<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/NCT03005184</url>
  </required_header>
  <id_info>
    <org_study_id>IRB#161306</org_study_id>
    <nct_id>NCT03005184</nct_id>
  </id_info>
  <brief_title>Mechanism(s) Underlying Cardiovascular Effects of ARB/NEP Inhibition - Aim 2</brief_title>
  <official_title>Mechanism(s) Underlying Cardiovascular Effects of ARB/NEP Inhibition - Aim 2</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vanderbilt University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Vanderbilt University Medical Center</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study tests the hypothesis that endogenous bradykinin contributes to effects of a&#xD;
      combined angiotensin receptor blocker/neprilysin inhibitor (LCZ696 or Entresto)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients with heart failure (HF) with reduced ejection fraction who qualify for the study&#xD;
      will undergo a three-week run-in period in which any prior angiotensin-converting enzyme&#xD;
      (ACE) inhibitor or angiotensin receptor blocker they were taking will be discontinued and&#xD;
      they will be given valsartan 80 mg bid in a single-blind fashion. After the run-in, subjects&#xD;
      will undergo four study periods in random order. During two study periods they will receive&#xD;
      enalapril 10 mg bid and during two they will receive sacubitril/valsartan (LCZ696) 200 mg bid&#xD;
      for seven days. On the seventh day or each period, subjects will complete a study day in&#xD;
      which they are randomized to receive either the bradykinin B2 receptor blocker icatibant or&#xD;
      placebo intravenously. Each study period will be separated by a three-week washout during&#xD;
      which subjects receive valsartan 80 mg bid.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Study is being redesigned and submitted as a new study.&#xD;
  </why_stopped>
  <start_date type="Anticipated">September 2017</start_date>
  <completion_date type="Anticipated">January 2020</completion_date>
  <primary_completion_date type="Anticipated">January 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>Crossover Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>change in systolic blood pressure</measure>
    <time_frame>7-hour period after 7-day intervention</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>change in plasma cGMP</measure>
    <time_frame>7-hour period after 7-day intervention</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>heart rate</measure>
    <time_frame>7-hour period after 7-day intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>renal plasma flow</measure>
    <time_frame>7-hour period after 7-day intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>glomerular filtration rate</measure>
    <time_frame>7-hour period after 7-day intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>change in diastolic blood pressure</measure>
    <time_frame>7-hour period after 7-day intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>fractional excretion of sodium</measure>
    <time_frame>7-hour period after 7-day intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>urine albumin-to-creatinine ratio</measure>
    <time_frame>7-hour period after 7-day intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>brain natriuretic peptide (BNP) to N-terminal pro-BNP ratio</measure>
    <time_frame>7-hour period after 7-day intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>plasminogen activator inhibitor-1</measure>
    <time_frame>7-hour period after 7-day intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>tissue plasminogen activator</measure>
    <time_frame>7-hour period after 7-day intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>aldosterone</measure>
    <time_frame>7-hour period after 7-day intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>urine cGMP</measure>
    <time_frame>7-hour period after 7-day intervention</time_frame>
  </secondary_outcome>
  <number_of_arms>12</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Heart Failure NYHA Class I</condition>
