<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/NCT02235077</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00057090</org_study_id>
    <secondary_id>5U01HL084904</secondary_id>
    <nct_id>NCT02235077</nct_id>
  </id_info>
  <brief_title>Study of High-dose Spironolactone vs. Placebo Therapy in Acute Heart Failure</brief_title>
  <acronym>ATHENA-HF</acronym>
  <official_title>Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy - HF (ATHENA-HF)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Duke University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Duke University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary objective of this study is to test the hypothesis that high-dose spironolactone&#xD;
      will lead to greater proportional reduction in NT-proBNP levels from randomization to 96&#xD;
      hours over standard of care.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Mineralocorticoid receptor antagonist (MRA) therapy is recommended in stable chronic systolic&#xD;
      heart failure (HF) and post-infarction HF patients for improving morbidity and mortality. MRA&#xD;
      therapy in AHF and in high doses is less well studied. The effectiveness and safety of early&#xD;
      high dose MRA therapy in AHF is supported by a single-blind study showing lower risk of&#xD;
      worsening renal function and need for loop diuretics, and improved congestion. MRA therapy in&#xD;
      AHF may improve outcomes by relieving congestion at higher doses through their natriuretic&#xD;
      property, in addition to preventing the deleterious effects of exacerbation of neuro-hormonal&#xD;
      activation by loop diuretics.&#xD;
&#xD;
      This randomized, double blind, placebo-controlled study of high-dose spironolactone vs.&#xD;
      placebo (for patients not receiving MRA at home) or low-dose spironolactone (for patients&#xD;
      already receiving low-dose spironolactone) in AHF, will enroll 360 participants at&#xD;
      approximately 30 clinical centers. After obtaining informed consent, subjects who fulfill all&#xD;
      the inclusion criteria and none of the exclusion criteria will be randomized. Randomization&#xD;
      will be performed by using procedures determined by the Coordinating Center (CC).&#xD;
&#xD;
        -  Patients receiving no MRA therapy at baseline will be randomized to receive either&#xD;
           spironolactone 100 mg or placebo daily for 96 hours.&#xD;
&#xD;
        -  Patients already receiving low-dose spironolactone at baseline (12.5 mg or 25 mg daily)&#xD;
           will be randomized to 100 mg or 25 mg spironolactone daily for 96 hours.&#xD;
&#xD;
      Within 24 hours prior to randomization, all study participants will undergo:&#xD;
&#xD;
        -  Medical History&#xD;
&#xD;
        -  Review of medications including pre-hospital loop diuretics, MRA, and potassium doses&#xD;
&#xD;
        -  Physical examination, vital signs and body weight&#xD;
&#xD;
        -  Measurement of creatinine, blood urea nitrogen (BUN), and electrolytes&#xD;
&#xD;
        -  Dyspnea Relief Assessments (7-point Likert and Visual Analog Scale)&#xD;
&#xD;
        -  Serum pregnancy test for all women of childbearing potential&#xD;
&#xD;
        -  Collection of samples for measurement of NT-proBNP levels (Core Lab)&#xD;
&#xD;
      Study drug will be initiated as follows:&#xD;
&#xD;
        -  Patients receiving no MRA therapy at baseline: 4x25 mg study capsules once daily;&#xD;
           starting dose 100 mg spironolactone or placebo; if dose adjustment is required, active&#xD;
           capsules will be adjusted by pharmacy to achieve the required dose.&#xD;
&#xD;
        -  Patients already receiving low-dose spironolactone at baseline: 4x25 mg study capsules&#xD;
           once daily; one capsule containing 25 mg spironolactone and 3x25 mg study capsules&#xD;
           containing spironolactone or placebo; if dose adjustment is required, active capsules&#xD;
           will be adjusted by pharmacy to achieve the required dose.&#xD;
&#xD;
      Patients will be followed every 24 hours following randomization through 96 hours. Study drug&#xD;
      will be administered daily for 96 hours. Study drug administration time is anchored to time&#xD;
      of randomization. Dose adjustments (continue, hold, stop) are permitted according to serum K+&#xD;
      and renal function.&#xD;
&#xD;
      Assessment at 24 hours post randomization includes: Review of medications, body weight, fluid&#xD;
      intake/urine output, creatinine, blood urea nitrogen (BUN), and electrolytes, and adverse&#xD;
      events.&#xD;
&#xD;
      If the 24 hour assessment is also the day of discharge, include:&#xD;
&#xD;
        -  Physical exam / Vital signs&#xD;
&#xD;
        -  Dyspnea Relief (7-Point Likert and VAS) worksheets&#xD;
&#xD;
        -  Biomarkers (NT-proBNP) (Core Lab)&#xD;
&#xD;
      Assessment at 48 hours post randomization includes: Review of medications, physical&#xD;
      exam/vital signs, body weight, fluid intake/urine output, Dyspnea Relief (7-Point Likert and&#xD;
      VAS) worksheets, creatinine, blood urea nitrogen (BUN), and electrolytes, biomarker levels&#xD;
      (NT-proBNP) by Core Lab.&#xD;
&#xD;
      Assessment at 72 hours post randomization includes: Review of medications, body weight, fluid&#xD;
      intake/urine output, creatinine, blood urea nitrogen (BUN), and electrolytes, and adverse&#xD;
      events.&#xD;
&#xD;
      If the 72 hour assessment is also the day of discharge, include:&#xD;
&#xD;
        -  Physical exam / Vital signs&#xD;
&#xD;
        -  Dyspnea Relief (7-Point Likert and VAS) worksheets&#xD;
&#xD;
        -  Biomarkers (NT-proBNP) (Core Lab)&#xD;
&#xD;
      Assessment at 96 hours post randomization includes: Review of medications, physical&#xD;
      exam/vital signs, body weight, fluid intake/urine output, creatinine, blood urea nitrogen&#xD;
      (BUN), and electrolytes, Dyspnea Relief (7-Point Likert and VAS), and biomarker levels&#xD;
      (NT-proBNP) by Core Lab.&#xD;
&#xD;
      If patient is clinically euvolemic in less than 96 hours, the investigator may consider&#xD;
      changing loop diuretics to oral dose.&#xD;
&#xD;
      Study drug will be discontinued after 96 hours and further use of MRA will be left to the&#xD;
      treating physician's discretion.&#xD;
&#xD;
      Assessment at Discharge: If discharge occurs after the 96 hour assessment but prior to the 30&#xD;
      day follow-up telephone call,the following will be documented: Medication review (prescribed&#xD;
      medications at the time of discharge), body weight (if available), creatinine, blood urea&#xD;
      nitrogen (BUN), and electrolytes (if available), and adverse events.&#xD;
&#xD;
      Ejection fraction data will be obtained from echocardiogram within 6 months prior to&#xD;
      randomization. Those patients who do not have an echocardiogram recorded within this time&#xD;
      frame will get an echocardiogram, nuclear perfusion study, MRI, or MUGA performed prior to&#xD;
      the 96 hour in-hospital assessment to ascertain ejection fraction.&#xD;
&#xD;
      Follow-up Telephone Call at Day 30: All participants will be contacted by telephone at day 30&#xD;
      (+3 days) following randomization to assess tertiary endpoints, including medication use and&#xD;
      adverse events.&#xD;
&#xD;
      Follow-up Telephone Call at Day 60: All participants will be contacted by telephone at day 60&#xD;
      (+/-3 days) following randomization to assess vital status.&#xD;
&#xD;
      During the consent process, patients will be asked if interested in donating samples and data&#xD;
      for research purposes via a biorepository and/or genetic study. Based on site and IRB&#xD;
      preference, this optional part of the study may be incorporated into the main consent or may&#xD;
      be a separate consent and IRB application.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 30, 2014</start_date>
  <completion_date type="Actual">June 6, 2016</completion_date>
  <primary_completion_date type="Actual">April 12, 2016</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>96 Hour Change in NT-proBNP</measure>
