<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/NCT03772041</url>
  </required_header>
  <id_info>
    <org_study_id>263-102-00003</org_study_id>
    <secondary_id>JapicCTI-184234</secondary_id>
    <nct_id>NCT03772041</nct_id>
  </id_info>
  <brief_title>Efficacy and Safety Trial of OPC-61815 Injection Compared With Tolvaptan 15-mg Tablet in Patients With Congestive Heart Failure</brief_title>
  <official_title>A Multicenter, Double-blind, Randomized, Active-controlled, Parallel-group, Non-inferiority Trial to Evaluate the Efficacy and Safety of OPC-61815 Injection Compared With Tolvaptan 15-mg Tablet in Patients With Congestive Heart Failure</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Otsuka Pharmaceutical Co., Ltd.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Otsuka Pharmaceutical Co., Ltd.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      To confirm the non-inferiority of OPC-61815 16-mg injection to tolvaptan 15-mg tablet using&#xD;
      as the primary endpoint the change in body weight following 5-day intravenous administration&#xD;
      of OPC-61815 16-mg injection or 5-day oral administration of tolvaptan 15-mg tablet to CHF&#xD;
      patients with volume overload despite having received diuretics other than vasopressin&#xD;
      antagonists&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 16, 2019</start_date>
  <completion_date type="Actual">July 29, 2020</completion_date>
  <primary_completion_date type="Actual">July 21, 2020</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change From Baseline in Body Weight</measure>
    <time_frame>Baseline, Day 6</time_frame>
    <description>Change in body weight from baseline (before investigational medicinal product [IMP] administration on Day 1) at time of final IMP administration (day after final IMP administration). A negative change from baseline indicates improvement.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Improvement Rate for Lower Limb Edema and Pulmonary Congestion</measure>
    <time_frame>Baseline, Day 6</time_frame>
    <description>The improvement rate was defined as the percentage of subjects in whom the symptom was present at baseline and it markedly improved or improved after IMP administration. Improvement category is a 4-point scale below:&#xD;
Markedly improved&#xD;
Improved&#xD;
Unchanged&#xD;
Deteriorated</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Jugular Venous Distension and Hepatomegaly</measure>
    <time_frame>Baseline, Day 6</time_frame>
    <description>Jugular Venous Distension: the presence of Jugular Venous Distension was checked, and if present, the height (in cm) from the sternal angle to the highest point of pulsation in the internal Jugular vein was measured with the subject in a semi-upright position. A negative change from baseline indicates improvement.&#xD;
Hepatomegaly: the presence of a palpable liver was checked, and if present, the width (distance from the right costal arch of the right chest, in cm) was measured. A negative change from baseline indicates improvement.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Subjects Who Achieve Resolution of Pulmonary Rales and Third Cardiac Sound</measure>
    <time_frame>Baseline, Day 6</time_frame>
    <description>Percentage of subjects in whom the symptom was present at baseline and disappeared after IMP administration was provided.&#xD;
The presence of pulmonary rales was checked by auscultation.&#xD;
The presence of cardiac third sound was checked by auscultation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Improvement Rate for New York Heart Association (NYHA) Classification</measure>
    <time_frame>Baseline, Day 6</time_frame>
    <description>NYHA classification assesses the severity of heart failure based on subjective symptoms as follows.&#xD;
Class I: No limitations of physical activity. Ordinary physical activity caused no undue fatigue, palpitation, dyspnea or anginal pain.&#xD;
Class II: Slight limitation of physical activity, comfortable at rest. Ordinary physical activity resulted in fatigue, palpitation, dyspnea or anginal pain.&#xD;
Class III: Marked limitation of physical activity, comfortable at rest. Less than ordinary physical activity caused fatigue, palpitation, dyspnea or anginal pain.&#xD;
Class IV: Inability to carry on any physical activity without discomfort. heart failure or anginal syndrome may have been present even at rest. If any physical activity was undertaken, discomfort was increased.&#xD;
Of the subjects with Class II or higher at baseline, the percentage of subjects whose NYHA classification stage at the time of final IMP administration improved by 1 or more grades was provided.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">294</enrollment>
  <condition>Congestive Heart Failure</condition>
  <arm_group>
    <arm_group_label>OPC-61815 injection 16 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 16 mg</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Tolvaptan tablet 15mg</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Once daily for 5 days tolvaptan 15-mg tablet will be orally administered, followed immediately by 1-hour intravenous administration of placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>OPC-61815</intervention_name>
    <description>Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 16 mg</description>
    <arm_group_label>OPC-61815 injection 16 mg</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tolvaptan Tab 15 MG</intervention_name>
    <description>Once daily for 5 days tolvaptan 15-mg tablet will be orally administered, followed immediately by 1-hour intravenous administration of placebo</description>
    <arm_group_label>Tolvaptan tablet 15mg</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients who are currently on treatment with any of the following diuretics&#xD;
&#xD;
               1. Loop diuretics equivalent to furosemide tablet or fine granules at a dose of 40&#xD;
                  mg/day or higher&#xD;
&#xD;
               2. Concomitant use of a loop diuretic and a thiazide diuretic (including thiazide&#xD;
                  analogs) at any dose&#xD;
&#xD;
               3. Concomitant use of a loop diuretic and an aldosterone antagonist or&#xD;
                  potassium-sparing diuretic agent at any dose&#xD;
&#xD;
          -  Patients with congestive heart failure in whom lower limb edema, pulmonary congestion,&#xD;
             and/or jugular venous distension due to volume overload is present&#xD;
&#xD;
