<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/NCT02230891</url>
  </required_header>
  <id_info>
    <org_study_id>CLNB-009-13F</org_study_id>
    <nct_id>NCT02230891</nct_id>
  </id_info>
  <brief_title>Biomarker Guided Therapies in Stage A/B Heart Failure</brief_title>
  <official_title>Biomarker Guided Therapies in Stage A/B Heart Failure</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>VA Office of Research and Development</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Baylor College of Medicine</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>VA Office of Research and Development</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Despite advances in cardiovascular care, the occurrence of heart failure (HF) is steadily&#xD;
      increasing. The increase in HF rates poses enormous challenges, as once an individual becomes&#xD;
      symptomatic or requires hospitalization with HF, the prognosis remains poor. Therefore,&#xD;
      prevention of HF is essential. HF prevention is a critical issue as HF risk factors that&#xD;
      include common medical conditions such as hypertension and diabetes are also increasing.&#xD;
      However, not everyone with these risk factors develops HF. Using novel blood tests, the&#xD;
      investigators propose to identify and treat subjects at higher HF risk to see if the&#xD;
      investigators can stabilize or improve ultrasound measures known to be associated with HF&#xD;
      risk. This study will enroll only Veterans.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Recently the investigators have shown that HF risk prediction can be improved using cardiac&#xD;
      troponin T measured with a novel high-sensitivity assay (hs-cTnT) and N-terminal pro-B-type&#xD;
      natriuretic peptide (NT-proBNP). Furthermore, hs-cTnT seems to identify individuals at higher&#xD;
      risk among those with established risk factors (such as hypertension) for HF. In preliminary&#xD;
      results, the investigators have shown that individuals with systolic blood pressure of&#xD;
      120-129 mm Hg and elevated hs-cTnT have a higher rate of incident HF than those with systolic&#xD;
      blood pressure of 140-159 mm Hg and undetectable hs-cTnT. Therefore, the investigators&#xD;
      believe that by using hs-cTnT to estimate HF risk the investigators can identify individuals&#xD;
      in whom aggressive modification of risk factors such as high blood pressure will be&#xD;
      associated with a favorable risk-benefit ratio.&#xD;
&#xD;
      The investigators' objective/specific aim therefore is to evaluate if treatment of selected&#xD;
      subjects with Stage A or B HF (i.e., those with hs-cTnT &gt;5 ng/L and an estimated 10-year HF&#xD;
      hospitalization risk of &gt;5%) who have reasonably well-controlled blood pressure with&#xD;
      antihypertensive agents (carvedilol or spironolactone) will be associated with improvement of&#xD;
      surrogate markers associated with incident HF (i.e., speckle-tracked cardiac and vascular&#xD;
      strain). Carvedilol and spironolactone were chosen for the following reasons: a) they are not&#xD;
      routinely used as first-line antihypertensive agents; b) beta-blockade was associated with&#xD;
      decreases in hs-cTnT in the preliminary analysis of subjects with established HF; and c) the&#xD;
      mechanism of actions of carvedilol and spironolactone provide a sound scientific rationale&#xD;
      for use in prevention of HF.&#xD;
&#xD;
      Using a prospective open-label blinded end point (PROBE) design, the investigators propose to&#xD;
      randomize 210 subjects aged &gt;40 years with systolic blood pressure between 120-155 mm Hg,&#xD;
      cardiac troponin T (measured with a novel high-sensitivity assay) level &gt;5 ng/L, and 10-year&#xD;
      HF risk &gt;5% (estimated using a validated laboratory model including demographic factors,&#xD;
      NT-proBNP, and hs-cTnT) to receive carvedilol (nonselective beta-blocker), spironolactone&#xD;
      (aldosterone antagonist), or usual care for 18 months. The primary end point will be change&#xD;
      in global longitudinal systolic myocardial strain estimated using 2D speckle tracking.&#xD;
      Additionally, changes in vascular strain and biomarkers will be evaluated. This study will&#xD;
      help us identify whether both or either of the medications can be further tested in large&#xD;
      randomized clinical trials to prevent the incidence of HF.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 1, 2014</start_date>
  <completion_date type="Actual">December 15, 2020</completion_date>
  <primary_completion_date type="Actual">December 15, 2020</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>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Cardiac Global Longitudinal Strain</measure>
    <time_frame>18 months</time_frame>
    <description>Change in myocardial speckle tracked strain (global longitudinal strain) after 18 months (baseline vs. 18 months) of therapy with carvedilol or spironolactone or usual care. The myocardial global longitudinal strain was measured using echocardiography</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in NTproBNP (Biomarker)</measure>