  <condition>Heart Failure NYHA Class II</condition>
  <condition>Heart Failure NYHA Class III</condition>
  <arm_group>
    <arm_group_label>S/V+Pla, S/V+I, Enal+Pla, Enal+I</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>S/V+Pla, Enal+I, S/V+I, Enal+Pla</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>S/V+Pla, Enal+Pla, Enal+I, S/V+I</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>S/V+I, S/V+Pla, Enal+I, Enal+P</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>S/V+I, Enal+Pla, S/V+Pla, Enal+I</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>S/V+I, Enal+I, Enal+Pla, S/V+Pla</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Enal+Pla, S/V+Pla, S/V+I, Enal+I</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Enal+Pla, S/V+I, Enal+I, S/V+Pla</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Enal+Pla, Enal+I, S/V+Pla, S/V+I</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Enal+I, S/V+Pla, Enal+Pla, S/V+I</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Enal+I, S/V+I, S/V+Pla, Enal+Pla</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Enal+I, Enal+Pla, S/V+I, S/V+Pla</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Valsartan 80 mg bid</intervention_name>
    <description>oral medication during run-in and washout period</description>
    <arm_group_label>Enal+I, Enal+Pla, S/V+I, S/V+Pla</arm_group_label>
    <arm_group_label>Enal+I, S/V+I, S/V+Pla, Enal+Pla</arm_group_label>
    <arm_group_label>Enal+I, S/V+Pla, Enal+Pla, S/V+I</arm_group_label>
    <arm_group_label>Enal+Pla, Enal+I, S/V+Pla, S/V+I</arm_group_label>
    <arm_group_label>Enal+Pla, S/V+I, Enal+I, S/V+Pla</arm_group_label>
    <arm_group_label>Enal+Pla, S/V+Pla, S/V+I, Enal+I</arm_group_label>
    <arm_group_label>S/V+I, Enal+I, Enal+Pla, S/V+Pla</arm_group_label>
    <arm_group_label>S/V+I, Enal+Pla, S/V+Pla, Enal+I</arm_group_label>
    <arm_group_label>S/V+I, S/V+Pla, Enal+I, Enal+P</arm_group_label>
    <arm_group_label>S/V+Pla, Enal+I, S/V+I, Enal+Pla</arm_group_label>
    <arm_group_label>S/V+Pla, Enal+Pla, Enal+I, S/V+I</arm_group_label>
    <arm_group_label>S/V+Pla, S/V+I, Enal+Pla, Enal+I</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Enalapril 10 mg bid</intervention_name>
    <description>oral medication</description>
    <arm_group_label>Enal+I, Enal+Pla, S/V+I, S/V+Pla</arm_group_label>
    <arm_group_label>Enal+I, S/V+I, S/V+Pla, Enal+Pla</arm_group_label>
    <arm_group_label>Enal+I, S/V+Pla, Enal+Pla, S/V+I</arm_group_label>
    <arm_group_label>Enal+Pla, Enal+I, S/V+Pla, S/V+I</arm_group_label>
    <arm_group_label>Enal+Pla, S/V+I, Enal+I, S/V+Pla</arm_group_label>
    <arm_group_label>Enal+Pla, S/V+Pla, S/V+I, Enal+I</arm_group_label>
    <arm_group_label>S/V+I, Enal+I, Enal+Pla, S/V+Pla</arm_group_label>
    <arm_group_label>S/V+I, Enal+Pla, S/V+Pla, Enal+I</arm_group_label>
    <arm_group_label>S/V+I, S/V+Pla, Enal+I, Enal+P</arm_group_label>
    <arm_group_label>S/V+Pla, Enal+I, S/V+I, Enal+Pla</arm_group_label>
    <arm_group_label>S/V+Pla, Enal+Pla, Enal+I, S/V+I</arm_group_label>
    <arm_group_label>S/V+Pla, S/V+I, Enal+Pla, Enal+I</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sacubitril-Valsartan 200 mg bid</intervention_name>
    <description>oral medication</description>
    <arm_group_label>Enal+I, Enal+Pla, S/V+I, S/V+Pla</arm_group_label>
    <arm_group_label>Enal+I, S/V+I, S/V+Pla, Enal+Pla</arm_group_label>
    <arm_group_label>Enal+I, S/V+Pla, Enal+Pla, S/V+I</arm_group_label>
    <arm_group_label>Enal+Pla, Enal+I, S/V+Pla, S/V+I</arm_group_label>
    <arm_group_label>Enal+Pla, S/V+I, Enal+I, S/V+Pla</arm_group_label>
    <arm_group_label>Enal+Pla, S/V+Pla, S/V+I, Enal+I</arm_group_label>
    <arm_group_label>S/V+I, Enal+I, Enal+Pla, S/V+Pla</arm_group_label>
    <arm_group_label>S/V+I, Enal+Pla, S/V+Pla, Enal+I</arm_group_label>
    <arm_group_label>S/V+I, S/V+Pla, Enal+I, Enal+P</arm_group_label>
    <arm_group_label>S/V+Pla, Enal+I, S/V+I, Enal+Pla</arm_group_label>
    <arm_group_label>S/V+Pla, Enal+Pla, Enal+I, S/V+I</arm_group_label>
