additionally, changes from baseline in blood pressure,&#xD;
      hematocrit, and biomarkers involved in the pathophysiology of heart failure, namely&#xD;
      NT-proBNP, will be evaluated at 6 months.&#xD;
&#xD;
      Study assessments and potential adverse events reporting will be undertaken at each study&#xD;
      visit.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 1, 2021</start_date>
  <completion_date type="Actual">July 31, 2022</completion_date>
  <primary_completion_date type="Actual">July 31, 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>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Left Ventricular (LV) mass</measure>
    <time_frame>6 months</time_frame>
    <description>Change in Left Ventricular (LV) mass (indexed to body surface area (BSA)) at 6 months. This will be measured using CMRI.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>LV end-diastolic volume</measure>
    <time_frame>6 months</time_frame>
    <description>Change in LV end-diastolic volume (indexed to BSA) at 6 months. This will be measured using CMRI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>LV end-systolic volume</measure>
    <time_frame>6 months</time_frame>
    <description>Change in LV end-systolic volume (indexed to BSA) at 6 months. This will be measured using CMRI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Left Ventricular Ejection Fraction (LVEF)</measure>
    <time_frame>6 months</time_frame>
    <description>Change in LVEF at 6 months. This will be measured using CMRI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>LV wall stress</measure>
    <time_frame>6 months</time_frame>
    <description>Change in LV wall stress at 6 months. This will be measured using CMRI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>LV systolic function</measure>
    <time_frame>6 months</time_frame>
    <description>Change in LV systolic function at 6 months. This will be measured using CMRI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>LV diastolic function</measure>
    <time_frame>6 months</time_frame>
    <description>Change in LV diastolic function at 6 months. This will be measured using CMRI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>NT-proBNP</measure>
    <time_frame>6 months</time_frame>
    <description>Change in circulating NT-proBNP at 6 months.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Systolic and diastolic blood pressure</measure>
    <time_frame>6 months</time_frame>
    <description>Change in systolic and diastolic blood pressure at 6 months.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hematocrit</measure>
    <time_frame>6 months</time_frame>
    <description>Change in hematocrit at 6 months in patients.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">169</enrollment>
  <condition>Cardiovascular Diseases</condition>
  <condition>Left Ventricular Hypertrophy</condition>
  <arm_group>
    <arm_group_label>Empagliflozin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Single 10 mg tablet, administered orally once daily for 6 months</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Single 10 mg tablet, administered orally once daily for 6 months</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Empagliflozin</intervention_name>
    <description>Single oral tablet</description>
    <arm_group_label>Empagliflozin</arm_group_label>
    <other_name>Jardiance</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo tablet manufactured to mimic empagliflozin 10 mg tablet</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Female Not of childbearing potential and male subjects ≥ 18 and ≤ 85 years of age&#xD;
             (Women Not of childbearing potential are females who are permanently sterile or&#xD;
             postmenopausal. Postmenopausal is defined as 12 consecutive months with no menses&#xD;
             without an alternative medical cause or ≥6 weeks post-surgical bilateral oophorectomy&#xD;
             prior to Screening.)&#xD;
&#xD;
          2. ≥1 of the major criteria or ≥2 of the minor criteria below:&#xD;
&#xD;
             Major criteria&#xD;
&#xD;
               -  Increased LVMi of ≥96 g/m2 for women and ≥116 g/m2 for men (as calculated by&#xD;
                  echocardiogram); or LVMi ≥81 g/m2 for women and ≥85 g/m2 for men (as calculated&#xD;
                  by cMRI)&#xD;
&#xD;
               -  ECG evidence of LV hypertrophy (as per the Sokolow-Lyon criteria)&#xD;
&#xD;
               -  Structural heart disease defined as interventricular septal thickness or&#xD;
                  posterior wall thickness at end-diastole of ≥11 mm (as measured by 2D&#xD;
                  echocardiography or cMRI)&#xD;
&#xD;
               -  Persistent hypertension (defined as office blood pressure ≥140/90 mmHg) despite&#xD;
                  being on ≥3 antihypertensive medications&#xD;
&#xD;
             Minor criteria&#xD;
&#xD;
               -  Prior history of a myocardial infarction (≥3 months ago)&#xD;
&#xD;
               -  eGFR ≥30 and ≤60 mL/min/1.73 m2 (as measured by the CKD-EPI formula)&#xD;
&#xD;
               -  Body mass index (BMI) ≥27 kg/m2&#xD;
&#xD;
          3. Willing and able to comply with scheduled visits, treatment plan, laboratory tests,&#xD;
             and other trial procedures&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Female subjects who are pregnant, lactating or of childbearing potential, or are&#xD;
             pre-menopausal&#xD;
&#xD;
          2. Known type 1 or type 2 diabetes&#xD;
&#xD;
          3. Hemoglobin A1C (A1C) ≥6.5%&#xD;
&#xD;
          4. eGFR &lt;30 mL/min/1.73m2&#xD;
&#xD;
          5. Known history of severe liver disease (e.g. Child Pugh Class B or C)&#xD;
&#xD;
          6. Known history of severe symptomatic untreated anemia in the last 3 months (e.g.&#xD;
             hemoglobin &lt; 90 g/L)&#xD;
&#xD;
          7. History of ketoacidosis, or increased chance of developing diabetic ketoacidosis (DKA)&#xD;
