xml: <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/NCT06027307</url>
    </required_header>
    <id_info>
      <org_study_id>2023-0070</org_study_id>
      <nct_id>NCT06027307</nct_id>
    </id_info>
    <brief_title>Enavogliflozin Outcome Trial in Functional Tricuspid Regurgitation</brief_title>
    <acronym>EVENT</acronym>
    <official_title>Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess the Effects of Enavogliflozin on Outcomes in Patients With Functional Tricuspid Regurgitation and Heart Failure With Preserved Left Ventricular Ejection Fraction</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Asan Medical Center</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Daewoong Pharmaceutical Co. LTD.</agency>
        <agency_class>Industry</agency_class>
      </collaborator>
    </sponsors>
    <source>Asan Medical Center</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>
    </oversight_info>
    <brief_summary>
      <textblock>
        The Enavogliflozin Outcome Trial in Functional Tricuspid Regurgitation (EVENT) was designed&#xD;
        to examine the hypothesis that, compared with placebo, therapy with the SGLT2 inhibitor&#xD;
        enavogliflozin would improve clinical and echocardiographic outcomes in heart failure (HF)&#xD;
        patients with functional tricuspid regurgitation (TR) and preserved left ventricular ejection&#xD;
        fraction (LVEF).&#xD;
  &#xD;
        The primary objective of the EVENT study is to test the hypothesis that, compared with&#xD;
        placebo, therapy with enavogliflozin for 18 months would improve a composite of&#xD;
        cardiovascular events or worsening of TR on follow-up echocardiography in HF patients with&#xD;
        functional TR and preserved LVEF. The secondary objective is to examine whether&#xD;
        enavogliflozin is effective in reduction of renal events and tricuspid regurgitation, and to&#xD;
        evaluate whether beneficial effects of enavogliflozin on primary outcomes are associated with&#xD;
        reduction of all-cause mortality.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Functional tricuspid regurgitation (TR) develops due to functional and structural alterations&#xD;
        related to heart failure (HF), mitral valve disease and atrial fibrillation. An increase in&#xD;
        cardiac filling pressure due to left ventricular (LV) systolic or diastolic dysfunction leads&#xD;
        to left atrial, right atrial (RA) and right ventricular (RV) remodeling, which causes&#xD;
        tricuspid annular dilatation and TR. The development of significant functional TR causes RV&#xD;
        dysfunction and further dilation of RV, which deteriorates TR. Functional TR may occur with&#xD;
        HF with preserved or reduced ejection fraction (EF), and the prevalence of moderate-to-severe&#xD;
        functional TR is around 19% in patients with HF. Regardless of LVEF or pulmonary artery&#xD;
        pressure, presence of moderate or severe functional TR is associated with more symptoms,&#xD;
        reduced cardiac output, and worse renal function. A vicious cycle of significant TR, RV&#xD;
        volume overload, adverse remodeling of RA, RV, and tricuspid annulus, and consequent&#xD;
        aggravation of TR is suggested as a pathophysiologic mechanism of the poor clinical outcomes&#xD;
        of patients with TR, and the presence of moderate or severe functional TR is a strong&#xD;
        independent determinant of mortality in patients with HF. Because functional TR has a strong&#xD;
        prognostic impact and plays an important pathophysiologic role in patients with HF,&#xD;
        functional TR is suggested as a therapeutic target in HF. However, there have been no proven&#xD;
        medical therapies for TR and only loop diuretics are cautiously recommended for relief of&#xD;
        congestive symptoms in patients with severe TR and signs of RV failure. In patients with&#xD;
        functional TR associated with systolic dysfunction, medical therapy for HF with a reduced EF&#xD;
        may diminish functional TR by improving LV systolic function. Otherwise, the morbidity and&#xD;
        mortality of patients with functional TR remain high and a novel therapeutic agent is needed&#xD;
        to improve clinical outcomes of HF patients with functional TR and a preserved LV ejection&#xD;
        fraction.&#xD;
  &#xD;
        Sodium-glucose co-transporter 2 (SGLT2) inhibitors induce urinary excretion of glucose and&#xD;
        sodium by blocking the SGLT2 transporter in the proximal tubule (8). SGLT2 inhibitor-induced&#xD;
        natriuresis lower cardiac preload and reduce pulmonary congestion and systemic edema. SGLT2&#xD;