    <time_frame>Randomization to 96 hours</time_frame>
    <description>The Core Laboratory at Vermont will determine NT-proBNP levels for calculation of the endpoint from samples obtained at randomization and 96 hours respectively. NT-proBNP was converted to log scale.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>96 Hour Change in Clinical Congestion Score</measure>
    <time_frame>Randomization through 96 hours</time_frame>
    <description>Clinical congestion score will be assessed at randomization, 96 hours, and at discharge. Scale consisted of sum of six signs and symptoms of congestion, each scored 0-3. Zero indicates no sign/symptom and 3 indicates worst case of sign/symptom. Score range 0-18 with 18 being worst score.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>96 Hour Change in Dyspnea Likert Score</measure>
    <time_frame>Randomization through 96 hours</time_frame>
    <description>Dyspnea relief via 7-point Likert scale will be assessed at randomization, 96 hours, and at discharge. The Likert score was defined as 1=markedly improved, 2=moderately improved, 3=minimally improved; 4=no change, 5=minimally worse, 6=moderately worse, and 7=markedly worse as compared with the degree of dyspnea present at randomization.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>96 Hour Change in Serum Creatinine</measure>
    <time_frame>Randomization through 96 hours</time_frame>
    <description>Renal function via serum creatinine, will be assessed at randomization and daily through 96 hours</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>96 Hour Net Fluid Output</measure>
    <time_frame>Randomization through 96 hours</time_frame>
    <description>Fluid intake and urine output will be assessed daily while in hospital through 96 hours. Net fluid output (output minus input) through 96 hours is reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>96 Hour Change in Body Weight</measure>
    <time_frame>Randomization through 96 hours or earlier discharge</time_frame>
    <description>Baseline body weight assessment will be completed, and changes in weight documented daily through 96 hours or earlier discharge</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>96 Hour Change in Serum Potassium Levels</measure>
    <time_frame>Baseline, 96 hours</time_frame>
    <description>Change in serum potassium levels at 96 hours as compared to baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Loop Diuretics Requirements From Baseline to 30 Days</measure>
    <time_frame>Randomization through Day 30</time_frame>
    <description>Medications will be reviewed to assess loop diuretic dose requirements through Day 30 following randomization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Presence of Outpatient Worsening Heart Failure Symptoms Through Day 30</measure>
    <time_frame>Hospital discharge through Day 30</time_frame>
    <description>Outpatient worsening heart failure symptoms will be assessed from discharge through Day 30</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>96 Hour Change in Dyspnea Visual Analog Scale</measure>
    <time_frame>Randomization to 96 hours</time_frame>
    <description>Dyspnea visual analog scale change from randomization to 96 hours. Scale range 0-100 with 100 being the best possible score.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Day 60 Mortality</measure>
    <time_frame>60 days post randomization</time_frame>
    <description>All participants will be contacted by telephone at 60 days, +/- 3 days post randomization to assess vital status (death).</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">360</enrollment>
  <condition>Heart Failure</condition>
  <arm_group>
    <arm_group_label>Spironolactone</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Spironolactone</intervention_name>
    <description>Patients receiving no MRA at home will receive spironolactone 100 mg (4x25 mg capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will be randomized to receive spironolactone 25 mg (1x25 mg capsules) or 100 mg (4x25 mg capsules) in hospital for 96 hours. The patients who are randomized to 25 mg spironolactone will also receive 75 mg placebo (3x25 mg capsules) in order to maintain blinding.</description>
    <arm_group_label>Spironolactone</arm_group_label>
    <other_name>aldactone</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Patients receiving no MRA at home will receive 100 mg placebo (4x25 mg capsules) once daily for 96 hours.&#xD;
Patients who are randomized to 25 mg spironolactone will also receive 75 mg placebo (3x25 mg capsules) in order to maintain blinding.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female patient ≥21 years old&#xD;
&#xD;
          -  Admitted to hospital for AHF with at least 1 symptom (dyspnea, orthopnea, or fatigue)&#xD;
             and 1 sign (rales on auscultation, peripheral edema, ascites, pulmonary vascular&#xD;
             congestion on chest radiography) of congestion&#xD;
&#xD;
          -  Patient must be randomized within 24 hours of first IV diuretic dose administered for&#xD;
             the current episode of decompensation (regardless of where the diuretic was given e.g.&#xD;
             office, ED, ambulance, hospital etc.)&#xD;
&#xD;
          -  Estimated GFR of ≥30 mL/min/1.73m2 determined by the MDRD equation&#xD;
&#xD;
          -  Serum K+ ≤5.0 mmol/L at enrollment&#xD;
&#xD;
          -  NT-proBNP ≥1000 pg/mL or BNP ≥250 pg/mL, measured within 24h from randomization&#xD;
&#xD;
          -  Not on MRA or on low-dose spironolactone (12.5 mg or 25 mg daily) at baseline&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Taking eplerenone or &gt;25 mg spironolactone at baseline&#xD;
&#xD;
          -  eGFR &lt; 30 ml/min/1.73m2&#xD;
&#xD;
          -  Serum K+ &gt;5.0 mmol/L. If a repeat measurement within the enrollment window is &lt;5.0,&#xD;
             the patient can be considered for inclusion.&#xD;
&#xD;
          -  Systolic blood pressure &lt;90 mmHg&#xD;
&#xD;
          -  Hemodynamically significant arrhythmias or defibrillator shock within 1 week&#xD;
&#xD;
          -  Acute coronary syndrome currently suspected or within the past 4 weeks&#xD;
&#xD;
          -  Severe liver disease (ALT or AST &gt;3 x normal, alkaline phosphatase or bilirubin &gt;2x&#xD;
             normal)&#xD;
&#xD;
          -  Active infection (current use of oral or IV antimicrobial agents)&#xD;
&#xD;
          -  Active gastrointestinal bleeding&#xD;
&#xD;
          -  Active malignancy other than non-melanoma skin cancers&#xD;
&#xD;
          -  Current or planned mechanical circulatory support within 30 days&#xD;
&#xD;
          -  Post cardiac transplant or listed for transplant and expected to receive one within 30&#xD;
             days&#xD;
&#xD;
          -  Current inotrope use&#xD;
&#xD;
          -  Complex congenital heart disease&#xD;
&#xD;
          -  Primary hypertrophic cardiomyopathy, infiltrative cardiomyopathy, acute myocarditis,&#xD;
             constrictive pericarditis or tamponade&#xD;
&#xD;
          -  Previous adverse reaction to MRAs&#xD;
&#xD;
          -  Enrollment in another randomized clinical trial during index hospitalization&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Adrian Hernandez, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Duke University Health Systems</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Eugene Braunwald, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Harvard University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Emory University School of Medicine</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Johns Hopkins Hospital</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21287</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tufts Medical Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02111</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Brigham and Women's Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Boston VA Healtcare System</name>
      <address>
        <city>West Roxbury</city>
        <state>Massachusetts</state>
        <zip>02132</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Louis University Hospital</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63117</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stony Brook University Medical Center</name>