             e.g. patients who suffer from excessive vomiting, diarrhea, or sweating; subjects who&#xD;
             are on a very low carbohydrate diet; or subjects who drink a lot of alcohol.&#xD;
&#xD;
          8. Systolic blood pressure &lt;95mmHg (as measured at the office/clinic visit)&#xD;
&#xD;
          9. Subjects in whom coronary revascularization by either percutaneous coronary&#xD;
             intervention or bypass surgery is being contemplated within the next 6 months, or who&#xD;
             have undergone coronary revascularization in the prior 3 months&#xD;
&#xD;
         10. Significant allergy or known intolerance to SGLT2is or any ingredient in the&#xD;
             formulations&#xD;
&#xD;
         11. Subjects currently experiencing any clinically significant or unstable medical&#xD;
             condition that in the opinion of the investigator might limit their ability to&#xD;
             complete the study, or to comply with the requirements of the protocol, including:&#xD;
             dermatologic disease, hematological disease, pulmonary disease, hepatic disease,&#xD;
             gastrointestinal disease, genitourinary disease, endocrine disease, neurological&#xD;
             disease, and psychiatric disease&#xD;
&#xD;
         12. Any malignancy not considered cured (except basal cell carcinoma of the skin). A&#xD;
             subject is considered cured if there has been no evidence of cancer recurrence for the&#xD;
             5 years prior to screening&#xD;
&#xD;
         13. Subjects who have participated in other interventional studies which may affect any of&#xD;
             the primary or secondary outcomes of the study within 30 days of the screening visit&#xD;
&#xD;
         14. Contraindications or inability to undergo magnetic resonance imaging such as severe&#xD;
             obesity (e.g. weight &gt;500 lbs) or the presence of metallic fragments, clips, or&#xD;
             devices&#xD;
&#xD;
         15. Known history of infiltrative cardiomyopathy such as cardiac amyloidosis or cardiac&#xD;
             sarcoidosis&#xD;
&#xD;
         16. Severe aortic stenosis&#xD;
&#xD;
         17. Severe aortic regurgitation&#xD;
&#xD;
         18. Severe mitral stenosis&#xD;
&#xD;
         19. Severe mitral regurgitation&#xD;
&#xD;
         20. Low voltage on ECG limb leads defined by the amplitude of the QRS complex in each limb&#xD;
             lead ≤0.5 mV&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Subodh Verma, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Unity Health Toronto</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Diagnostic Assessment Centre (AMS Diagnostics)</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M1S 4N6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Michael's Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5B 1W8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>North York Diagnostic and Cardiac Centre</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M6B 3H7</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chang Gung Memorial Hospital</name>
      <address>
        <city>Keelung</city>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
    <country>Taiwan</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>July 2, 2020</study_first_submitted>
  <study_first_submitted_qc>July 2, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 8, 2020</study_first_posted>
  <last_update_submitted>February 16, 2023</last_update_submitted>
  <last_update_submitted_qc>February 16, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 17, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Cardiovascular disease</keyword>
  <keyword>Cardiac Magnetic Resonance Imaging</keyword>
  <keyword>Sodium-Glucose Transporter 2 Inhibitors</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cardiovascular Diseases</mesh_term>
    <mesh_term>Hypertrophy, Left Ventricular</mesh_term>
    <mesh_term>Hypertrophy</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Empagliflozin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT04461041
org study id: 1245-0206
nct id: NCT04461041
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
The purpose of this study is to evaluate the effects of empagliflozin on cardiac structure,
      function and circulating biomarkers in patients with cardiovascular risk factors, but without
      diabetes. Empagliflozin is an antihyperglycemic agent approved by Health Canada and the FDA
      for the treatment of type 2 diabetes. Previous post-marketing clinical trials demonstrated a
      reduction in cardiovascular deaths and heart failure in patients with type 2 diabetes treated
      with empagliflozin. In the first EMPA-HEART trial, we demonstrated that empagliflozin reduces
      cardiac mass in patients with type 2 diabetes, as seen through cardiac magnetic resonance
      imaging (cMRI). Therefore, the aim of this study, EMPA-HEART 2, is to determine whether
      empagliflozin can similarly impact cardiac structure in patients without diabetes, but with
      various cardiovascular risk factors.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors (empagliflozin, canagliflozin and
      dapagliflozin) are approved medications to improve glycemic control in adult patients with
      type 2 diabetes. When added to current standard-of-care diabetes treatment, SGLT2 inhibitors
      are associated with clinically meaningful reductions in major adverse cardiovascular events,
      reduced rates of hospitalization for heart failure and a decrease in major adverse kidney
      outcomes. Importantly, these benefits were observed consistently in people with and without
      type 2 diabetes and across all levels of baseline glycemic control. These data point towards
      a glucose-independent, cardioprotective effect of SGLT2 inhibition. How SGLT2 inhibition
      might reduce cardiac outcomes in people without diabetes remains unclear, and this is the
      specific objective of EMPA-HEART 2.