        inhibitors also restore tubuloglomerular feedback and lower the intraglomerular pressure by&#xD;
        vasoconstriction of the afferent arterioles and consequently reduce hyperfiltration-related&#xD;
        renal damage. The beneficial effects of SGLT2 inhibitors on the heart and kidneys may halt&#xD;
        the vicious cardiorenal cycle in patients with functional TR (9), which results in&#xD;
        deterioration of renal function, hospitalization for heart failure, and cardiovascular&#xD;
        mortality.&#xD;
  &#xD;
        Accordingly, the Enavogliflozin Outcome Trial in Functional Tricuspid Regurgitation (EVENT)&#xD;
        will test the hypothesis that, compared with placebo, therapy with the SGLT2 inhibitor&#xD;
        enavogliflozin for 18 months would improve clinical and echocardiographic outcomes in HF&#xD;
        patients with functional TR and preserved LVEF.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">October 2023</start_date>
    <completion_date type="Anticipated">October 2027</completion_date>
    <primary_completion_date type="Anticipated">April 2026</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Cardiovascular event</measure>
      <time_frame>18 months</time_frame>
      <description>A composite of cardiovascular death, hospitalization for HF, or worsening of tricuspid regurgitation that occurs during follow-up</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>All-cause death</measure>
      <time_frame>18 months</time_frame>
      <description>All-cause death occurring during follow-up</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Cardiovascular clinical event</measure>
      <time_frame>18 months</time_frame>
      <description>A cardiovascular composite (cardiovascular mortality or hospitalization for HF) occurring during follow-up</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Renal event</measure>
      <time_frame>18 months</time_frame>
      <description>A renal composite (doubling of serum creatinine, decrease in the eGFR of 30% or more, renal replacement therapy, or renal death) occurring during follow-up</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change of TR</measure>
      <time_frame>18 months</time_frame>
      <description>Change of TR on echocardiography from baseline to 18 months follow-up</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change of RV strain</measure>
      <time_frame>18 months</time_frame>
      <description>Change of RV strain on echocardiography from baseline to 18 months follow-up</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">540</enrollment>
    <condition>Tricuspid Regurgitation</condition>
    <condition>Heart Failure With Preserved Ejection Fraction</condition>
    <arm_group>
      <arm_group_label>Enavogliflozin</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Enavogliflozin 0.3 mg qd for 18 months</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Placebo</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <description>Placebo qd for 18 months</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Enavogliflozin</intervention_name>
      <description>All study patients will receive enavogliflozin in addition to their prior medications. They will receive optimal medical treatment for their underlying disease such as hypertension, diabetes, arrhythmia and/or coronary artery disease.</description>
      <arm_group_label>Enavogliflozin</arm_group_label>
      <other_name>Enblo</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Placebo</intervention_name>
      <description>All study patients will receive placebo in addition to their prior medications. They will receive optimal medical treatment for their underlying disease such as hypertension, diabetes, arrhythmia and/or coronary artery disease.</description>
      <arm_group_label>Placebo</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Patients must agree to the study protocol and provide written informed consent&#xD;
  &#xD;
            -  Outpatients male or female between the age of 20 and 80&#xD;
  &#xD;
            -  Non-diabetic or type2 DM patients with HbA1c 6.5-10.5%&#xD;
  &#xD;
            -  HF with dyspnea of NYHA functional class II or III&#xD;
  &#xD;
            -  Presence of moderate or severe functional TR and preserved LVEF on echocardiography&#xD;
  &#xD;
                 -  TR whose vena contracta ≥ 0.3cm, effective regurgitant orifice area ≥ 0.20 cm2,&#xD;
                    or jet area &gt; 10cm2&#xD;
  &#xD;
                 -  LVEF ≥ 50%&#xD;
  &#xD;
            -  NT-proBNP &gt;125 pg/mL or BNP ≥35 pg/mL&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  History of hypersensitivity or allergy to the study drugs, drugs of similar chemical&#xD;