      <address>
        <city>Stony Brook</city>
        <state>New York</state>
        <zip>11794</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Duke University</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27705</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Southeastern Regional Medical Center</name>
      <address>
        <city>Lumberton</city>
        <state>North Carolina</state>
        <zip>28358</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospitals - Case Medical Center</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44106</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Metro Health System</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cleveland Clinic</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44195</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lancaster General Hospital</name>
      <address>
        <city>Lancaster</city>
        <state>Pennsylvania</state>
        <zip>17603</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pennsylvania</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Jefferson Medical College</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Michael Debakey VA Medical Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Utah School of Medicine</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84132</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Utah VA Medical Center</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84132</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The University of Vermont- Fletcher Allen Health Care</name>
      <address>
        <city>Burlington</city>
        <state>Vermont</state>
        <zip>05401</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2017</verification_date>
  <study_first_submitted>September 3, 2014</study_first_submitted>
  <study_first_submitted_qc>September 5, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 9, 2014</study_first_posted>
  <results_first_submitted>April 7, 2017</results_first_submitted>
  <results_first_submitted_qc>April 7, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">May 17, 2017</results_first_posted>
  <last_update_submitted>May 22, 2017</last_update_submitted>
  <last_update_submitted_qc>May 22, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">June 14, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Heart Failure</keyword>
  <keyword>Heart Diseases</keyword>
  <keyword>Cardiovascular Diseases</keyword>
  <keyword>Spironolactone</keyword>
  <keyword>Aldactone</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Spironolactone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Spironolactone</title>
          <description>Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours&#xD;
Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours&#xD;
Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="182"/>
                <participants group_id="P2" count="178"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="164"/>
                <participants group_id="P2" count="159"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
                <participants group_id="P2" count="19"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="7"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="5"/>
              </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="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Spironolactone</title>
          <description>Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours&#xD;
Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours&#xD;
Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
        </group>
        <group group_id="B3">
          <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="182"/>
            <count group_id="B2" value="178"/>
            <count group_id="B3" value="360"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="65.9" spread="13.7"/>
                    <measurement group_id="B2" value="63.5" spread="14.4"/>
                    <measurement group_id="B3" value="64.7" spread="14.1"/>
                  </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>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="65"/>
                    <measurement group_id="B2" value="64"/>
                    <measurement group_id="B3" value="129"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="117"/>
                    <measurement group_id="B2" value="114"/>
                    <measurement group_id="B3" value="231"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="180"/>
                    <measurement group_id="B2" value="172"/>
                    <measurement group_id="B3" value="352"/>
                  </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_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>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="4"/>
                  </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_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="74"/>
                    <measurement group_id="B2" value="77"/>
                    <measurement group_id="B3" value="151"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="101"/>
                    <measurement group_id="B2" value="99"/>
                    <measurement group_id="B3" value="200"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </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_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>96 Hour Change in NT-proBNP</title>
        <description>The Core Laboratory at Vermont will determine NT-proBNP levels for calculation of the endpoint from samples obtained at randomization and 96 hours respectively. NT-proBNP was converted to log scale.</description>
        <time_frame>Randomization to 96 hours</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Spironolactone</title>
            <description>Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours&#xD;
Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours&#xD;
Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
          </group>
        </group_list>
        <measure>
          <title>96 Hour Change in NT-proBNP</title>
          <description>The Core Laboratory at Vermont will determine NT-proBNP levels for calculation of the endpoint from samples obtained at randomization and 96 hours respectively. NT-proBNP was converted to log scale.</description>
          <units>log 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="182"/>
                <count group_id="O2" value="178"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.58" spread="0.69"/>
                    <measurement group_id="O2" value="-0.61" spread="0.72"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.5688</p_value>
            <method>Regression, Linear</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>0.05</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.11</ci_lower_limit>
            <ci_upper_limit>0.20</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>96 Hour Change in Clinical Congestion Score</title>
        <description>Clinical congestion score will be assessed at randomization, 96 hours, and at discharge. Scale consisted of sum of six signs and symptoms of congestion, each scored 0-3. Zero indicates no sign/symptom and 3 indicates worst case of sign/symptom. Score range 0-18 with 18 being worst score.</description>
        <time_frame>Randomization through 96 hours</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Spironolactone</title>
            <description>Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours&#xD;
Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours&#xD;
Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
          </group>
        </group_list>
        <measure>
          <title>96 Hour Change in Clinical Congestion Score</title>
          <description>Clinical congestion score will be assessed at randomization, 96 hours, and at discharge. Scale consisted of sum of six signs and symptoms of congestion, each scored 0-3. Zero indicates no sign/symptom and 3 indicates worst case of sign/symptom. Score range 0-18 with 18 being worst score.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="182"/>