    <arm_group_label>S/V+Pla, S/V+I, Enal+Pla, Enal+I</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Icatibant</intervention_name>
    <description>intravenous medication</description>
    <arm_group_label>Enal+I, Enal+Pla, S/V+I, S/V+Pla</arm_group_label>
    <arm_group_label>Enal+I, S/V+I, S/V+Pla, Enal+Pla</arm_group_label>
    <arm_group_label>Enal+I, S/V+Pla, Enal+Pla, S/V+I</arm_group_label>
    <arm_group_label>Enal+Pla, Enal+I, S/V+Pla, S/V+I</arm_group_label>
    <arm_group_label>Enal+Pla, S/V+I, Enal+I, S/V+Pla</arm_group_label>
    <arm_group_label>Enal+Pla, S/V+Pla, S/V+I, Enal+I</arm_group_label>
    <arm_group_label>S/V+I, Enal+I, Enal+Pla, S/V+Pla</arm_group_label>
    <arm_group_label>S/V+I, Enal+Pla, S/V+Pla, Enal+I</arm_group_label>
    <arm_group_label>S/V+I, S/V+Pla, Enal+I, Enal+P</arm_group_label>
    <arm_group_label>S/V+Pla, Enal+I, S/V+I, Enal+Pla</arm_group_label>
    <arm_group_label>S/V+Pla, Enal+Pla, Enal+I, S/V+I</arm_group_label>
    <arm_group_label>S/V+Pla, S/V+I, Enal+Pla, Enal+I</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>intravenous medication</description>
    <arm_group_label>Enal+I, Enal+Pla, S/V+I, S/V+Pla</arm_group_label>
    <arm_group_label>Enal+I, S/V+I, S/V+Pla, Enal+Pla</arm_group_label>
    <arm_group_label>Enal+I, S/V+Pla, Enal+Pla, S/V+I</arm_group_label>
    <arm_group_label>Enal+Pla, Enal+I, S/V+Pla, S/V+I</arm_group_label>
    <arm_group_label>Enal+Pla, S/V+I, Enal+I, S/V+Pla</arm_group_label>
    <arm_group_label>Enal+Pla, S/V+Pla, S/V+I, Enal+I</arm_group_label>
    <arm_group_label>S/V+I, Enal+I, Enal+Pla, S/V+Pla</arm_group_label>
    <arm_group_label>S/V+I, Enal+Pla, S/V+Pla, Enal+I</arm_group_label>
    <arm_group_label>S/V+I, S/V+Pla, Enal+I, Enal+P</arm_group_label>
    <arm_group_label>S/V+Pla, Enal+I, S/V+I, Enal+Pla</arm_group_label>
    <arm_group_label>S/V+Pla, Enal+Pla, Enal+I, S/V+I</arm_group_label>
    <arm_group_label>S/V+Pla, S/V+I, Enal+Pla, Enal+I</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Stable patients with a reduced EF&#xD;
&#xD;
               1. EF less than or equal to 40% (confirmed by echocardiogram within the last six&#xD;
                  months), and&#xD;
&#xD;
               2. history of symptoms of New York Heart Association class I, II or III HF&#xD;
&#xD;
               3. stable clinical symptoms including no hospitalizations for the last six months&#xD;
&#xD;
               4. treatment with a stable dose of an ACEi or ARB and with a beta blocker (unless&#xD;
                  contraindicated or not tolerated) for at least four weeks&#xD;
&#xD;
               5. treatment with a stable dose of an MR antagonist for at least four weeks unless&#xD;
                  not possible due to renal function or serum potassium.&#xD;
&#xD;
          2. For female subjects, the following conditions must be met:&#xD;
&#xD;
               1. postmenopausal status for at least one year, or&#xD;
&#xD;
               2. status post-surgical sterilization&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. History of hypersensitivity or allergy to any of the study drugs, drugs of similar&#xD;
             chemical classes, ACEi, ARBs, or NEPi, as well as known or suspected contraindications&#xD;
             to the study drugs&#xD;
&#xD;
          2. History of angioedema&#xD;
&#xD;
          3. History of pancreatitis or known pancreatic lesions&#xD;
&#xD;
          4. History of decompensated HF within the last six months (exacerbation of chronic HF&#xD;
             manifested by signs and symptoms that required intravenous therapy or hospitalization)&#xD;
&#xD;
          5. History of heart transplant or on a transplant list or with left ventricular&#xD;
             assistance device&#xD;
&#xD;
          6. Symptomatic hypotension and/or a SBP&lt;100 mmHg at screening or &lt;90 mmHg during the&#xD;
             study&#xD;
&#xD;
          7. Serum potassium &gt;5.2 mmol/L at screening or &gt;5.4 mmol/L during the study&#xD;
&#xD;
          8. Acute coronary syndrome, cardiac, carotid, or other major cardiovascular surgery,&#xD;