               classes, as well as known or suspected contraindications to the study drug&#xD;
  &#xD;
            -  Current use or prior use of a SGLT-2 inhibitor or combined SGLT-1 and 2 inhibitor&#xD;
  &#xD;
            -  Any evidence of structural tricuspid valve disease&#xD;
  &#xD;
            -  Any significant left-sided valve disease&#xD;
  &#xD;
            -  Left ventricular ejection fraction &lt;50%&#xD;
  &#xD;
            -  Marked bradycardia or 2nd or 3rd degree AV block&#xD;
  &#xD;
            -  Intracardiac devices (CRT, ICD, Pacemaker)&#xD;
  &#xD;
            -  Hypertrophic or restrictive cardiomyopathy&#xD;
  &#xD;
            -  Severe pulmonary hypertension: TR Vmax &gt; 3.5m/s at screening&#xD;
  &#xD;
            -  Medical history of hospitalization within 4 weeks&#xD;
  &#xD;
            -  Current acute decompensated heart failure or dyspnea of NYHA functional class IV&#xD;
  &#xD;
            -  Symptomatic hypotension and/or a SBP &lt; 90 mmHg at screening&#xD;
  &#xD;
            -  Uncontrolled hypertension (SBP≥180mmHg or DBP≥110mmHg)&#xD;
  &#xD;
            -  Estimated GFR &lt; 30 mL/min/1.73m2&#xD;
  &#xD;
            -  History of ketoacidosis&#xD;
  &#xD;
            -  Evidence of hepatic disease as determined by any one of the following: AST or ALT&#xD;
               values exceeding 2 x upper limit of normal (ULN) at screening visit (Visit 0), history&#xD;
               of hepatic encephalopathy, history of esophageal varices, or history of portocaval&#xD;
               shunt.&#xD;
  &#xD;
            -  Acute coronary syndrome, stroke, major CV surgery, PCI within 3 months&#xD;
  &#xD;
            -  Plan for cardiac surgery, PCI or ablation of atrial flutter of fibrillation&#xD;
  &#xD;
            -  History of severe pulmonary disease&#xD;
  &#xD;
            -  Women of child-bearing potential, defined as all women physiologically capable of&#xD;
               becoming pregnant, unless they are using a barrier method plus a hormonal method&#xD;
  &#xD;
            -  Pregnant or nursing (lactating) women&#xD;
  &#xD;
            -  Any clinically significant abnormality identified at the screening visit, physical&#xD;
               examination, laboratory tests, or electrocardiogram which, in the judgment of the&#xD;
               investigator, would preclude safe completion of the study&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>20 Years</minimum_age>
      <maximum_age>80 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>DUK HYUN KANG, MD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Asan Medical Center</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>DUK HYUN KANG, MD</last_name>
      <phone>82-2-3010-3166</phone>
      <email>dhkang@amc.seoul.kr</email>
    </overall_contact>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 31, 2023</study_first_submitted>
    <study_first_submitted_qc>August 31, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 7, 2023</study_first_posted>
    <last_update_submitted>August 31, 2023</last_update_submitted>
    <last_update_submitted_qc>August 31, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 7, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Asan Medical Center</investigator_affiliation>
      <investigator_full_name>Duk-Hyun Kang</investigator_full_name>
      <investigator_title>Professor</investigator_title>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Heart Failure</mesh_term>
      <mesh_term>Tricuspid Valve Insufficiency</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06027307
  org study id: 2023-0070
  nct id: NCT06027307
  lead sponsor: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  The Enavogliflozin Outcome Trial in Functional Tricuspid Regurgitation (EVENT) was designed
        to examine the hypothesis that, compared with placebo, therapy with the SGLT2 inhibitor
        enavogliflozin would improve clinical and echocardiographic outcomes in heart failure (HF)
        patients with functional tricuspid regurgitation (TR) and preserved left ventricular ejection
        fraction (LVEF).
  
        The primary objective of the EVENT study is to test the hypothesis that, compared with
        placebo, therapy with enavogliflozin for 18 months would improve a composite of
        cardiovascular events or worsening of TR on follow-up echocardiography in HF patients with
        functional TR and preserved LVEF. The secondary objective is to examine whether
        enavogliflozin is effective in reduction of renal events and tricuspid regurgitation, and to
        evaluate whether beneficial effects of enavogliflozin on primary outcomes are associated with
        reduction of all-cause mortality.