                <count group_id="O2" value="178"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-5.59" spread="3.34"/>
                    <measurement group_id="O2" value="-5.82" spread="3.32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.4155</p_value>
            <method>Regression, Linear</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>0.25</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.35</ci_lower_limit>
            <ci_upper_limit>0.86</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>96 Hour Change in Dyspnea Likert Score</title>
        <description>Dyspnea relief via 7-point Likert scale will be assessed at randomization, 96 hours, and at discharge. The Likert score was defined as 1=markedly improved, 2=moderately improved, 3=minimally improved; 4=no change, 5=minimally worse, 6=moderately worse, and 7=markedly worse as compared with the degree of dyspnea present at randomization.</description>
        <time_frame>Randomization through 96 hours</time_frame>
        <population>All data for completed assessments was analyzed. For outcomes where the number of participants analyzed is less than 182 spironolactone / 178 placebo, the number of subjects analyzed represents the number of subjects for whom the data was collected.</population>
        <group_list>
          <group group_id="O1">
            <title>Spironolactone</title>
            <description>Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours&#xD;
Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours&#xD;
Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
          </group>
        </group_list>
        <measure>
          <title>96 Hour Change in Dyspnea Likert Score</title>
          <description>Dyspnea relief via 7-point Likert scale will be assessed at randomization, 96 hours, and at discharge. The Likert score was defined as 1=markedly improved, 2=moderately improved, 3=minimally improved; 4=no change, 5=minimally worse, 6=moderately worse, and 7=markedly worse as compared with the degree of dyspnea present at randomization.</description>
          <population>All data for completed assessments was analyzed. For outcomes where the number of participants analyzed is less than 182 spironolactone / 178 placebo, the number of subjects analyzed represents the number of subjects for whom the data was collected.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="166"/>
                <count group_id="O2" value="163"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Markedly improved</title>
                  <measurement_list>
                    <measurement group_id="O1" value="64"/>
                    <measurement group_id="O2" value="79"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Moderately improved</title>
                  <measurement_list>
                    <measurement group_id="O1" value="56"/>
                    <measurement group_id="O2" value="39"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Minimally improved</title>
                  <measurement_list>
                    <measurement group_id="O1" value="24"/>
                    <measurement group_id="O2" value="18"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No change</title>
                  <measurement_list>
                    <measurement group_id="O1" value="17"/>
                    <measurement group_id="O2" value="21"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Minimally worse</title>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Moderately worse</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Markedly worse</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.3039</p_value>
            <method>Chi-squared</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>1.23</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.83</ci_lower_limit>
            <ci_upper_limit>1.81</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>96 Hour Change in Serum Creatinine</title>
        <description>Renal function via serum creatinine, will be assessed at randomization and daily through 96 hours</description>
        <time_frame>Randomization through 96 hours</time_frame>
        <population>All data for completed assessments was analyzed. For outcomes where the number of participants analyzed is less than 182 spironolactone / 178 placebo, the number of subjects analyzed represents the number of subjects for whom the data was collected.</population>
        <group_list>
          <group group_id="O1">
            <title>Spironolactone</title>
            <description>Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours&#xD;
Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours&#xD;
Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
          </group>
        </group_list>
        <measure>
          <title>96 Hour Change in Serum Creatinine</title>
          <description>Renal function via serum creatinine, will be assessed at randomization and daily through 96 hours</description>
          <population>All data for completed assessments was analyzed. For outcomes where the number of participants analyzed is less than 182 spironolactone / 178 placebo, the number of subjects analyzed represents the number of subjects for whom the data was collected.</population>
          <units>mg/dl</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="100"/>
                <count group_id="O2" value="101"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.15" spread="0.30"/>
                    <measurement group_id="O2" value="0.16" spread="0.30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.7673</p_value>
            <method>Regression, Linear</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-0.01</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.09</ci_lower_limit>
            <ci_upper_limit>0.07</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>96 Hour Net Fluid Output</title>
        <description>Fluid intake and urine output will be assessed daily while in hospital through 96 hours. Net fluid output (output minus input) through 96 hours is reported.</description>
        <time_frame>Randomization through 96 hours</time_frame>
        <population>All data for completed assessments was analyzed. For outcomes where the number of participants analyzed is less than 182 spironolactone / 178 placebo, the number of subjects analyzed represents the number of subjects for whom the data was collected.</population>
        <group_list>
          <group group_id="O1">
            <title>Spironolactone</title>
            <description>Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours&#xD;
Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours&#xD;
Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
          </group>
        </group_list>
        <measure>
          <title>96 Hour Net Fluid Output</title>
          <description>Fluid intake and urine output will be assessed daily while in hospital through 96 hours. Net fluid output (output minus input) through 96 hours is reported.</description>
          <population>All data for completed assessments was analyzed. For outcomes where the number of participants analyzed is less than 182 spironolactone / 178 placebo, the number of subjects analyzed represents the number of subjects for whom the data was collected.</population>
          <units>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="87"/>
                <count group_id="O2" value="96"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5824" spread="4007"/>
                    <measurement group_id="O2" value="5507" spread="3633"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.5734</p_value>
            <method>Regression, Linear</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>319.2</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-797.4</ci_lower_limit>
            <ci_upper_limit>1435.8</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>96 Hour Change in Body Weight</title>
        <description>Baseline body weight assessment will be completed, and changes in weight documented daily through 96 hours or earlier discharge</description>