             percutaneous coronary intervention, or carotid angioplasty within six months prior to&#xD;
             screening&#xD;
&#xD;
          9. Coronary or carotid artery disease likely to require surgical or percutaneous&#xD;
             intervention within six months of screening&#xD;
&#xD;
         10. History of serious neurologic disease such as cerebral hemorrhage, stroke, seizure, or&#xD;
             transient ischemic attack within six months&#xD;
&#xD;
         11. History of ventricular arrhythmia with syncopal episodes&#xD;
&#xD;
         12. Symptomatic bradycardia or second- or third-degree atrioventricular block without a&#xD;
             pacemaker&#xD;
&#xD;
         13. Presence of hemodynamically significant mitral and/or aortic valve disease, except&#xD;
             mitral regurgitation secondary to LV dilatation&#xD;
&#xD;
         14. Presence of other hemodynamically significant obstructive lesions of the left&#xD;
             ventricular outflow tract, including aortic and subaortic stenosis&#xD;
&#xD;
         15. Type 1 diabetes&#xD;
&#xD;
         16. Poorly controlled type 2 diabetes mellitus (T2DM), defined as a HgbA1c &gt;9%&#xD;
&#xD;
         17. Hematocrit &lt;35%&#xD;
&#xD;
         18. Impaired renal function (eGFR of &lt;30mL/min/1.73 m2) as determined by the four-variable&#xD;
             Modification of Diet in Renal Disease (MDRD) equation, where serum creatinine (Scr) is&#xD;
             expressed in mg/dL and age in years:&#xD;
&#xD;
             eGFR (mL/min/1.73m2)=175 • Scr-1.154 • age-0.203 • (1.212 if Black) • (0.742 if&#xD;
             female)&#xD;
&#xD;
         19. Use of hormone-replacement therapy&#xD;
&#xD;
         20. Breast feeding and pregnancy&#xD;
&#xD;
         21. History or presence of immunological or hematological disorders&#xD;
&#xD;
         22. History of malignancy other than non-melanoma skin cancer&#xD;
&#xD;
         23. Diagnosis of asthma requiring use of inhaled beta agonist more than once a week&#xD;
&#xD;
         24. Clinically significant gastrointestinal impairment that could interfere with drug&#xD;
             absorption&#xD;
&#xD;
         25. Impaired hepatic function [aspartate amino transaminase (AST) and/or alanine amino&#xD;
             transaminase (ALT) &gt;3.0 x upper limit of normal range]&#xD;
&#xD;
         26. Any underlying or acute disease requiring regular medication which could possibly pose&#xD;
             a threat to the subject or make implementation of the protocol or interpretation of&#xD;
             the study results difficult, such as arthritis treated with non-steroidal&#xD;
             anti-inflammatory drugs&#xD;
&#xD;
         27. Treatment with chronic systemic glucocorticoid therapy within the last year&#xD;
&#xD;
         28. Treatment with lithium salts&#xD;
&#xD;
         29. History of alcohol or drug abuse&#xD;
&#xD;
         30. Treatment with any investigational drug in the one month preceding the study&#xD;
&#xD;
         31. Mental conditions rendering the subject unable to understand the nature, scope, and&#xD;
             possible consequences of the study&#xD;
&#xD;
         32. Inability to comply with the protocol, e.g., uncooperative attitude, inability to&#xD;
             return for follow-up visits, and unlikelihood of completing the study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Vanderbilt University Medical Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2018</verification_date>
  <study_first_submitted>December 22, 2016</study_first_submitted>
  <study_first_submitted_qc>December 22, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 29, 2016</study_first_posted>
  <last_update_submitted>January 9, 2018</last_update_submitted>
  <last_update_submitted_qc>January 9, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">January 11, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Vanderbilt University Medical Center</investigator_affiliation>
    <investigator_full_name>Nancy J. Brown</investigator_full_name>
    <investigator_title>Hugh J. Morgan Professor of Medicine and Pharmacology</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Icatibant</mesh_term>
