<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/NCT04438213</url>
  </required_header>
  <id_info>
    <org_study_id>2000027951</org_study_id>
    <secondary_id>MISP59625</secondary_id>
    <nct_id>NCT04438213</nct_id>
  </id_info>
  <brief_title>Ertugliflozin in Chronic Heart Failure</brief_title>
  <official_title>Ertugliflozin in Chronic Heart Failure: Cardio-renal and Diuretic Effects</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Yale University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</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>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine the effects on heart failure signs and symptoms of&#xD;
      the use of either ertugliflozin, metolazone or placebo, in conjunction with intravenous loop&#xD;
      diuretic use in acute settings and chronic oral loop diuretic therapy.&#xD;
&#xD;
      There are two general purposes for this study. The proposed study is both larger and more&#xD;
      rigorous than essentially all PK/PD studies that form the basis of current practice with loop&#xD;
      diuretics as well as all studies looking at add-on thiazide therapy (current&#xD;
      guideline-recommended adjuvant). The second is to generate a mechanistic understanding of the&#xD;
      pleotropic cardio-renal factors with chronic therapy that differentiate ertugliflozin from&#xD;
      traditional diuretics particularly in how they maintain reduced blood volume without the&#xD;
      complication of over-diuresis and volume depletion.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a randomized placebo controlled mechanistic study to understand the utility of&#xD;
      ertugliflozin in acute and post-acute hospitalized heart failure patients with or without&#xD;
      diabetes, compared to both placebo and the active control metolazone. The broad study design&#xD;
      will be designed around evaluation of change in gold standard determined body fluid spaces&#xD;
      (blood volume, extracellular fluid, total body water), administering a sodium chloride&#xD;
      challenge, and collecting the necessary biospecimens to test our hypotheses. The general&#xD;
      study design will randomize to ertugliflozin vs. placebo early during IV diuretic therapy&#xD;
      with continuation post discharge for a total therapy of 6 weeks.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">March 10, 2021</start_date>
  <completion_date type="Anticipated">July 2024</completion_date>
  <primary_completion_date type="Anticipated">January 31, 2024</primary_completion_date>
  <phase>Phase 2</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>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Natriuretic effect of adjuvant to loop diuretic therapy</measure>
    <time_frame>1 day</time_frame>
    <description>The natriuretic effect (urine sodium concentration) of each arm with loop diuretic therapy will be measured by the urine sodium output.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change from baseline to day 7 of total body water by add-on to loop diuretic therapy (Chronic)</measure>
    <time_frame>7 days</time_frame>
    <description>The primary outcome of the chronic effects of add-on placebo, thiazide-like diuretic, or SGLT2 inhibitor is to determine the change in total body water from baseline to day 7</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change from baseline to 6 weeks total body water by add-on to loop diuretic therapy (Chronic)</measure>
    <time_frame>6 weeks</time_frame>
    <description>The primary outcome of the chronic effects of add-on placebo, thiazide-like diuretic, or SGLT2 inhibitor is to determine the change in total body water from baseline to 6 weeks.</description>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">90</enrollment>
  <condition>Heart Failure</condition>
  <arm_group>
    <arm_group_label>Ertugliflozin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Metolazone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ertugliflozin</intervention_name>
    <description>Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo</description>
    <arm_group_label>Ertugliflozin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metolazone</intervention_name>
    <description>Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo</description>
    <arm_group_label>Metolazone</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. A clinical diagnosis of ADHF with at least one objective sign of volume overload&#xD;
             (rales, edema, elevated JVP, or preadmission weight gain)&#xD;
&#xD;
          2. As judged by the treating physician, a projected need and ability to tolerate&#xD;
             treatment with an extended need for IV diuretics with the goal of significant fluid&#xD;
             removal (i.e., goal &gt;1L/day net fluid loss)&#xD;
&#xD;
          3. Chronic daily oral loop diuretic dose &gt; or equal to 20mg furosemide equivalents for at&#xD;
             least one month prior to admission&#xD;
&#xD;
          4. eGFR 30 mL/min/1.73 m2&#xD;
&#xD;
          5. Signed informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Current use or plan to initiate renal replacement therapy or ultrafiltration this&#xD;
             hospital admission&#xD;
&#xD;
          2. Significant bladder dysfunction or urinary incontinence&#xD;
&#xD;
          3. Inability to comply with the serial urine collection procedures&#xD;
&#xD;
          4. Current use of a thiazide or thiazide like diuretics or use within 5 half-lives of the&#xD;
             drug, including metolazone&#xD;