        <time_frame>Randomization through 96 hours or earlier discharge</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Spironolactone</title>
            <description>Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours&#xD;
Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours&#xD;
Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
          </group>
        </group_list>
        <measure>
          <title>96 Hour Change in Body Weight</title>
          <description>Baseline body weight assessment will be completed, and changes in weight documented daily through 96 hours or earlier discharge</description>
          <units>pounds</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="182"/>
                <count group_id="O2" value="178"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-8.1" spread="10.7"/>
                    <measurement group_id="O2" value="-7.5" spread="9.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.3528</p_value>
            <method>Regression, Linear</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-1.02</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-3.05</ci_lower_limit>
            <ci_upper_limit>1.01</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>96 Hour Change in Serum Potassium Levels</title>
        <description>Change in serum potassium levels at 96 hours as compared to baseline.</description>
        <time_frame>Baseline, 96 hours</time_frame>
        <population>All data for completed assessments was analyzed. For outcomes where the number of participants analyzed is less than 182 spironolactone / 178 placebo, the number of subjects analyzed represents the number of subjects for whom the data was collected.</population>
        <group_list>
          <group group_id="O1">
            <title>Spironolactone</title>
            <description>Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours&#xD;
Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours&#xD;
Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
          </group>
        </group_list>
        <measure>
          <title>96 Hour Change in Serum Potassium Levels</title>
          <description>Change in serum potassium levels at 96 hours as compared to baseline.</description>
          <population>All data for completed assessments was analyzed. For outcomes where the number of participants analyzed is less than 182 spironolactone / 178 placebo, the number of subjects analyzed represents the number of subjects for whom the data was collected.</population>
          <units>mEq/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="99"/>
                <count group_id="O2" value="101"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.31" spread="0.54"/>
                    <measurement group_id="O2" value="0.15" spread="0.69"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0846</p_value>
            <method>Regression, Linear</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>0.11</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.02</ci_lower_limit>
            <ci_upper_limit>0.25</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Loop Diuretics Requirements From Baseline to 30 Days</title>
        <description>Medications will be reviewed to assess loop diuretic dose requirements through Day 30 following randomization</description>
        <time_frame>Randomization through Day 30</time_frame>
        <population>All data for completed assessments was analyzed. For outcomes where the number of participants analyzed is less than 182 spironolactone / 178 placebo, the number of subjects analyzed represents the number of subjects for whom the data was collected.</population>
        <group_list>
          <group group_id="O1">
            <title>Spironolactone</title>
            <description>Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours&#xD;
Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours&#xD;
Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Loop Diuretics Requirements From Baseline to 30 Days</title>
          <description>Medications will be reviewed to assess loop diuretic dose requirements through Day 30 following randomization</description>
          <population>All data for completed assessments was analyzed. For outcomes where the number of participants analyzed is less than 182 spironolactone / 178 placebo, the number of subjects analyzed represents the number of subjects for whom the data was collected.</population>
          <units>mg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="164"/>
                <count group_id="O2" value="158"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19.66" spread="69.95"/>
                    <measurement group_id="O2" value="30.70" spread="68.29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0842</p_value>
            <method>Regression, Linear</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-12.17</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-25.98</ci_lower_limit>
            <ci_upper_limit>1.65</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Presence of Outpatient Worsening Heart Failure Symptoms Through Day 30</title>
        <description>Outpatient worsening heart failure symptoms will be assessed from discharge through Day 30</description>
        <time_frame>Hospital discharge through Day 30</time_frame>
        <population>All data for completed assessments was analyzed. For outcomes where the number of participants analyzed is less than 182 spironolactone / 178 placebo, the number of subjects analyzed represents the number of subjects for whom the data was collected.</population>
        <group_list>
          <group group_id="O1">
            <title>Spironolactone</title>
            <description>Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours&#xD;
Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours&#xD;
Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
          </group>
        </group_list>
        <measure>
          <title>Presence of Outpatient Worsening Heart Failure Symptoms Through Day 30</title>
          <description>Outpatient worsening heart failure symptoms will be assessed from discharge through Day 30</description>
          <population>All data for completed assessments was analyzed. For outcomes where the number of participants analyzed is less than 182 spironolactone / 178 placebo, the number of subjects analyzed represents the number of subjects for whom the data was collected.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="166"/>
                <count group_id="O2" value="163"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19"/>
                    <measurement group_id="O2" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.7628</p_value>
            <method>Regression, Logistic</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>1.11</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.56</ci_lower_limit>
            <ci_upper_limit>2.23</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>96 Hour Change in Dyspnea Visual Analog Scale</title>
        <description>Dyspnea visual analog scale change from randomization to 96 hours. Scale range 0-100 with 100 being the best possible score.</description>
        <time_frame>Randomization to 96 hours</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Spironolactone</title>
            <description>Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours&#xD;
Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours&#xD;
Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
          </group>
        </group_list>
        <measure>
          <title>96 Hour Change in Dyspnea Visual Analog Scale</title>
          <description>Dyspnea visual analog scale change from randomization to 96 hours. Scale range 0-100 with 100 being the best possible score.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="182"/>
                <count group_id="O2" value="178"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="17.2" spread="25.0"/>
                    <measurement group_id="O2" value="17.9" spread="24.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.6102</p_value>