          -  Patients who are currently hospitalized or who are able to be hospitalized during the&#xD;
             trial&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with acute heart failure&#xD;
&#xD;
          -  Patients who are on a ventricular assist device&#xD;
&#xD;
          -  Patients who are unable to sense thirst or who have difficulty with fluid intake&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Osamu Sato</last_name>
    <role>Study Director</role>
    <affiliation>Otsuka Pharmaceutical Co., Ltd.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Saiseikai Kumamoto Hospital</name>
      <address>
        <city>Kumamoto</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Japan</country>
  </location_countries>
  <verification_date>July 2021</verification_date>
  <study_first_submitted>December 5, 2018</study_first_submitted>
  <study_first_submitted_qc>December 10, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 11, 2018</study_first_posted>
  <results_first_submitted>July 14, 2021</results_first_submitted>
  <results_first_submitted_qc>July 14, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">August 5, 2021</results_first_posted>
  <last_update_submitted>July 14, 2021</last_update_submitted>
  <last_update_submitted_qc>July 14, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 5, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </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>Tolvaptan</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal.</ipd_description>
    <ipd_time_frame>Data will be available after marketing approval in global markets, or beginning 1-3 years following article Publication. There is no end date to the availability of the data.</ipd_time_frame>
    <ipd_access_criteria>Otsuka will share data on an Otsuka-owned remotely accessible data sharing platform with Python and R analytical software. Research requests should be directed to https://clinical-trials.otsuka.com/contact-us</ipd_access_criteria>
    <ipd_url>https://clinical-trials.otsuka.com/contact-us</ipd_url>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>March 27, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/41/NCT03772041/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>September 14, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/41/NCT03772041/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>OPC-61815 Injection 16 mg</title>
          <description>Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 16 mg.</description>
        </group>
        <group group_id="P2">
          <title>Tolvaptan Tablet 15mg</title>
          <description>Once daily for 5 days tolvaptan 15-mg tablet will be orally administered, followed immediately by 1-hour intravenous administration of placebo.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="149"/>
                <participants group_id="P2" count="145"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="135"/>
                <participants group_id="P2" count="135"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
                <participants group_id="P2" count="10"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>OPC-61815 Injection 16 mg</title>
          <description>Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 16 mg.</description>
        </group>
        <group group_id="B2">
          <title>Tolvaptan Tablet 15mg</title>
          <description>Once daily for 5 days tolvaptan 15-mg tablet will be orally administered, followed immediately by 1-hour intravenous administration of placebo.</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="149"/>
            <count group_id="B2" value="145"/>
            <count group_id="B3" value="294"/>
          </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="74.0" spread="10.2"/>
                    <measurement group_id="B2" value="75.4" spread="8.2"/>
                    <measurement group_id="B3" value="74.7" spread="9.3"/>
                  </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="37"/>
                    <measurement group_id="B2" value="47"/>
                    <measurement group_id="B3" value="84"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="112"/>
                    <measurement group_id="B2" value="98"/>
                    <measurement group_id="B3" value="210"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Asian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="149"/>
                    <measurement group_id="B2" value="145"/>
                    <measurement group_id="B3" value="294"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Japan</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="149"/>
                    <measurement group_id="B2" value="145"/>
                    <measurement group_id="B3" value="294"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change From Baseline in Body Weight</title>
        <description>Change in body weight from baseline (before investigational medicinal product [IMP] administration on Day 1) at time of final IMP administration (day after final IMP administration). A negative change from baseline indicates improvement.</description>
        <time_frame>Baseline, Day 6</time_frame>
        <population>Full Analysis Set: subjects who received at least one dose of IMP and had at least one postbaseline weight measurement</population>
        <group_list>
          <group group_id="O1">
            <title>OPC-61815 Injection 16 mg</title>
            <description>Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 16 mg.</description>
          </group>
          <group group_id="O2">
            <title>Tolvaptan Tablet 15mg</title>
            <description>Once daily for 5 days tolvaptan 15-mg tablet will be orally administered, followed immediately by 1-hour intravenous administration of placebo.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Body Weight</title>
          <description>Change in body weight from baseline (before investigational medicinal product [IMP] administration on Day 1) at time of final IMP administration (day after final IMP administration). A negative change from baseline indicates improvement.</description>
          <population>Full Analysis Set: subjects who received at least one dose of IMP and had at least one postbaseline weight measurement</population>
          <units>kg</units>
          <param>Least Squares Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="149"/>
                <count group_id="O2" value="144"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.67" lower_limit="-1.93" upper_limit="-1.41"/>