    <mesh_term>Valsartan</mesh_term>
    <mesh_term>Enalapril</mesh_term>
    <mesh_term>Sacubitril and valsartan sodium hydrate drug combination</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03005184
org study id: IRB#161306
nct id: NCT03005184
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This study tests the hypothesis that endogenous bradykinin contributes to effects of a
      combined angiotensin receptor blocker/neprilysin inhibitor (LCZ696 or Entresto)
Patients with heart failure (HF) with reduced ejection fraction who qualify for the study
      will undergo a three-week run-in period in which any prior angiotensin-converting enzyme
      (ACE) inhibitor or angiotensin receptor blocker they were taking will be discontinued and
      they will be given valsartan 80 mg bid in a single-blind fashion. After the run-in, subjects
      will undergo four study periods in random order. During two study periods they will receive
      enalapril 10 mg bid and during two they will receive sacubitril/valsartan (LCZ696) 200 mg bid
      for seven days. On the seventh day or each period, subjects will complete a study day in
      which they are randomized to receive either the bradykinin B2 receptor blocker icatibant or
      placebo intravenously. Each study period will be separated by a three-week washout during
      which subjects receive valsartan 80 mg bid.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: change in systolic blood pressure
time frame: 7-hour period after 7-day intervention
measure: change in plasma cGMP
time frame: 7-hour period after 7-day intervention
measure: heart rate
time frame: 7-hour period after 7-day intervention
measure: renal plasma flow
time frame: 7-hour period after 7-day intervention
measure: glomerular filtration rate
time frame: 7-hour period after 7-day intervention
measure: change in diastolic blood pressure
time frame: 7-hour period after 7-day intervention
measure: fractional excretion of sodium
time frame: 7-hour period after 7-day intervention
measure: urine albumin-to-creatinine ratio
time frame: 7-hour period after 7-day intervention
measure: brain natriuretic peptide (BNP) to N-terminal pro-BNP ratio
time frame: 7-hour period after 7-day intervention
measure: plasminogen activator inhibitor-1
time frame: 7-hour period after 7-day intervention
measure: tissue plasminogen activator
time frame: 7-hour period after 7-day intervention
measure: aldosterone
time frame: 7-hour period after 7-day intervention
measure: urine cGMP
time frame: 7-hour period after 7-day intervention
arm group label: S/V+Pla, S/V+I, Enal+Pla, Enal+I
arm group type: Experimental
description: Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
arm group label: S/V+Pla, Enal+I, S/V+I, Enal+Pla
arm group type: Experimental
description: Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
arm group label: S/V+Pla, Enal+Pla, Enal+I, S/V+I
arm group type: Experimental
description: Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
arm group label: S/V+I, S/V+Pla, Enal+I, Enal+P
arm group type: Experimental
description: Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
arm group label: S/V+I, Enal+Pla, S/V+Pla, Enal+I
arm group type: Experimental
description: Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
arm group label: S/V+I, Enal+I, Enal+Pla, S/V+Pla
arm group type: Experimental
description: Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
arm group label: Enal+Pla, S/V+Pla, S/V+I, Enal+I
arm group type: Experimental
description: Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
arm group label: Enal+Pla, S/V+I, Enal+I, S/V+Pla
arm group type: Experimental
description: Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
arm group label: Enal+Pla, Enal+I, S/V+Pla, S/V+I
arm group type: Experimental
description: Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
arm group label: Enal+I, S/V+Pla, Enal+Pla, S/V+I
arm group type: Experimental
description: Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
arm group label: Enal+I, S/V+I, S/V+Pla, Enal+Pla
