<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/NCT03027960</url>
  </required_header>
  <id_info>
    <org_study_id>2000020019</org_study_id>
    <nct_id>NCT03027960</nct_id>
  </id_info>
  <brief_title>Empagliflozin in Heart Failure: Diuretic and Cardio-Renal Effects</brief_title>
  <acronym>EMPA</acronym>
  <official_title>Empagliflozin in Heart Failure: Diuretic and Cardio-Renal Effects</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Yale University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Yale University</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>
      The investigators propose a small pilot proof of concept study to not only prove the&#xD;
      existence of, but also probe the mechanisms underlying cardio-renal effects of empagliflozin&#xD;
      in patients with heart failure. The investigators propose a 50 patient randomized,&#xD;
      double-blind, placebo-controlled crossover study with patients with stable HF, type II&#xD;
      diabetes and an eGFR &gt;45ml/min/1.73 m2 who are chronically receiving loop diuretics.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study Objectives&#xD;
&#xD;
        1. Study the acute/short term effect and cardio-renal mechanisms of sodium-glucose&#xD;
           cotransporter 2 (SGLT2) inhibition in patients with heart failure.&#xD;
&#xD;
        2. Determine the effect of chronic combined SLLGT2 and loop diuretic exposure in patients&#xD;
           with heart failure.&#xD;
&#xD;
      Primary Outcomes&#xD;
&#xD;
        1. Aim 1 (Acute): Determine if acute SGLT2 inhibition will improve the natriuretic effect&#xD;
           of a loop diuretic compared to placebo.&#xD;
&#xD;
        2. Aim 2 (Chronic): Determine the effect of 14 days of SGLT2 inhibition on blood volume.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 27, 2017</start_date>
  <completion_date type="Actual">June 1, 2019</completion_date>
  <primary_completion_date type="Actual">May 14, 2019</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Care Provider)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>urine sodium concentrations via ion selective electrodes</measure>
    <time_frame>36 days</time_frame>
    <description>Determine if acute SGLT2 inhibition will improve the natriuretic effect of a loop diuretic compared to placebo.&#xD;
Measuring the natriuretic effect of a loop diuretic (placebo v acute SGLT2 inhibition) via urine sodium output.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>blood volume</measure>
    <time_frame>14 days</time_frame>
    <description>Determine the effect of 14 days of SGLT2 inhibition on blood volume.&#xD;
Daxor Blood Volume Sample Collection&#xD;
Volumex Injection: The Volumex tracer (radiolabeled albumin) is injected as an intravenous bolus (IV-push). (As soon as the tracer injection begins, a stopwatch is started and never zeroed out. Running times are used for the entire procedure).&#xD;
Serial Blood Collection A series of 5 post-Volumex blood samples is collected, after tracer injection, allowing for complete mixing in the bloodstream.&#xD;
Sample Timing: Samples are ideally spaced ~6 minutes apart, and are collected approximately 12, 18, 24, 30 and 36 minutes after Volumex administration.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">21</enrollment>
  <condition>Heart Failure</condition>
  <condition>Type II; Diabetes</condition>
  <arm_group>
    <arm_group_label>Placebo, then empagliflozin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients are randomized upon enrollment to determine whether they take empagliflozin or the matched placebo during the first 2-week treatment phase of the study. All patients then undergo a 2-week &quot;washout period&quot; before crossing over to the alternate therapy.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Empagliflozin, then Placebo</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients are randomized upon enrollment to determine whether they take empagliflozin or the matched placebo during the first 2-week treatment phase of the study. All patients then undergo a 2-week &quot;washout period&quot; before crossing over to the alternate therapy.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Empagliflozin</intervention_name>
    <description>10mg empagliflozin for a 2-week period</description>
    <arm_group_label>Empagliflozin, then Placebo</arm_group_label>
    <arm_group_label>Placebo, then empagliflozin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Capsule</intervention_name>
    <description>10 mg placebo for a 2-week period</description>
    <arm_group_label>Empagliflozin, then Placebo</arm_group_label>
    <arm_group_label>Placebo, then empagliflozin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Stable HF as defined by:&#xD;
&#xD;
          -  No hospitalization for &gt;60 days&#xD;
&#xD;
          -  Stable HF medications for &gt;=2 weeks, and stable diuretics for 4 weeks&#xD;
&#xD;
          -  Opinion of HF cardiologist that the patient is at their optimal volume status&#xD;
&#xD;
          -  Chronic daily oral loop diuretic dose &gt;=20mg furosemide equivalents&#xD;
&#xD;
          -  Diagnosis of type II diabetes&#xD;
&#xD;
          -  Patient monitors blood glucose regularly at home&#xD;
&#xD;
          -  eGFR &gt;=45 mL/min/1.73 m2&#xD;
&#xD;
          -  &gt;=18 years old&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Active titration of chronic HF medications expected during the study period&#xD;
&#xD;
          -  Use of a non-loop diuretic, aside from an aldosterone antagonist (&lt;=25mg&#xD;
             spironolactone or &lt;=50mg eplerenone)&#xD;
&#xD;
          -  Critical stenotic valvular disease, complex congenital heart disease, or prior heart&#xD;
             transplant&#xD;
&#xD;
          -  History of diabetic ketoacidosis, &quot;brittle&quot; diabetes, and/or frequent hypoglycemia or&#xD;
             severe hypoglycemic episodes requiring emergent intervention (ER visit or EMS&#xD;
             response, glucagon administration or forced oral carbs) in the last 6 months&#xD;
&#xD;
          -  History of bladder dysfunction, incontinence, pyelonephritis, urosepsis, or frequent&#xD;
             urinary tract infections&#xD;
&#xD;
          -  Anemia (defined as hemoglobin &lt;8g/dL)&#xD;
&#xD;
          -  Pregnancy or breastfeeding&#xD;
&#xD;
          -  History of serious hypersensitivity&#xD;
&#xD;
          -  Participation in another trial with an investigational drug within the 30 days prior&#xD;
             to informed consent&#xD;
&#xD;
          -  Use of another SGLT-2 inhibitor&#xD;
&#xD;
          -  Appears unlikely, or unable to participate in the required study procedures, as&#xD;
             assessed by the study PI or research RN (ex: clinically-significant psychiatric,&#xD;
             addictive, or neurological disease)&#xD;
&#xD;
          -  Inability to give written informed consent or follow study protocol&#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>Jeffrey Testani, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Yale University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Yale New Haven Hospital</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06511</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>January 17, 2017</study_first_submitted>
  <study_first_submitted_qc>January 17, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 23, 2017</study_first_posted>
  <last_update_submitted>June 24, 2020</last_update_submitted>
  <last_update_submitted_qc>June 24, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 26, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>cardio-renal</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>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/NCT03027960
org study id: 2000020019
nct id: NCT03027960
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
The investigators propose a small pilot proof of concept study to not only prove the
      existence of, but also probe the mechanisms underlying cardio-renal effects of empagliflozin
      in patients with heart failure. The investigators propose a 50 patient randomized,
      double-blind, placebo-controlled crossover study with patients with stable HF, type II
      diabetes and an eGFR >45ml/min/1.73 m2 who are chronically receiving loop diuretics.
Study Objectives

