<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/NCT02183792</url>
  </required_header>
  <id_info>
    <org_study_id>HS-13-00705</org_study_id>
    <nct_id>NCT02183792</nct_id>
  </id_info>
  <brief_title>Aquaresis Utility for Hyponatremic Acute Heart Failure Study</brief_title>
  <acronym>AQUA-AHF</acronym>
  <official_title>Aquaresis Utility for Hyponatremic Acute Heart Failure Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Southern California</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Otsuka America Pharmaceutical</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Southern California</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Hyponatremia is a common finding in acute heart failure (HF) patients and is associated with&#xD;
      worse prognosis. In addition to its prognostic value, hyponatremia may have importance during&#xD;
      the acute management of HF. We've recently shown that acute or chronic hyponatremia,&#xD;
      especially &lt;130 mEq/L, was associated with higher loop diuretic dose requirements and more&#xD;
      frequent need for escalation of the diuretic regimen to achieve the same level of diuresis as&#xD;
      normonatremic HF patients. Aquaresis with tolvaptan represents a potentially advantageous&#xD;
      approach to the management of volume overload in HF, especially in patients presenting with&#xD;
      concomitant hyponatremia. The purpose of the current study is to prospectively evaluate the&#xD;
      comparative efficacy and safety of a tolvaptan-based diuretic regimen compared to&#xD;
      conventional diuresis with a furosemide-based regimen on short-term clinical and treatment&#xD;
      outcomes in hyponatremic acute HF patients.&#xD;
&#xD;
      This will be a prospective, open-label, parallel-group, randomized study comparing a&#xD;
      tolvaptan-based aquaretic regimen to a conventional continuous infusion loop diuretic-based&#xD;
      regimen of furosemide. Up to 55 (target sample size of 50) adult subjects admitted with acute&#xD;
      HF and signs of volume overload, and serum sodium less than 135 mEq/L will be randomized to&#xD;
      tolvaptan or furosemide treatment arms. The initial 24 hours of study treatment will compare&#xD;
      tolvaptan monotherapy to furosemide monotherapy. After the initial 24 hours, treatment&#xD;
      regimens may be altered to achieve desired clinical goals. Patients will be followed for up&#xD;
      to 96 hours and at discharge for study purposes.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>December 2014</start_date>
  <completion_date type="Actual">March 2018</completion_date>
  <primary_completion_date type="Actual">February 2018</primary_completion_date>
  <phase>Phase 4</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Median Urine Output at 24 Hours Post Randomization</measure>
    <time_frame>24 hours post randomization</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Median Change in Serum Creatinine at 24 Hours Post Randomization</measure>
    <time_frame>24 hours post randomization</time_frame>
    <description>Comparison between baseline and 24 hours post randomization concentrations.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Total Urine Output</measure>
    <time_frame>Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Glomerular Filtration Rate (Estimated)</measure>
    <time_frame>Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>In-hospital Mortality</measure>
    <time_frame>Participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Mean Hourly Urine Output at 24 Hours</measure>
    <time_frame>Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Serum Sodium Change</measure>
    <time_frame>Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
    <description>Difference assessed at baseline, 8, 24, 48, 72 and 96 hours.</description>
  </other_outcome>
  <other_outcome>
    <measure>Weight Change</measure>
    <time_frame>Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
    <description>Difference assessed at baseline, 8, 24, 48, 72 and 96 hours.</description>
  </other_outcome>
  <other_outcome>
    <measure>Cumulative Furosemide Dose</measure>
    <time_frame>Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Cumulative Metolazone Use</measure>
    <time_frame>Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Change in Self-rated Dyspnea</measure>
    <time_frame>At baseline, 24 and 96 hours post randomization</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Acute Worsening of Kidney Function (Defined as an Increase in Serum Creatinine 0.3 mg/dL or 25% Above Baseline)</measure>
    <time_frame>Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Incidence of Electrolyte Abnormalities</measure>
    <time_frame>Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
    <description>Hypo- and hyperkalemia defined as outside the range of 3.5 to 5.0 mEq/L Hypo- and hypermagnesemia defined as outside the range of 1.5-2.4 mEq/L</description>
  </other_outcome>
  <other_outcome>
    <measure>Symptomatic Hypotension</measure>
    <time_frame>Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Change in Plasma Renin Activity</measure>
    <time_frame>At baseline, 24 and 96 hours post randomization</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Change in Copeptin</measure>
    <time_frame>At baseline, 24 and 96 hours post randomization</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Change in N-terminal Pro-B-type Natriuretic Peptide</measure>
    <time_frame>At baseline, 24 and 96 hours post randomization</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Change in Cystatin C</measure>
    <time_frame>At baseline, 24 and 96 hours post randomization</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Change in Urinary Neutrophil Gelatinase-associated Lipocalin (NGAL)</measure>
    <time_frame>At baseline, 24, 48, 72 and 96 hours post randomization</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Hospital Length of Stay</measure>
    <time_frame>Participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">33</enrollment>
  <condition>Heart Failure</condition>
  <arm_group>
    <arm_group_label>Tolvaptan</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Tolvaptan 30-60mg once daily (with rescue loop diuretic or metolazone)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Furosemide</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Furosemide continuous infusion 5mg/h with option to titrate (with rescue metolazone)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tolvaptan</intervention_name>
    <arm_group_label>Tolvaptan</arm_group_label>