    <time_frame>18 months</time_frame>
    <description>Change in levels of NT-proBNP (measured in blood samples) between baseline and 18 months after therapy with carvedilol or spironolactone or usual care</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Pulse Wave Velocity</measure>
    <time_frame>18 months</time_frame>
    <description>Changes in arterial stiffness between baseline and 18 months after therapy with carvedilol, spironolactone or usual care. Arterial stiffness was measured by pulse wave velocity (Sphygmocor device)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Troponin T Measured Using a High Sensitivity Assay</measure>
    <time_frame>18 months</time_frame>
    <description>Change in levels of troponin T (measured with a high sensitivity assay in blood samples) between baseline and 18 months after therapy with carvedilol or spironolactone or usual care</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">58</enrollment>
  <condition>Hypertension</condition>
  <condition>Diabetes</condition>
  <condition>Cardiovascular Disease</condition>
  <arm_group>
    <arm_group_label>Carvedilol</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Approximately 70 subjects will be randomized to carvedilol</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Spironolactone</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Approximately 70 subjects will be randomized to spironolactone</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Usual care</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Approximately 70 subjects will be randomized to usual care/ standard care by primary care providers</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carvedilol</intervention_name>
    <description>Carvedilol is a non selective beta blocker</description>
    <arm_group_label>Carvedilol</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Spironolactone</intervention_name>
    <description>Spironolactone is an aldosterone antagonist and can lower blood pressure/ is used in heart failure</description>
    <arm_group_label>Spironolactone</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Usual care</intervention_name>
    <description>standard care as per primary care provider</description>
    <arm_group_label>Usual care</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Only Veterans are eligible to participate. Other inclusion criteria include&#xD;
&#xD;
          -  Age greater than 40 years&#xD;
&#xD;
          -  One of the following in order to establish Stage A HF a. Hypertension b. Diabetes&#xD;
             mellitus (controlled: defined as hemoglobin A1c less than 9%) c. Obesity (defined as&#xD;
             BMI greater than 30 kg/m2) d. Metabolic syndrome (using the National Cholesterol&#xD;
             Education Panel definition) e. Left ventricular hypertrophy (by ECG) f. Coronary or&#xD;
             cerebrovascular arterial disease&#xD;
&#xD;
          -  Troponin T measured by the high sensitivity assay of greater than 5ng/L&#xD;
&#xD;
          -  Systolic BP 120-155 mmHg at primary care provider (PCP) visit and prerandomization&#xD;
             visit (i.e., 2 separate confirmations of the same). If there is discordance between&#xD;
             the PCP visit and pre-randomization the investigators will bring patient back to&#xD;
             recheck his BP and use that as the tie breaker. Not orthostatic with measurements&#xD;
             (defined as a fall in systolic BP greater than 20 mmHg when subjects assume an upright&#xD;
             position). - Estimated 10-yr HF risk (based on Atherosclerosis Risk in Communities HF&#xD;
             Lab model) greater than 5%&#xD;
&#xD;
          -  Provides informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        The exclusion criteria include&#xD;
&#xD;
          -  Active Atrial fibrillation&#xD;
&#xD;
          -  History of chest/ neck radiation&#xD;
&#xD;
          -  High-risk chronic obstructive pulmonary disease (COPD) (GOLD classification 3-4 with&#xD;
             greater than equal to 2 COPD exacerbations in the last 12 months)&#xD;
&#xD;
          -  Known allergy to carvedilol or spironolactone&#xD;
&#xD;
          -  Renal insufficiency with estimated Glomerular Filtration Rate (eGFR) less than 60&#xD;
             ml/min&#xD;
&#xD;
          -  Serum potassium greater than 5 meq/L&#xD;
&#xD;
          -  Current use of carvedilol, spironolactone, any other beta-blockers or aldosterone&#xD;
             antagonists&#xD;
&#xD;
          -  Signs of clinical HF on initial examination (pulmonary rales/crackles, elevated&#xD;
             jugular venous pulse with S3/S4 on auscultation)&#xD;
&#xD;
          -  Left ventricular ejection fraction &lt;50% by echo&#xD;
&#xD;
          -  Moderate or greater valve stenosis or regurgitation&#xD;
&#xD;
          -  Hypertrophic cardiomyopathy&#xD;
&#xD;
          -  Exposure to known cardiotoxic chemotherapy&#xD;
&#xD;
          -  Poor echo image quality&#xD;
&#xD;
          -  Right ventricular dysfunction more than mild&#xD;