            <method>Regression, Linear</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-1.04</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-5.02</ci_lower_limit>
            <ci_upper_limit>2.95</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Day 60 Mortality</title>
        <description>All participants will be contacted by telephone at 60 days, +/- 3 days post randomization to assess vital status (death).</description>
        <time_frame>60 days post randomization</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Spironolactone</title>
            <description>Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours&#xD;
Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours&#xD;
Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
          </group>
        </group_list>
        <measure>
          <title>Day 60 Mortality</title>
          <description>All participants will be contacted by telephone at 60 days, +/- 3 days post randomization to assess vital status (death).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="182"/>
                <count group_id="O2" value="178"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                    <measurement group_id="O2" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.5818</p_value>
            <method>Regression, Logistic</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>0.76</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.29</ci_lower_limit>
            <ci_upper_limit>1.99</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse event data was collected by the sites from randomization through 30 days, but was not collected on the case report form. Only Serious Adverse Events were collected on the data forms.</time_frame>
      <desc>Adverse event data was collected by the sites from randomization through 30 days, but was not collected on the case report form.</desc>
      <group_list>
        <group group_id="E1">
          <title>Spironolactone</title>
          <description>Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours&#xD;
Spironolactone: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours&#xD;
Placebo: Patients receiving no MRA at home will receive either spironolactone 100 mg or matching placebo (4x25 mg study capsules) once daily for 96 hours.&#xD;
Patients already receiving low-dose MRA at home will receive spironolactone 100 mg vs. 25 mg (1x25 mg spironolactone and 3 placebo study capsules) in hospital for 96 hours.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (Unspecified)</default_vocab>
        <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="5" subjects_at_risk="182"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="21" subjects_at_risk="182"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="178"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Aortic valve stenosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Cardiogenic shock</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Gastrointestinal Haemmorhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Protalgia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Multi-organ failure</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Systemic inflammatory response syndrome</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>H1N1 Influenza</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Oesophageal Candidiasis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="182"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="182"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Tooth abscess</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="182"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Post-procedural haemotoma</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="182"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Traumatic haemotoma</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Vascular pseudoaneurysm</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="182"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="178"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>International Normalised Ratio Increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Gout</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="182"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Hyperglycaemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Hypokalaemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Lactic acidosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="182"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="178"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Adenocarcinoma of colon</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Basal cell carcinoma</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="182"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="178"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Hepatic encephalopathy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="182"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Partial seizures with secondary generalisation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="182"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="178"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Delerium</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Psychogenic seizure</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="182"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Suicidal ideation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="182"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="178"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Bronchial haemmorhage</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="182"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Chronic obstructive pulmonary disease</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Pneumonia aspiration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Aortic dissection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Distributive shock</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="182"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Hypertensive crisis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Hypertensive emergency</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
              <event>
                <sub_title>Hypovolaemic shock</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="182"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="178"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>To minimize the probability of inaccurate data in published materials, it is the policy of the Heart Failure Network that all data and text considered for all papers, and all abstracts for presentation at scientific meetings be submitted to the Publication and Presentation Subcommittee, the NHLBI Project Officer, and the Coordinating Center for review and approval prior to presentation or publication.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Adrian Hernandez, MD</name_or_title>
      <organization>Duke Clinical Research Institute</organization>
      <phone>919 668 7515</phone>
      <email>adrian.hernandez@duke.edu</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/NCT02235077
org study id: Pro00057090
secondary id: 5U01HL084904
nct id: NCT02235077
lead sponsor: 
collaborator: 
has dmc: Yes
The primary objective of this study is to test the hypothesis that high-dose spironolactone
      will lead to greater proportional reduction in NT-proBNP levels from randomization to 96
      hours over standard of care.
Mineralocorticoid receptor antagonist (MRA) therapy is recommended in stable chronic systolic
      heart failure (HF) and post-infarction HF patients for improving morbidity and mortality. MRA
      therapy in AHF and in high doses is less well studied. The effectiveness and safety of early
      high dose MRA therapy in AHF is supported by a single-blind study showing lower risk of
      worsening renal function and need for loop diuretics, and improved congestion. MRA therapy in
      AHF may improve outcomes by relieving congestion at higher doses through their natriuretic
      property, in addition to preventing the deleterious effects of exacerbation of neuro-hormonal
      activation by loop diuretics.