    <other_name>Samsca</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Furosemide</intervention_name>
    <arm_group_label>Furosemide</arm_group_label>
    <other_name>Lasix</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Acute HF with signs or symptoms of volume overload [i.e. elevated jugular venous&#xD;
             pulsation (JVP), rales, edema]&#xD;
&#xD;
          -  Serum sodium &lt; 135 mEq/L at time of or within first 48 hours of hospitalization&#xD;
&#xD;
          -  Randomized within 48 hours of presentation to hospital&#xD;
&#xD;
          -  ≥ 18 years of age&#xD;
&#xD;
          -  Informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Severe symptomatic hyponatremia requiring acute treatment&#xD;
&#xD;
          -  Severe renal impairment upon admission (creatinine clearance &lt; 20 mL/min)&#xD;
&#xD;
          -  Renal replacement therapy dependent, or requiring upon admission&#xD;
&#xD;
          -  Acute coronary syndrome on admission&#xD;
&#xD;
          -  Requires or has a mechanical circulatory support device&#xD;
&#xD;
          -  Evidence of cardiogenic shock requiring intravenous vasopressors&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Patient requiring concomitant use of strong CYP3A4 inhibitors (clarithromycin,&#xD;
             ketoconazole, itraconazole, ritonavir, indinavir, nelfinavir, saquinavir, nefazodone,&#xD;
             and telithromycin)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Tien Ng, PharmD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Southern California</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Uri Elkayam, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Southern California</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Keck Medical Center of USC</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>LAC+USC Medical Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2019</verification_date>
  <study_first_submitted>June 25, 2014</study_first_submitted>
  <study_first_submitted_qc>July 2, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 8, 2014</study_first_posted>
  <results_first_submitted>May 2, 2019</results_first_submitted>
  <results_first_submitted_qc>May 24, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">May 28, 2019</results_first_posted>
  <last_update_submitted>May 24, 2019</last_update_submitted>
  <last_update_submitted_qc>May 24, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">May 28, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Southern California</investigator_affiliation>
    <investigator_full_name>Tien Ng</investigator_full_name>
    <investigator_title>Associate Professor of Clinical Pharmacy and Medicine</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Furosemide</mesh_term>
    <mesh_term>Tolvaptan</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>August 9, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/92/NCT02183792/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Tolvaptan</title>
          <description>Tolvaptan 30-60mg once daily (with rescue loop diuretic or metolazone)&#xD;
Tolvaptan</description>
        </group>
        <group group_id="P2">
          <title>Furosemide</title>
          <description>Furosemide continuous infusion 5mg/h with option to titrate (with rescue metolazone)&#xD;
Furosemide</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
                <participants group_id="P2" count="15"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
                <participants group_id="P2" count="15"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Tolvaptan</title>
          <description>Tolvaptan 30-60mg once daily (with rescue loop diuretic or metolazone)&#xD;
Tolvaptan</description>
        </group>
        <group group_id="B2">
          <title>Furosemide</title>
          <description>Furosemide continuous infusion 5mg/h with option to titrate (with rescue metolazone)&#xD;
Furosemide</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="18"/>
            <count group_id="B2" value="15"/>
            <count group_id="B3" value="33"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="18"/>
                    <count group_id="B2" value="15"/>
                    <count group_id="B3" value="33"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="53" spread="11.7"/>
                    <measurement group_id="B2" value="59" spread="8.9"/>
                    <measurement group_id="B3" value="56" spread="10.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="18"/>
                    <count group_id="B2" value="15"/>
                    <count group_id="B3" value="33"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race and Ethnicity Not Collected</title>
          <population>Race and Ethnicity were not collected from any participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="18"/>
                    <count group_id="B2" value="15"/>
                    <count group_id="B3" value="33"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Home Loop Diuretic Dose (Furosemide equivalents)</title>
          <units>mg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="18"/>
                    <count group_id="B2" value="15"/>
                    <count group_id="B3" value="33"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="93" spread="63.5"/>
                    <measurement group_id="B2" value="108" spread="77.5"/>
                    <measurement group_id="B3" value="100" spread="68.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Median Urine Output at 24 Hours Post Randomization</title>
        <time_frame>24 hours post randomization</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Tolvaptan</title>
            <description>Tolvaptan 30-60mg once daily (with rescue loop diuretic or metolazone)&#xD;
Tolvaptan</description>
          </group>
          <group group_id="O2">
            <title>Furosemide</title>
            <description>Furosemide continuous infusion 5mg/h with option to titrate (with rescue metolazone)&#xD;
Furosemide</description>
          </group>
        </group_list>
        <measure>
          <title>Median Urine Output at 24 Hours Post Randomization</title>
          <units>mL</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="15"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2910" lower_limit="1100" upper_limit="4225"/>
                    <measurement group_id="O2" value="3150" lower_limit="2375" upper_limit="5680"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Change in Serum Creatinine at 24 Hours Post Randomization</title>