&#xD;
          -  Any valvular dysfunction that is more than mild&#xD;
&#xD;
          -  Any life-threatening disease expected to result in death within the next 2 years&#xD;
&#xD;
          -  Active severe liver disease (evaluated at Visit 1): cirrhosis, active hepatitis,&#xD;
             aspartate transaminase (ALT) or alanine transaminase (AST) greater than 3 x ULN, or&#xD;
             biliary obstruction with hyperbilirubinemia (total bilirubin greater than 2 x ULN).&#xD;
&#xD;
          -  Participation in another clinical trial involving an investigational agent within 90&#xD;
             days prior to randomization&#xD;
&#xD;
          -  Any condition or therapy which, in the opinion of the investigator, might pose a risk&#xD;
             to the patient or make participation in the study not in the patient s best interest&#xD;
&#xD;
          -  Drug or alcohol abuse within the past 6 months, and unable/unwilling to abstain from&#xD;
             drug abuse and excessive alcohol consumption during the study. Excessive alcohol&#xD;
             consumption is on average greater than 2 units of alcohol per day. A unit of alcohol&#xD;
             is defined as a 12-ounce (350 mL) beer, 5-ounce (150 mL) wine, or 1.5-ounce (45 mL) of&#xD;
             80 ]proof alcohol for drinks.&#xD;
&#xD;
          -  Mental/psychological impairment or any other reason to expect patient difficulty in&#xD;
             complying with the requirements of the study.&#xD;
&#xD;
          -  Any immunosuppressed condition where intercurrent illnesses may affect interpretation&#xD;
             of study results&#xD;
&#xD;
          -  Pregnant women or any woman planning a pregnancy during the study period&#xD;
&#xD;
          -  Not meeting any of the inclusion criteria&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Vijay Nambi, MBBS</last_name>
    <role>Principal Investigator</role>
    <affiliation>Michael E. DeBakey VA Medical Center, Houston, TX</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Michael E. DeBakey VA Medical Center, Houston, TX</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>August 28, 2014</study_first_submitted>
  <study_first_submitted_qc>August 28, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 3, 2014</study_first_posted>
  <results_first_submitted>June 30, 2022</results_first_submitted>
  <results_first_submitted_qc>September 1, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">September 29, 2022</results_first_posted>
  <disposition_first_submitted>December 10, 2021</disposition_first_submitted>
  <disposition_first_submitted_qc>December 10, 2021</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">December 15, 2021</disposition_first_posted>
  <last_update_submitted>October 19, 2022</last_update_submitted>
  <last_update_submitted_qc>October 19, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 21, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>heart failure</keyword>
  <keyword>biomarkers</keyword>
  <keyword>troponin</keyword>
  <keyword>BNP</keyword>
  <keyword>carvedilol</keyword>
  <keyword>spironolactone</keyword>
  <keyword>prevention</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
    <mesh_term>Cardiovascular Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carvedilol</mesh_term>
    <mesh_term>Spironolactone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>April 22, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/91/NCT02230891/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Carvedilol</title>
          <description>Approximately 70 subjects will be randomized to carvedilol&#xD;
Carvedilol: Carvedilol is a non selective beta blocker. Dose will be 3.125 mg two times daily with increases in dose if blood pressure permits</description>
        </group>
        <group group_id="P2">
          <title>Spironolactone</title>
          <description>Approximately 70 subjects will be randomized to spironolactone&#xD;
Spironolactone: Spironolactone is an aldosterone antagonist and can lower blood pressure/ is used in heart failure. Spironolactone dose will be 25 mg by mouth once daily</description>
        </group>
        <group group_id="P3">
          <title>Usual Care</title>
          <description>Approximately 70 subjects will be randomized to usual care/ standard care by primary care providers&#xD;
Usual care: standard care as per primary care provider</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Baseline</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="18"/>
                <participants group_id="P3" count="19"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="17"/>
                <participants group_id="P3" count="18"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Did not meet inclusion</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>2 Week</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="17"/>
                <participants group_id="P3" count="0">No week 2 for subjects in usual care</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
                <participants group_id="P2" count="15"/>