arm group type: Experimental
description: Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
arm group label: Enal+I, Enal+Pla, S/V+I, S/V+Pla
arm group type: Experimental
description: Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
intervention type: Drug
intervention name: Valsartan 80 mg bid
description: oral medication during run-in and washout period
arm group label: Enal+I, Enal+Pla, S/V+I, S/V+Pla
arm group label: Enal+I, S/V+I, S/V+Pla, Enal+Pla
arm group label: Enal+I, S/V+Pla, Enal+Pla, S/V+I
arm group label: Enal+Pla, Enal+I, S/V+Pla, S/V+I
arm group label: Enal+Pla, S/V+I, Enal+I, S/V+Pla
arm group label: Enal+Pla, S/V+Pla, S/V+I, Enal+I
arm group label: S/V+I, Enal+I, Enal+Pla, S/V+Pla
arm group label: S/V+I, Enal+Pla, S/V+Pla, Enal+I
arm group label: S/V+I, S/V+Pla, Enal+I, Enal+P
arm group label: S/V+Pla, Enal+I, S/V+I, Enal+Pla
arm group label: S/V+Pla, Enal+Pla, Enal+I, S/V+I
arm group label: S/V+Pla, S/V+I, Enal+Pla, Enal+I
intervention type: Drug
intervention name: Enalapril 10 mg bid
description: oral medication
arm group label: Enal+I, Enal+Pla, S/V+I, S/V+Pla
arm group label: Enal+I, S/V+I, S/V+Pla, Enal+Pla
arm group label: Enal+I, S/V+Pla, Enal+Pla, S/V+I
arm group label: Enal+Pla, Enal+I, S/V+Pla, S/V+I
arm group label: Enal+Pla, S/V+I, Enal+I, S/V+Pla
arm group label: Enal+Pla, S/V+Pla, S/V+I, Enal+I
arm group label: S/V+I, Enal+I, Enal+Pla, S/V+Pla
arm group label: S/V+I, Enal+Pla, S/V+Pla, Enal+I
arm group label: S/V+I, S/V+Pla, Enal+I, Enal+P
arm group label: S/V+Pla, Enal+I, S/V+I, Enal+Pla
arm group label: S/V+Pla, Enal+Pla, Enal+I, S/V+I
arm group label: S/V+Pla, S/V+I, Enal+Pla, Enal+I
intervention type: Drug
intervention name: Sacubitril-Valsartan 200 mg bid
description: oral medication
arm group label: Enal+I, Enal+Pla, S/V+I, S/V+Pla
arm group label: Enal+I, S/V+I, S/V+Pla, Enal+Pla
arm group label: Enal+I, S/V+Pla, Enal+Pla, S/V+I
arm group label: Enal+Pla, Enal+I, S/V+Pla, S/V+I
arm group label: Enal+Pla, S/V+I, Enal+I, S/V+Pla
arm group label: Enal+Pla, S/V+Pla, S/V+I, Enal+I
arm group label: S/V+I, Enal+I, Enal+Pla, S/V+Pla
arm group label: S/V+I, Enal+Pla, S/V+Pla, Enal+I
arm group label: S/V+I, S/V+Pla, Enal+I, Enal+P
arm group label: S/V+Pla, Enal+I, S/V+I, Enal+Pla
arm group label: S/V+Pla, Enal+Pla, Enal+I, S/V+I
arm group label: S/V+Pla, S/V+I, Enal+Pla, Enal+I
intervention type: Drug
intervention name: Icatibant
description: intravenous medication
arm group label: Enal+I, Enal+Pla, S/V+I, S/V+Pla
arm group label: Enal+I, S/V+I, S/V+Pla, Enal+Pla
arm group label: Enal+I, S/V+Pla, Enal+Pla, S/V+I
arm group label: Enal+Pla, Enal+I, S/V+Pla, S/V+I
arm group label: Enal+Pla, S/V+I, Enal+I, S/V+Pla
arm group label: Enal+Pla, S/V+Pla, S/V+I, Enal+I
arm group label: S/V+I, Enal+I, Enal+Pla, S/V+Pla
arm group label: S/V+I, Enal+Pla, S/V+Pla, Enal+I
arm group label: S/V+I, S/V+Pla, Enal+I, Enal+P
arm group label: S/V+Pla, Enal+I, S/V+I, Enal+Pla
arm group label: S/V+Pla, Enal+Pla, Enal+I, S/V+I
arm group label: S/V+Pla, S/V+I, Enal+Pla, Enal+I
intervention type: Drug
intervention name: Placebo
description: intravenous medication
arm group label: Enal+I, Enal+Pla, S/V+I, S/V+Pla
arm group label: Enal+I, S/V+I, S/V+Pla, Enal+Pla
arm group label: Enal+I, S/V+Pla, Enal+Pla, S/V+I
arm group label: Enal+Pla, Enal+I, S/V+Pla, S/V+I
arm group label: Enal+Pla, S/V+I, Enal+I, S/V+Pla
arm group label: Enal+Pla, S/V+Pla, S/V+I, Enal+I
arm group label: S/V+I, Enal+I, Enal+Pla, S/V+Pla
arm group label: S/V+I, Enal+Pla, S/V+Pla, Enal+I
arm group label: S/V+I, S/V+Pla, Enal+I, Enal+P
arm group label: S/V+Pla, Enal+I, S/V+I, Enal+Pla
arm group label: S/V+Pla, Enal+Pla, Enal+I, S/V+I
arm group label: S/V+Pla, S/V+I, Enal+Pla, Enal+I
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Vanderbilt University Medical Center
investigator full name: Nancy J. Brown
investigator title: Hugh J. Morgan Professor of Medicine and Pharmacology
mesh term: Heart Failure
mesh term: Icatibant
mesh term: Valsartan
mesh term: Enalapril
mesh term: Sacubitril and valsartan sodium hydrate drug combination
sharing ipd: No