        <description>Comparison between baseline and 24 hours post randomization concentrations.</description>
        <time_frame>24 hours post randomization</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Tolvaptan</title>
            <description>Tolvaptan 30-60mg once daily (with rescue loop diuretic or metolazone)&#xD;
Tolvaptan</description>
          </group>
          <group group_id="O2">
            <title>Furosemide</title>
            <description>Furosemide continuous infusion 5mg/h with option to titrate (with rescue metolazone)&#xD;
Furosemide</description>
          </group>
        </group_list>
        <measure>
          <title>Median Change in Serum Creatinine at 24 Hours Post Randomization</title>
          <description>Comparison between baseline and 24 hours post randomization concentrations.</description>
          <units>mg/dL</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="15"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Median Scr at Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.15" lower_limit="0.88" upper_limit="1.51"/>
                    <measurement group_id="O2" value="0.87" lower_limit="0.76" upper_limit="1.22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Median Scr at 24h</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.06" lower_limit="0.76" upper_limit="1.37"/>
                    <measurement group_id="O2" value="0.96" lower_limit="-0.19" upper_limit="1.53"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Median 24h Change</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.08" lower_limit="-0.14" upper_limit="-0.04"/>
                    <measurement group_id="O2" value="-0.01" lower_limit="-0.19" upper_limit="0.15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Total Urine Output</title>
        <time_frame>Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Glomerular Filtration Rate (Estimated)</title>
        <time_frame>Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>In-hospital Mortality</title>
        <time_frame>Participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Mean Hourly Urine Output at 24 Hours</title>
        <time_frame>Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Serum Sodium Change</title>
        <description>Difference assessed at baseline, 8, 24, 48, 72 and 96 hours.</description>
        <time_frame>Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Weight Change</title>
        <description>Difference assessed at baseline, 8, 24, 48, 72 and 96 hours.</description>
        <time_frame>Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Cumulative Furosemide Dose</title>
        <time_frame>Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Cumulative Metolazone Use</title>
        <time_frame>Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Change in Self-rated Dyspnea</title>
        <time_frame>At baseline, 24 and 96 hours post randomization</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Acute Worsening of Kidney Function (Defined as an Increase in Serum Creatinine 0.3 mg/dL or 25% Above Baseline)</title>
        <time_frame>Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Incidence of Electrolyte Abnormalities</title>
        <description>Hypo- and hyperkalemia defined as outside the range of 3.5 to 5.0 mEq/L Hypo- and hypermagnesemia defined as outside the range of 1.5-2.4 mEq/L</description>
        <time_frame>Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Symptomatic Hypotension</title>
        <time_frame>Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Change in Plasma Renin Activity</title>
        <time_frame>At baseline, 24 and 96 hours post randomization</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Change in Copeptin</title>
        <time_frame>At baseline, 24 and 96 hours post randomization</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Change in N-terminal Pro-B-type Natriuretic Peptide</title>
        <time_frame>At baseline, 24 and 96 hours post randomization</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Change in Cystatin C</title>
        <time_frame>At baseline, 24 and 96 hours post randomization</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Change in Urinary Neutrophil Gelatinase-associated Lipocalin (NGAL)</title>
        <time_frame>At baseline, 24, 48, 72 and 96 hours post randomization</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Hospital Length of Stay</title>
        <time_frame>Participants will be followed for the duration of hospital stay, an expected average of 5 days</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>During hospitalization (up to 96 hours post randomization)</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Tolvaptan</title>
          <description>Tolvaptan 30-60mg once daily (with rescue loop diuretic or metolazone)&#xD;
Tolvaptan</description>
        </group>
        <group group_id="E2">
          <title>Furosemide</title>
          <description>Furosemide continuous infusion 5mg/h with option to titrate (with rescue metolazone)&#xD;
Furosemide</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</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="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
              </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>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Tien Ng, Pharm.D.</name_or_title>
      <organization>University of Southern California School of Pharmacy</organization>
      <phone>3234421840</phone>
      <email>tienng@usc.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/NCT02183792
org study id: HS-13-00705
nct id: NCT02183792
lead sponsor: 
collaborator: 
has dmc: No
Hyponatremia is a common finding in acute heart failure (HF) patients and is associated with
      worse prognosis. In addition to its prognostic value, hyponatremia may have importance during
      the acute management of HF. We've recently shown that acute or chronic hyponatremia,
      especially <130 mEq/L, was associated with higher loop diuretic dose requirements and more
      frequent need for escalation of the diuretic regimen to achieve the same level of diuresis as
      normonatremic HF patients. Aquaresis with tolvaptan represents a potentially advantageous
      approach to the management of volume overload in HF, especially in patients presenting with
      concomitant hyponatremia. The purpose of the current study is to prospectively evaluate the
      comparative efficacy and safety of a tolvaptan-based diuretic regimen compared to
      conventional diuresis with a furosemide-based regimen on short-term clinical and treatment
      outcomes in hyponatremic acute HF patients.