                <participants group_id="P3" count="0">No week 2 for subjects in usual care</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Consent withdrawn</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>6 Month</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
                <participants group_id="P2" count="15"/>
                <participants group_id="P3" count="18"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
                <participants group_id="P2" count="12"/>
                <participants group_id="P3" count="17"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>12 Month</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
                <participants group_id="P2" count="12"/>
                <participants group_id="P3" count="17"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="16"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="17"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>18 Month End of Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="16"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="17"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="16"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Hear failure, lost to follow up</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>These include individuals who participated in the study. Patient who withdrew consent and one who did not meet eligibility criteria and hence was excluded not included</population>
      <group_list>
        <group group_id="B1">
          <title>Carvedilol</title>
          <description>Approximately 70 subjects will be randomized to carvedilol&#xD;
Carvedilol: Carvedilol is a non selective beta blocker</description>
        </group>
        <group group_id="B2">
          <title>Spironolactone</title>
          <description>Approximately 70 subjects will be randomized to spironolactone&#xD;
Spironolactone: Spironolactone is an aldosterone antagonist and can lower blood pressure/ is used in heart failure</description>
        </group>
        <group group_id="B3">
          <title>Usual Care</title>
          <description>Approximately 70 subjects will be randomized to usual care/ standard care by primary care providers&#xD;
Usual care: standard care as per primary care provider</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="20"/>
            <count group_id="B2" value="18"/>
            <count group_id="B3" value="18"/>
            <count group_id="B4" value="56"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="20"/>
                    <count group_id="B2" value="18"/>
                    <count group_id="B3" value="18"/>
                    <count group_id="B4" value="56"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="15"/>
                    <measurement group_id="B4" value="48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="20"/>
                    <count group_id="B2" value="18"/>
                    <count group_id="B3" value="18"/>
                    <count group_id="B4" value="56"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="70.6" spread="5.3"/>
                    <measurement group_id="B2" value="69.2" spread="6.5"/>
                    <measurement group_id="B3" value="70.6" spread="5.8"/>
                    <measurement group_id="B4" value="70.1" spread="5.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="20"/>
                    <count group_id="B2" value="18"/>
                    <count group_id="B3" value="18"/>
                    <count group_id="B4" value="56"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="18"/>
                    <measurement group_id="B3" value="18"/>
                    <measurement group_id="B4" value="56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="20"/>
                    <count group_id="B2" value="18"/>
                    <count group_id="B3" value="18"/>
                    <count group_id="B4" value="56"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="5"/>
                    <measurement group_id="B4" value="26"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="13"/>
                    <measurement group_id="B4" value="30"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="20"/>
                    <count group_id="B2" value="18"/>
                    <count group_id="B3" value="18"/>
                    <count group_id="B4" value="56"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="18"/>
                    <measurement group_id="B3" value="18"/>
                    <measurement group_id="B4" value="58"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Baseline troponin</title>
          <population>One subject baseline biomarker not available</population>
          <units>ng/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="19"/>
                    <count group_id="B2" value="18"/>
                    <count group_id="B3" value="18"/>
                    <count group_id="B4" value="55"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="14.6" spread="3.3"/>
                    <measurement group_id="B2" value="15.4" spread="4.6"/>
                    <measurement group_id="B3" value="17.1" spread="4.4"/>