        1. Study the acute/short term effect and cardio-renal mechanisms of sodium-glucose
           cotransporter 2 (SGLT2) inhibition in patients with heart failure.

        2. Determine the effect of chronic combined SLLGT2 and loop diuretic exposure in patients
           with heart failure.

      Primary Outcomes

        1. Aim 1 (Acute): Determine if acute SGLT2 inhibition will improve the natriuretic effect
           of a loop diuretic compared to placebo.

        2. Aim 2 (Chronic): Determine the effect of 14 days of SGLT2 inhibition on blood volume.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Double (Participant, Care Provider)
measure: urine sodium concentrations via ion selective electrodes
time frame: 36 days
description: Determine if acute SGLT2 inhibition will improve the natriuretic effect of a loop diuretic compared to placebo.
Measuring the natriuretic effect of a loop diuretic (placebo v acute SGLT2 inhibition) via urine sodium output.
measure: blood volume
time frame: 14 days
description: Determine the effect of 14 days of SGLT2 inhibition on blood volume.
Daxor Blood Volume Sample Collection
Volumex Injection: The Volumex tracer (radiolabeled albumin) is injected as an intravenous bolus (IV-push). (As soon as the tracer injection begins, a stopwatch is started and never zeroed out. Running times are used for the entire procedure).
Serial Blood Collection A series of 5 post-Volumex blood samples is collected, after tracer injection, allowing for complete mixing in the bloodstream.
Sample Timing: Samples are ideally spaced ~6 minutes apart, and are collected approximately 12, 18, 24, 30 and 36 minutes after Volumex administration.
arm group label: Placebo, then empagliflozin
arm group type: Experimental
description: Patients are randomized upon enrollment to determine whether they take empagliflozin or the matched placebo during the first 2-week treatment phase of the study. All patients then undergo a 2-week "washout period" before crossing over to the alternate therapy.
arm group label: Empagliflozin, then Placebo
arm group type: Experimental
description: Patients are randomized upon enrollment to determine whether they take empagliflozin or the matched placebo during the first 2-week treatment phase of the study. All patients then undergo a 2-week "washout period" before crossing over to the alternate therapy.
intervention type: Drug
intervention name: Empagliflozin
description: 10mg empagliflozin for a 2-week period
arm group label: Empagliflozin, then Placebo
arm group label: Placebo, then empagliflozin
intervention type: Drug
intervention name: Placebo Oral Capsule
description: 10 mg placebo for a 2-week period
arm group label: Empagliflozin, then Placebo
arm group label: Placebo, then empagliflozin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jeffrey Testani, MD
role: Principal Investigator
affiliation: Yale University
facility: 
country: United States
responsible party type: Sponsor
mesh term: Heart Failure
mesh term: Diabetes Mellitus, Type 2
mesh term: Empagliflozin
sharing ipd: No