      The study drug, empagliflozin (marketed as Jardiance), belongs to a class of medications that
      lowers blood glucose (sugar) by preventing glucose from entering back into blood circulation
      and ensures it is eliminated in urine. Empagliflozin is approved by the FDA and Health Canada
      for the treatment of type 2 diabetes.

      This is a double-blind, randomized, placebo-controlled, parallel-group study of empagliflozin
      vs. placebo in patients without diabetes but with various cardiovascular risk factors. The
      purpose is to determine the effects of empagliflozin on cardiac structure by using cMRI.
      Patients who have given informed consent will undergo a baseline cMRI and will then be
      randomly assigned in a 1:1 basis to either empagliflozin 10 mg once daily or matching
      placebo. An end of study cMRI will be performed at 26 weeks (6 months after starting the
      study drug).

      The study subjects will be followed for 6 months. The patients will be assessed using cMRI,
      which is considered the "gold standard" for measuring left ventricular (LV) volume, mass, and
      ejection fraction. The investigators will assess changes from baseline in LV mass, LV
      end-diastolic volume, end-systolic volume, LV ejection fraction, LV diastolic and systolic
      function, and LV wall stress via cMRI in enrolled patients treated with empagliflozin
      compared to those who receive placebo. Additionally, changes from baseline in blood pressure,
      hematocrit, and biomarkers involved in the pathophysiology of heart failure, namely
      NT-proBNP, will be evaluated at 6 months.

      Study assessments and potential adverse events reporting will be undertaken at each study
      visit.
allocation: Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Left Ventricular (LV) mass
time frame: 6 months
description: Change in Left Ventricular (LV) mass (indexed to body surface area (BSA)) at 6 months. This will be measured using CMRI.
measure: LV end-diastolic volume
time frame: 6 months
description: Change in LV end-diastolic volume (indexed to BSA) at 6 months. This will be measured using CMRI.
measure: LV end-systolic volume
time frame: 6 months
description: Change in LV end-systolic volume (indexed to BSA) at 6 months. This will be measured using CMRI.
measure: Left Ventricular Ejection Fraction (LVEF)
time frame: 6 months
description: Change in LVEF at 6 months. This will be measured using CMRI.
measure: LV wall stress
time frame: 6 months
description: Change in LV wall stress at 6 months. This will be measured using CMRI.
measure: LV systolic function
time frame: 6 months
description: Change in LV systolic function at 6 months. This will be measured using CMRI.
measure: LV diastolic function
time frame: 6 months
description: Change in LV diastolic function at 6 months. This will be measured using CMRI.
measure: NT-proBNP
time frame: 6 months
description: Change in circulating NT-proBNP at 6 months.
measure: Systolic and diastolic blood pressure
time frame: 6 months
description: Change in systolic and diastolic blood pressure at 6 months.
measure: Hematocrit
time frame: 6 months
description: Change in hematocrit at 6 months in patients.
arm group label: Empagliflozin
arm group type: Active Comparator
description: Single 10 mg tablet, administered orally once daily for 6 months
arm group label: Placebo
arm group type: Placebo Comparator
description: Single 10 mg tablet, administered orally once daily for 6 months
intervention type: Drug
intervention name: Empagliflozin
description: Single oral tablet
arm group label: Empagliflozin
other name: Jardiance
intervention type: Drug
intervention name: Placebo
description: Placebo tablet manufactured to mimic empagliflozin 10 mg tablet
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: No
last name: Subodh Verma, MD PhD
role: Principal Investigator
affiliation: Unity Health Toronto
facility: 
facility: 
facility: 
facility: 
country: Canada
country: Taiwan
responsible party type: Sponsor
mesh term: Cardiovascular Diseases
mesh term: Hypertrophy, Left Ventricular
mesh term: Hypertrophy
mesh term: Empagliflozin
sharing ipd: No