                    <measurement group_id="B4" value="15.7" spread="4.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>N-terminal (NT)-pro hormone BNP (NT-proBNP)</title>
          <population>One subject baseline biomarker not available</population>
          <units>pg/ml</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="19"/>
                    <count group_id="B2" value="18"/>
                    <count group_id="B3" value="18"/>
                    <count group_id="B4" value="55"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="97.0" spread="78.7"/>
                    <measurement group_id="B2" value="72.2" spread="73.5"/>
                    <measurement group_id="B3" value="96.6" spread="76.4"/>
                    <measurement group_id="B4" value="88.7" spread="75.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Pulse wave velocity (PWV)</title>
          <population>Based on available data for analysis</population>
          <units>m/sec</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="14"/>
                    <count group_id="B2" value="14"/>
                    <count group_id="B3" value="13"/>
                    <count group_id="B4" value="41"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10.6" spread="4.9"/>
                    <measurement group_id="B2" value="9.4" spread="5.5"/>
                    <measurement group_id="B3" value="8.5" spread="4.1"/>
                    <measurement group_id="B4" value="9.5" spread="4.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Cardiac Global Longitudinal Strain</title>
        <description>Change in myocardial speckle tracked strain (global longitudinal strain) after 18 months (baseline vs. 18 months) of therapy with carvedilol or spironolactone or usual care. The myocardial global longitudinal strain was measured using echocardiography</description>
        <time_frame>18 months</time_frame>
        <population>Difference is global longitudinal strain between baseline and 18 months for those who completed both visits and had data available</population>
        <group_list>
          <group group_id="O1">
            <title>Carvedilol</title>
            <description>Approximately 70 subjects will be randomized to carvedilol&#xD;
Carvedilol: Carvedilol is a non selective beta blocker</description>
          </group>
          <group group_id="O2">
            <title>Spironolactone</title>
            <description>Approximately 70 subjects will be randomized to spironolactone&#xD;
Spironolactone: Spironolactone is an aldosterone antagonist and can lower blood pressure/ is used in heart failure</description>
          </group>
          <group group_id="O3">
            <title>Usual Care</title>
            <description>Approximately 70 subjects will be randomized to usual care/ standard care by primary care providers&#xD;
Usual care: standard care as per primary care provider</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Cardiac Global Longitudinal Strain</title>
          <description>Change in myocardial speckle tracked strain (global longitudinal strain) after 18 months (baseline vs. 18 months) of therapy with carvedilol or spironolactone or usual care. The myocardial global longitudinal strain was measured using echocardiography</description>
          <population>Difference is global longitudinal strain between baseline and 18 months for those who completed both visits and had data available</population>
          <units>% systolic deformation</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="15"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.4" spread="4.4"/>
                    <measurement group_id="O2" value="-1.74" spread="3.25"/>
                    <measurement group_id="O3" value="-1.14" spread="4.13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in NTproBNP (Biomarker)</title>
        <description>Change in levels of NT-proBNP (measured in blood samples) between baseline and 18 months after therapy with carvedilol or spironolactone or usual care</description>
        <time_frame>18 months</time_frame>
        <population>Those who completed study and had data available</population>
        <group_list>
          <group group_id="O1">
            <title>Carvedilol</title>
            <description>Approximately 70 subjects will be randomized to carvedilol&#xD;
Carvedilol: Carvedilol is a non selective beta blocker</description>
          </group>
          <group group_id="O2">
            <title>Spironolactone</title>
            <description>Approximately 70 subjects will be randomized to spironolactone&#xD;
Spironolactone: Spironolactone is an aldosterone antagonist and can lower blood pressure/ is used in heart failure</description>
          </group>
          <group group_id="O3">
            <title>Usual Care</title>
            <description>Approximately 70 subjects will be randomized to usual care/ standard care by primary care providers&#xD;
Usual care: standard care as per primary care provider</description>
          </group>
        </group_list>
        <measure>