  Functional tricuspid regurgitation (TR) develops due to functional and structural alterations
        related to heart failure (HF), mitral valve disease and atrial fibrillation. An increase in
        cardiac filling pressure due to left ventricular (LV) systolic or diastolic dysfunction leads
        to left atrial, right atrial (RA) and right ventricular (RV) remodeling, which causes
        tricuspid annular dilatation and TR. The development of significant functional TR causes RV
        dysfunction and further dilation of RV, which deteriorates TR. Functional TR may occur with
        HF with preserved or reduced ejection fraction (EF), and the prevalence of moderate-to-severe
        functional TR is around 19% in patients with HF. Regardless of LVEF or pulmonary artery
        pressure, presence of moderate or severe functional TR is associated with more symptoms,
        reduced cardiac output, and worse renal function. A vicious cycle of significant TR, RV
        volume overload, adverse remodeling of RA, RV, and tricuspid annulus, and consequent
        aggravation of TR is suggested as a pathophysiologic mechanism of the poor clinical outcomes
        of patients with TR, and the presence of moderate or severe functional TR is a strong
        independent determinant of mortality in patients with HF. Because functional TR has a strong
        prognostic impact and plays an important pathophysiologic role in patients with HF,
        functional TR is suggested as a therapeutic target in HF. However, there have been no proven
        medical therapies for TR and only loop diuretics are cautiously recommended for relief of
        congestive symptoms in patients with severe TR and signs of RV failure. In patients with
        functional TR associated with systolic dysfunction, medical therapy for HF with a reduced EF
        may diminish functional TR by improving LV systolic function. Otherwise, the morbidity and
        mortality of patients with functional TR remain high and a novel therapeutic agent is needed
        to improve clinical outcomes of HF patients with functional TR and a preserved LV ejection
        fraction.
  
        Sodium-glucose co-transporter 2 (SGLT2) inhibitors induce urinary excretion of glucose and
        sodium by blocking the SGLT2 transporter in the proximal tubule (8). SGLT2 inhibitor-induced
        natriuresis lower cardiac preload and reduce pulmonary congestion and systemic edema. SGLT2
        inhibitors also restore tubuloglomerular feedback and lower the intraglomerular pressure by
        vasoconstriction of the afferent arterioles and consequently reduce hyperfiltration-related
        renal damage. The beneficial effects of SGLT2 inhibitors on the heart and kidneys may halt
        the vicious cardiorenal cycle in patients with functional TR (9), which results in
        deterioration of renal function, hospitalization for heart failure, and cardiovascular
        mortality.
  
        Accordingly, the Enavogliflozin Outcome Trial in Functional Tricuspid Regurgitation (EVENT)
        will test the hypothesis that, compared with placebo, therapy with the SGLT2 inhibitor
        enavogliflozin for 18 months would improve clinical and echocardiographic outcomes in HF
        patients with functional TR and preserved LVEF.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  measure: Cardiovascular event
  time frame: 18 months
  description: A composite of cardiovascular death, hospitalization for HF, or worsening of tricuspid regurgitation that occurs during follow-up
  measure: All-cause death
  time frame: 18 months
  description: All-cause death occurring during follow-up
  measure: Cardiovascular clinical event
  time frame: 18 months
  description: A cardiovascular composite (cardiovascular mortality or hospitalization for HF) occurring during follow-up
  measure: Renal event
  time frame: 18 months
  description: A renal composite (doubling of serum creatinine, decrease in the eGFR of 30% or more, renal replacement therapy, or renal death) occurring during follow-up
  measure: Change of TR
  time frame: 18 months
  description: Change of TR on echocardiography from baseline to 18 months follow-up
  measure: Change of RV strain
  time frame: 18 months
  description: Change of RV strain on echocardiography from baseline to 18 months follow-up
  arm group label: Enavogliflozin
  arm group type: Experimental
  description: Enavogliflozin 0.3 mg qd for 18 months
  arm group label: Placebo
  arm group type: Placebo Comparator
  description: Placebo qd for 18 months
  intervention type: Drug
  intervention name: Enavogliflozin
  description: All study patients will receive enavogliflozin in addition to their prior medications. They will receive optimal medical treatment for their underlying disease such as hypertension, diabetes, arrhythmia and/or coronary artery disease.
  arm group label: Enavogliflozin
  other name: Enblo
  intervention type: Drug
  intervention name: Placebo
  description: All study patients will receive placebo in addition to their prior medications. They will receive optimal medical treatment for their underlying disease such as hypertension, diabetes, arrhythmia and/or coronary artery disease.
  arm group label: Placebo
  criteria: 
  gender: All
  minimum age: 20 Years
  maximum age: 80 Years
  healthy volunteers: No
  last name: DUK HYUN KANG, MD
  role: Principal Investigator
  affiliation: Asan Medical Center
  last name: DUK HYUN KANG, MD
  phone: 82-2-3010-3166
  email: dhkang@amc.seoul.kr
  responsible party type: Principal Investigator
  investigator affiliation: Asan Medical Center
  investigator full name: Duk-Hyun Kang
  investigator title: Professor
  mesh term: Heart Failure
  mesh term: Tricuspid Valve Insufficiency
  sharing ipd: No