      This randomized, double blind, placebo-controlled study of high-dose spironolactone vs.
      placebo (for patients not receiving MRA at home) or low-dose spironolactone (for patients
      already receiving low-dose spironolactone) in AHF, will enroll 360 participants at
      approximately 30 clinical centers. After obtaining informed consent, subjects who fulfill all
      the inclusion criteria and none of the exclusion criteria will be randomized. Randomization
      will be performed by using procedures determined by the Coordinating Center (CC).

        -  Patients receiving no MRA therapy at baseline will be randomized to receive either
           spironolactone 100 mg or placebo daily for 96 hours.

        -  Patients already receiving low-dose spironolactone at baseline (12.5 mg or 25 mg daily)
           will be randomized to 100 mg or 25 mg spironolactone daily for 96 hours.

      Within 24 hours prior to randomization, all study participants will undergo:

        -  Medical History

        -  Review of medications including pre-hospital loop diuretics, MRA, and potassium doses

        -  Physical examination, vital signs and body weight

        -  Measurement of creatinine, blood urea nitrogen (BUN), and electrolytes

        -  Dyspnea Relief Assessments (7-point Likert and Visual Analog Scale)

        -  Serum pregnancy test for all women of childbearing potential

        -  Collection of samples for measurement of NT-proBNP levels (Core Lab)

      Study drug will be initiated as follows:

        -  Patients receiving no MRA therapy at baseline: 4x25 mg study capsules once daily;
           starting dose 100 mg spironolactone or placebo; if dose adjustment is required, active
           capsules will be adjusted by pharmacy to achieve the required dose.

        -  Patients already receiving low-dose spironolactone at baseline: 4x25 mg study capsules
           once daily; one capsule containing 25 mg spironolactone and 3x25 mg study capsules
           containing spironolactone or placebo; if dose adjustment is required, active capsules
           will be adjusted by pharmacy to achieve the required dose.

      Patients will be followed every 24 hours following randomization through 96 hours. Study drug
      will be administered daily for 96 hours. Study drug administration time is anchored to time
      of randomization. Dose adjustments (continue, hold, stop) are permitted according to serum K+
      and renal function.

      Assessment at 24 hours post randomization includes: Review of medications, body weight, fluid
      intake/urine output, creatinine, blood urea nitrogen (BUN), and electrolytes, and adverse
      events.

      If the 24 hour assessment is also the day of discharge, include:

        -  Physical exam / Vital signs

        -  Dyspnea Relief (7-Point Likert and VAS) worksheets

        -  Biomarkers (NT-proBNP) (Core Lab)

      Assessment at 48 hours post randomization includes: Review of medications, physical
      exam/vital signs, body weight, fluid intake/urine output, Dyspnea Relief (7-Point Likert and
      VAS) worksheets, creatinine, blood urea nitrogen (BUN), and electrolytes, biomarker levels
      (NT-proBNP) by Core Lab.

      Assessment at 72 hours post randomization includes: Review of medications, body weight, fluid
      intake/urine output, creatinine, blood urea nitrogen (BUN), and electrolytes, and adverse
      events.

      If the 72 hour assessment is also the day of discharge, include:

        -  Physical exam / Vital signs

        -  Dyspnea Relief (7-Point Likert and VAS) worksheets

        -  Biomarkers (NT-proBNP) (Core Lab)

      Assessment at 96 hours post randomization includes: Review of medications, physical
      exam/vital signs, body weight, fluid intake/urine output, creatinine, blood urea nitrogen
      (BUN), and electrolytes, Dyspnea Relief (7-Point Likert and VAS), and biomarker levels
      (NT-proBNP) by Core Lab.