          <title>Change in NTproBNP (Biomarker)</title>
          <description>Change in levels of NT-proBNP (measured in blood samples) between baseline and 18 months after therapy with carvedilol or spironolactone or usual care</description>
          <population>Those who completed study and had data available</population>
          <units>pg/ml</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="15"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="14"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="87.9" spread="243.5"/>
                    <measurement group_id="O2" value="-16.5" spread="39.3"/>
                    <measurement group_id="O3" value="3.65" spread="91.03"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Pulse Wave Velocity</title>
        <description>Changes in arterial stiffness between baseline and 18 months after therapy with carvedilol, spironolactone or usual care. Arterial stiffness was measured by pulse wave velocity (Sphygmocor device)</description>
        <time_frame>18 months</time_frame>
        <population>Based on available measures at baseline and end of study. Reported values are change in Pulse wave velocity (PWV) between visits</population>
        <group_list>
          <group group_id="O1">
            <title>Carvedilol</title>
            <description>Approximately 70 subjects will be randomized to carvedilol&#xD;
Carvedilol: Carvedilol is a non selective beta blocker</description>
          </group>
          <group group_id="O2">
            <title>Spironolactone</title>
            <description>Approximately 70 subjects will be randomized to spironolactone&#xD;
Spironolactone: Spironolactone is an aldosterone antagonist and can lower blood pressure/ is used in heart failure</description>
          </group>
          <group group_id="O3">
            <title>Usual Care</title>
            <description>Approximately 70 subjects will be randomized to usual care/ standard care by primary care providers&#xD;
Usual care: standard care as per primary care provider</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Pulse Wave Velocity</title>
          <description>Changes in arterial stiffness between baseline and 18 months after therapy with carvedilol, spironolactone or usual care. Arterial stiffness was measured by pulse wave velocity (Sphygmocor device)</description>
          <population>Based on available measures at baseline and end of study. Reported values are change in Pulse wave velocity (PWV) between visits</population>
          <units>m/sec</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.71" spread="1.6"/>
                    <measurement group_id="O2" value="-0.77" spread="5.7"/>
                    <measurement group_id="O3" value="-0.59" spread="3.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Troponin T Measured Using a High Sensitivity Assay</title>
        <description>Change in levels of troponin T (measured with a high sensitivity assay in blood samples) between baseline and 18 months after therapy with carvedilol or spironolactone or usual care</description>
        <time_frame>18 months</time_frame>
        <population>Those who completed study and had data available</population>
        <group_list>
          <group group_id="O1">
            <title>Carvedilol</title>
            <description>Approximately 70 subjects will be randomized to carvedilol&#xD;
Carvedilol: Carvedilol is a non selective beta blocker. Dose will be 3.125 mg two times daily with increases in dose if blood pressure permits</description>
          </group>
          <group group_id="O2">
            <title>Spironolactone</title>
            <description>Approximately 70 subjects will be randomized to spironolactone&#xD;
Spironolactone: Spironolactone is an aldosterone antagonist and can lower blood pressure/ is used in heart failure. Spironolactone dose will be 25 mg by mouth once daily</description>
          </group>
          <group group_id="O3">
            <title>Usual Care</title>
            <description>Approximately 70 subjects will be randomized to usual care/ standard care by primary care providers&#xD;
Usual care: standard care as per primary care provider</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Troponin T Measured Using a High Sensitivity Assay</title>
          <description>Change in levels of troponin T (measured with a high sensitivity assay in blood samples) between baseline and 18 months after therapy with carvedilol or spironolactone or usual care</description>
          <population>Those who completed study and had data available</population>
          <units>ng/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="15"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="14"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.2" spread="5.2"/>
                    <measurement group_id="O2" value="1.4" spread="3.9"/>
                    <measurement group_id="O3" value="0.35" spread="6.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>The study had a follow up period of 18 months from randomization during which subjects were followed for adverse events. However, 4 subjects had longer follow up due to the coronavirus infection of 2019 (COVID 19) and inability to schedule follow ups (approximately 6 to 8 months additional follow up for these subjects)</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Carvedilol</title>