      This will be a prospective, open-label, parallel-group, randomized study comparing a
      tolvaptan-based aquaretic regimen to a conventional continuous infusion loop diuretic-based
      regimen of furosemide. Up to 55 (target sample size of 50) adult subjects admitted with acute
      HF and signs of volume overload, and serum sodium less than 135 mEq/L will be randomized to
      tolvaptan or furosemide treatment arms. The initial 24 hours of study treatment will compare
      tolvaptan monotherapy to furosemide monotherapy. After the initial 24 hours, treatment
      regimens may be altered to achieve desired clinical goals. Patients will be followed for up
      to 96 hours and at discharge for study purposes.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Median Urine Output at 24 Hours Post Randomization
time frame: 24 hours post randomization
measure: Median Change in Serum Creatinine at 24 Hours Post Randomization
time frame: 24 hours post randomization
description: Comparison between baseline and 24 hours post randomization concentrations.
measure: Total Urine Output
time frame: Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days
measure: Glomerular Filtration Rate (Estimated)
time frame: Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days
measure: In-hospital Mortality
time frame: Participants will be followed for the duration of hospital stay, an expected average of 5 days
measure: Mean Hourly Urine Output at 24 Hours
time frame: Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days
measure: Serum Sodium Change
time frame: Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days
description: Difference assessed at baseline, 8, 24, 48, 72 and 96 hours.
measure: Weight Change
time frame: Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days
description: Difference assessed at baseline, 8, 24, 48, 72 and 96 hours.
measure: Cumulative Furosemide Dose
time frame: Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days
measure: Cumulative Metolazone Use
time frame: Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days
measure: Change in Self-rated Dyspnea
time frame: At baseline, 24 and 96 hours post randomization
measure: Acute Worsening of Kidney Function (Defined as an Increase in Serum Creatinine 0.3 mg/dL or 25% Above Baseline)
time frame: Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days
measure: Incidence of Electrolyte Abnormalities
time frame: Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days
description: Hypo- and hyperkalemia defined as outside the range of 3.5 to 5.0 mEq/L Hypo- and hypermagnesemia defined as outside the range of 1.5-2.4 mEq/L
measure: Symptomatic Hypotension
time frame: Up to 96 hours post randomization and participants will be followed for the duration of hospital stay, an expected average of 5 days
measure: Change in Plasma Renin Activity
time frame: At baseline, 24 and 96 hours post randomization
measure: Change in Copeptin
time frame: At baseline, 24 and 96 hours post randomization
measure: Change in N-terminal Pro-B-type Natriuretic Peptide
time frame: At baseline, 24 and 96 hours post randomization
measure: Change in Cystatin C
time frame: At baseline, 24 and 96 hours post randomization
measure: Change in Urinary Neutrophil Gelatinase-associated Lipocalin (NGAL)
time frame: At baseline, 24, 48, 72 and 96 hours post randomization
measure: Hospital Length of Stay
time frame: Participants will be followed for the duration of hospital stay, an expected average of 5 days
arm group label: Tolvaptan
arm group type: Experimental
description: Tolvaptan 30-60mg once daily (with rescue loop diuretic or metolazone)
arm group label: Furosemide
arm group type: Active Comparator
description: Furosemide continuous infusion 5mg/h with option to titrate (with rescue metolazone)
intervention type: Drug
intervention name: Tolvaptan
arm group label: Tolvaptan
other name: Samsca
intervention type: Drug
intervention name: Furosemide
arm group label: Furosemide
other name: Lasix
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Tien Ng, PharmD
role: Principal Investigator
affiliation: University of Southern California
last name: Uri Elkayam, MD
role: Principal Investigator
affiliation: University of Southern California
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Southern California
investigator full name: Tien Ng
investigator title: Associate Professor of Clinical Pharmacy and Medicine
mesh term: Heart Failure
mesh term: Furosemide
mesh term: Tolvaptan
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 