      If patient is clinically euvolemic in less than 96 hours, the investigator may consider
      changing loop diuretics to oral dose.

      Study drug will be discontinued after 96 hours and further use of MRA will be left to the
      treating physician's discretion.

      Assessment at Discharge: If discharge occurs after the 96 hour assessment but prior to the 30
      day follow-up telephone call,the following will be documented: Medication review (prescribed
      medications at the time of discharge), body weight (if available), creatinine, blood urea
      nitrogen (BUN), and electrolytes (if available), and adverse events.

      Ejection fraction data will be obtained from echocardiogram within 6 months prior to
      randomization. Those patients who do not have an echocardiogram recorded within this time
      frame will get an echocardiogram, nuclear perfusion study, MRI, or MUGA performed prior to
      the 96 hour in-hospital assessment to ascertain ejection fraction.

      Follow-up Telephone Call at Day 30: All participants will be contacted by telephone at day 30
      (+3 days) following randomization to assess tertiary endpoints, including medication use and
      adverse events.

      Follow-up Telephone Call at Day 60: All participants will be contacted by telephone at day 60
      (+/-3 days) following randomization to assess vital status.

      During the consent process, patients will be asked if interested in donating samples and data
      for research purposes via a biorepository and/or genetic study. Based on site and IRB
      preference, this optional part of the study may be incorporated into the main consent or may
      be a separate consent and IRB application.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: 96 Hour Change in NT-proBNP
time frame: Randomization to 96 hours
description: The Core Laboratory at Vermont will determine NT-proBNP levels for calculation of the endpoint from samples obtained at randomization and 96 hours respectively. NT-proBNP was converted to log scale.
measure: 96 Hour Change in Clinical Congestion Score
time frame: Randomization through 96 hours
description: Clinical congestion score will be assessed at randomization, 96 hours, and at discharge. Scale consisted of sum of six signs and symptoms of congestion, each scored 0-3. Zero indicates no sign/symptom and 3 indicates worst case of sign/symptom. Score range 0-18 with 18 being worst score.
measure: 96 Hour Change in Dyspnea Likert Score
time frame: Randomization through 96 hours
description: Dyspnea relief via 7-point Likert scale will be assessed at randomization, 96 hours, and at discharge. The Likert score was defined as 1=markedly improved, 2=moderately improved, 3=minimally improved; 4=no change, 5=minimally worse, 6=moderately worse, and 7=markedly worse as compared with the degree of dyspnea present at randomization.
measure: 96 Hour Change in Serum Creatinine
time frame: Randomization through 96 hours
description: Renal function via serum creatinine, will be assessed at randomization and daily through 96 hours
measure: 96 Hour Net Fluid Output
time frame: Randomization through 96 hours
description: Fluid intake and urine output will be assessed daily while in hospital through 96 hours. Net fluid output (output minus input) through 96 hours is reported.
measure: 96 Hour Change in Body Weight
time frame: Randomization through 96 hours or earlier discharge
description: Baseline body weight assessment will be completed, and changes in weight documented daily through 96 hours or earlier discharge
measure: 96 Hour Change in Serum Potassium Levels
time frame: Baseline, 96 hours
description: Change in serum potassium levels at 96 hours as compared to baseline.
measure: Change in Loop Diuretics Requirements From Baseline to 30 Days
time frame: Randomization through Day 30
description: Medications will be reviewed to assess loop diuretic dose requirements through Day 30 following randomization
measure: Presence of Outpatient Worsening Heart Failure Symptoms Through Day 30
time frame: Hospital discharge through Day 30
description: Outpatient worsening heart failure symptoms will be assessed from discharge through Day 30
measure: 96 Hour Change in Dyspnea Visual Analog Scale
time frame: Randomization to 96 hours
description: Dyspnea visual analog scale change from randomization to 96 hours. Scale range 0-100 with 100 being the best possible score.
measure: Day 60 Mortality
time frame: 60 days post randomization
description: All participants will be contacted by telephone at 60 days, +/- 3 days post randomization to assess vital status (death).
arm group label: Spironolactone
arm group type: Active Comparator
description: Spironolactone 25mg or 100 mg orally, once daily while in the hospital for 96 hours
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo 25mg or 100mg orally, once daily while in the hospital for 96 hours
intervention type: Drug
intervention name: Spironolactone
description: Patients receiving no MRA at home will receive spironolactone 100 mg (4x25 mg capsules) once daily for 96 hours.
Patients already receiving low-dose MRA at home will be randomized to receive spironolactone 25 mg (1x25 mg capsules) or 100 mg (4x25 mg capsules) in hospital for 96 hours. The patients who are randomized to 25 mg spironolactone will also receive 75 mg placebo (3x25 mg capsules) in order to maintain blinding.
arm group label: Spironolactone
other name: aldactone
intervention type: Drug
intervention name: Placebo
description: Patients receiving no MRA at home will receive 100 mg placebo (4x25 mg capsules) once daily for 96 hours.
Patients who are randomized to 25 mg spironolactone will also receive 75 mg placebo (3x25 mg capsules) in order to maintain blinding.
arm group label: Placebo
criteria: 
gender: All
minimum age: 21 Years
maximum age: N/A
healthy volunteers: No
last name: Adrian Hernandez, MD
role: Principal Investigator
affiliation: Duke University Health Systems
last name: Eugene Braunwald, MD
role: Study Chair
affiliation: Harvard University
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country: United States
responsible party type: Sponsor
mesh term: Heart Failure
mesh term: Spironolactone
sharing ipd: No
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 