&#xD;
          5. Prior heart transplant, critical stenotic valvular disease or complex congenital heart&#xD;
&#xD;
          6. History of type 1 diabetes, diabetic ketoacidosis, &quot;brittle&quot; diabetes or frequent&#xD;
             hypoglycemia or severe hypoglycemic episodes requiring emergent intervention (ER visit&#xD;
             or EMS response, glucagon administration or forced oral carbs) in the last 3 months&#xD;
&#xD;
          7. History of or current urosepsis or frequent urinary tract infections&#xD;
&#xD;
          8. Anemia with hemoglobin &lt;8g/dL (due to required phlebotomy for the study)&#xD;
&#xD;
          9. Pregnancy or breastfeeding&#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_contact>
    <last_name>Katherine Keith, RN</last_name>
    <phone>(203) 737-3571</phone>
    <email>katherine.keith@yale.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Veena Rao, PhD</last_name>
    <phone>(203) 785-7917</phone>
    <email>veena.s.rao@yale.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Yale School of Medicine</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06510</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Jeffrey Testani, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>June 3, 2020</study_first_submitted>
  <study_first_submitted_qc>June 16, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 18, 2020</study_first_posted>
  <last_update_submitted>February 17, 2023</last_update_submitted>
  <last_update_submitted_qc>February 17, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 21, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Ertugliflozin</keyword>
  <keyword>Metolazone</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ertugliflozin</mesh_term>
    <mesh_term>Metolazone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT04438213
org study id: 2000027951
secondary id: MISP59625
nct id: NCT04438213
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
The purpose of this study is to determine the effects on heart failure signs and symptoms of
      the use of either ertugliflozin, metolazone or placebo, in conjunction with intravenous loop
      diuretic use in acute settings and chronic oral loop diuretic therapy.

      There are two general purposes for this study. The proposed study is both larger and more
      rigorous than essentially all PK/PD studies that form the basis of current practice with loop
      diuretics as well as all studies looking at add-on thiazide therapy (current
      guideline-recommended adjuvant). The second is to generate a mechanistic understanding of the
      pleotropic cardio-renal factors with chronic therapy that differentiate ertugliflozin from
      traditional diuretics particularly in how they maintain reduced blood volume without the
      complication of over-diuresis and volume depletion.
This is a randomized placebo controlled mechanistic study to understand the utility of
      ertugliflozin in acute and post-acute hospitalized heart failure patients with or without
      diabetes, compared to both placebo and the active control metolazone. The broad study design
      will be designed around evaluation of change in gold standard determined body fluid spaces
      (blood volume, extracellular fluid, total body water), administering a sodium chloride
      challenge, and collecting the necessary biospecimens to test our hypotheses. The general
      study design will randomize to ertugliflozin vs. placebo early during IV diuretic therapy
      with continuation post discharge for a total therapy of 6 weeks.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Natriuretic effect of adjuvant to loop diuretic therapy
time frame: 1 day
description: The natriuretic effect (urine sodium concentration) of each arm with loop diuretic therapy will be measured by the urine sodium output.
measure: Change from baseline to day 7 of total body water by add-on to loop diuretic therapy (Chronic)
time frame: 7 days
description: The primary outcome of the chronic effects of add-on placebo, thiazide-like diuretic, or SGLT2 inhibitor is to determine the change in total body water from baseline to day 7
measure: Change from baseline to 6 weeks total body water by add-on to loop diuretic therapy (Chronic)
time frame: 6 weeks
description: The primary outcome of the chronic effects of add-on placebo, thiazide-like diuretic, or SGLT2 inhibitor is to determine the change in total body water from baseline to 6 weeks.
arm group label: Ertugliflozin
arm group type: Experimental
description: Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo
arm group label: Metolazone
arm group type: Experimental
description: Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo
arm group label: Placebo
arm group type: Placebo Comparator
description: Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo
intervention type: Drug
intervention name: Ertugliflozin
description: Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo
arm group label: Ertugliflozin
intervention type: Drug
intervention name: Metolazone
description: Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo
arm group label: Metolazone
intervention type: Drug
intervention name: Placebo
description: Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Katherine Keith, RN
phone: (203) 737-3571
email: katherine.keith@yale.edu
last name: Veena Rao, PhD
phone: (203) 785-7917
email: veena.s.rao@yale.edu
facility: 
status: Recruiting
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Heart Failure
mesh term: Ertugliflozin
mesh term: Metolazone
sharing ipd: Undecided