          <description>Approximately 70 subjects will be randomized to carvedilol&#xD;
Carvedilol: Carvedilol is a non selective beta blocker</description>
        </group>
        <group group_id="E2">
          <title>Spironolactone</title>
          <description>Approximately 70 subjects will be randomized to spironolactone&#xD;
Spironolactone: Spironolactone is an aldosterone antagonist and can lower blood pressure/ is used in heart failure</description>
        </group>
        <group group_id="E3">
          <title>Usual Care</title>
          <description>Approximately 70 subjects will be randomized to usual care/ standard care by primary care providers&#xD;
Usual care: standard care as per primary care provider</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="18"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Hospitalization for chest pain/ heart failure</sub_title>
                <description>ER visit/ hospitalization for chest pain/ hear failure</description>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Hypotension, ER visit</sub_title>
                <description>Low BP needing ER visit</description>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Hospitalization for planned surgery</sub_title>
                <description>Hospitalizations for planned surgery (hip, cataract, cancer, ablation)</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Hospitalization for infection</sub_title>
                <assessment>Non-systematic Assessment</assessment>
                <description>Infections including pneumonia, COVID, pyelonephritis</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Hospitalization for falls, accidents</sub_title>
                <assessment>Non-systematic Assessment</assessment>
                <description>Falls (mechanical, unclear etc)</description>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Hospitalization for shortness of breath</sub_title>
                <assessment>Non-systematic Assessment</assessment>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>1</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="18"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness/ Drowsiness/ Disequilibrium</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>chest pain</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Atrial arrhythmia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Breast tenderness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>abdominal discomfort</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Musculoskeletal pain</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E3" events="10" subjects_affected="6" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Falls</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Renal dysfunction</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Vijay Nambi</name_or_title>
      <organization>Michael E DeBakey Veterans Affairs Hospital</organization>
      <phone>713-794-7300</phone>
      <email>vijay.nambi@va.gov</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02230891
org study id: CLNB-009-13F
nct id: NCT02230891
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Despite advances in cardiovascular care, the occurrence of heart failure (HF) is steadily
      increasing. The increase in HF rates poses enormous challenges, as once an individual becomes
      symptomatic or requires hospitalization with HF, the prognosis remains poor. Therefore,
      prevention of HF is essential. HF prevention is a critical issue as HF risk factors that
      include common medical conditions such as hypertension and diabetes are also increasing.
      However, not everyone with these risk factors develops HF. Using novel blood tests, the
      investigators propose to identify and treat subjects at higher HF risk to see if the
      investigators can stabilize or improve ultrasound measures known to be associated with HF
      risk. This study will enroll only Veterans.
Recently the investigators have shown that HF risk prediction can be improved using cardiac
      troponin T measured with a novel high-sensitivity assay (hs-cTnT) and N-terminal pro-B-type
      natriuretic peptide (NT-proBNP). Furthermore, hs-cTnT seems to identify individuals at higher
      risk among those with established risk factors (such as hypertension) for HF. In preliminary
      results, the investigators have shown that individuals with systolic blood pressure of
      120-129 mm Hg and elevated hs-cTnT have a higher rate of incident HF than those with systolic
      blood pressure of 140-159 mm Hg and undetectable hs-cTnT. Therefore, the investigators
      believe that by using hs-cTnT to estimate HF risk the investigators can identify individuals
      in whom aggressive modification of risk factors such as high blood pressure will be
      associated with a favorable risk-benefit ratio.

      The investigators' objective/specific aim therefore is to evaluate if treatment of selected
      subjects with Stage A or B HF (i.e., those with hs-cTnT >5 ng/L and an estimated 10-year HF
      hospitalization risk of >5%) who have reasonably well-controlled blood pressure with
      antihypertensive agents (carvedilol or spironolactone) will be associated with improvement of
      surrogate markers associated with incident HF (i.e., speckle-tracked cardiac and vascular
      strain). Carvedilol and spironolactone were chosen for the following reasons: a) they are not
      routinely used as first-line antihypertensive agents; b) beta-blockade was associated with
      decreases in hs-cTnT in the preliminary analysis of subjects with established HF; and c) the
      mechanism of actions of carvedilol and spironolactone provide a sound scientific rationale
      for use in prevention of HF.

      Using a prospective open-label blinded end point (PROBE) design, the investigators propose to
      randomize 210 subjects aged >40 years with systolic blood pressure between 120-155 mm Hg,
      cardiac troponin T (measured with a novel high-sensitivity assay) level >5 ng/L, and 10-year
      HF risk >5% (estimated using a validated laboratory model including demographic factors,
      NT-proBNP, and hs-cTnT) to receive carvedilol (nonselective beta-blocker), spironolactone
      (aldosterone antagonist), or usual care for 18 months. The primary end point will be change
      in global longitudinal systolic myocardial strain estimated using 2D speckle tracking.
      Additionally, changes in vascular strain and biomarkers will be evaluated. This study will
      help us identify whether both or either of the medications can be further tested in large
      randomized clinical trials to prevent the incidence of HF.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Change in Cardiac Global Longitudinal Strain
time frame: 18 months
description: Change in myocardial speckle tracked strain (global longitudinal strain) after 18 months (baseline vs. 18 months) of therapy with carvedilol or spironolactone or usual care. The myocardial global longitudinal strain was measured using echocardiography
measure: Change in NTproBNP (Biomarker)
time frame: 18 months
description: Change in levels of NT-proBNP (measured in blood samples) between baseline and 18 months after therapy with carvedilol or spironolactone or usual care
measure: Change in Pulse Wave Velocity
time frame: 18 months
description: Changes in arterial stiffness between baseline and 18 months after therapy with carvedilol, spironolactone or usual care. Arterial stiffness was measured by pulse wave velocity (Sphygmocor device)
measure: Change in Troponin T Measured Using a High Sensitivity Assay
time frame: 18 months
description: Change in levels of troponin T (measured with a high sensitivity assay in blood samples) between baseline and 18 months after therapy with carvedilol or spironolactone or usual care
arm group label: Carvedilol
arm group type: Active Comparator
description: Approximately 70 subjects will be randomized to carvedilol
arm group label: Spironolactone
arm group type: Active Comparator
description: Approximately 70 subjects will be randomized to spironolactone
arm group label: Usual care
arm group type: Other
description: Approximately 70 subjects will be randomized to usual care/ standard care by primary care providers
intervention type: Drug
intervention name: Carvedilol
description: Carvedilol is a non selective beta blocker
arm group label: Carvedilol
intervention type: Drug
intervention name: Spironolactone
description: Spironolactone is an aldosterone antagonist and can lower blood pressure/ is used in heart failure
arm group label: Spironolactone
intervention type: Other
intervention name: Usual care
description: standard care as per primary care provider
arm group label: Usual care
criteria: 
gender: All
minimum age: 40 Years
maximum age: 85 Years
healthy volunteers: No
last name: Vijay Nambi, MBBS
role: Principal Investigator
affiliation: Michael E. DeBakey VA Medical Center, Houston, TX
facility: 
country: United States
responsible party type: Sponsor
mesh term: Heart Failure
mesh term: Cardiovascular Diseases
mesh term: Carvedilol
mesh term: Spironolactone
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 