                    <measurement group_id="O2" value="-1.36" lower_limit="-1.62" upper_limit="-1.10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Improvement Rate for Lower Limb Edema and Pulmonary Congestion</title>
        <description>The improvement rate was defined as the percentage of subjects in whom the symptom was present at baseline and it markedly improved or improved after IMP administration. Improvement category is a 4-point scale below:&#xD;
Markedly improved&#xD;
Improved&#xD;
Unchanged&#xD;
Deteriorated</description>
        <time_frame>Baseline, Day 6</time_frame>
        <population>Full Analysis Set: subjects who received at least one dose of IMP and had at least one postbaseline weight measurement were included in the full analysis. &quot;Number Analyzed&quot; = number of subjects with baseline symptoms.</population>
        <group_list>
          <group group_id="O1">
            <title>OPC-61815 Injection 16 mg</title>
            <description>Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 16 mg.</description>
          </group>
          <group group_id="O2">
            <title>Tolvaptan Tablet 15mg</title>
            <description>Once daily for 5 days tolvaptan 15-mg tablet will be orally administered, followed immediately by 1-hour intravenous administration of placebo.</description>
          </group>
        </group_list>
        <measure>
          <title>Improvement Rate for Lower Limb Edema and Pulmonary Congestion</title>
          <description>The improvement rate was defined as the percentage of subjects in whom the symptom was present at baseline and it markedly improved or improved after IMP administration. Improvement category is a 4-point scale below:&#xD;
Markedly improved&#xD;
Improved&#xD;
Unchanged&#xD;
Deteriorated</description>
          <population>Full Analysis Set: subjects who received at least one dose of IMP and had at least one postbaseline weight measurement were included in the full analysis. &quot;Number Analyzed&quot; = number of subjects with baseline symptoms.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="149"/>
                <count group_id="O2" value="145"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Lower Limb Edema</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="122"/>
                    <count group_id="O2" value="111"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="68.9"/>
                    <measurement group_id="O2" value="75.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Pulmonary Congestion</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="123"/>
                    <count group_id="O2" value="119"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="56.1"/>
                    <measurement group_id="O2" value="64.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Jugular Venous Distension and Hepatomegaly</title>
        <description>Jugular Venous Distension: the presence of Jugular Venous Distension was checked, and if present, the height (in cm) from the sternal angle to the highest point of pulsation in the internal Jugular vein was measured with the subject in a semi-upright position. A negative change from baseline indicates improvement.&#xD;
Hepatomegaly: the presence of a palpable liver was checked, and if present, the width (distance from the right costal arch of the right chest, in cm) was measured. A negative change from baseline indicates improvement.</description>
        <time_frame>Baseline, Day 6</time_frame>
        <population>Subjects with baseline values in the Full Analysis Set</population>
        <group_list>
          <group group_id="O1">
            <title>OPC-61815 Injection 16 mg</title>
            <description>Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 16 mg.</description>
          </group>
          <group group_id="O2">
            <title>Tolvaptan Tablet 15mg</title>
            <description>Once daily for 5 days tolvaptan 15-mg tablet will be orally administered, followed immediately by 1-hour intravenous administration of placebo.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Jugular Venous Distension and Hepatomegaly</title>
          <description>Jugular Venous Distension: the presence of Jugular Venous Distension was checked, and if present, the height (in cm) from the sternal angle to the highest point of pulsation in the internal Jugular vein was measured with the subject in a semi-upright position. A negative change from baseline indicates improvement.&#xD;
Hepatomegaly: the presence of a palpable liver was checked, and if present, the width (distance from the right costal arch of the right chest, in cm) was measured. A negative change from baseline indicates improvement.</description>
          <population>Subjects with baseline values in the Full Analysis Set</population>
          <units>cm</units>
          <param>Least Squares Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="149"/>
                <count group_id="O2" value="145"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Jugular Venous Distension</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="52"/>
                    <count group_id="O2" value="59"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-2.89" lower_limit="-3.45" upper_limit="-2.33"/>
                    <measurement group_id="O2" value="-3.15" lower_limit="-3.68" upper_limit="-2.62"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hepatomegaly</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="12"/>
                    <count group_id="O2" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.93" lower_limit="-1.44" upper_limit="-0.43"/>
                    <measurement group_id="O2" value="-0.88" lower_limit="-1.43" upper_limit="-0.33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Subjects Who Achieve Resolution of Pulmonary Rales and Third Cardiac Sound</title>
        <description>Percentage of subjects in whom the symptom was present at baseline and disappeared after IMP administration was provided.&#xD;
The presence of pulmonary rales was checked by auscultation.&#xD;
The presence of cardiac third sound was checked by auscultation.</description>
        <time_frame>Baseline, Day 6</time_frame>
        <population>Full Analysis Set: subjects who received at least one dose of IMP and had at least one postbaseline weight measurement were included in the full analysis. &quot;Number Analyzed&quot; = number of subjects with baseline symptoms.</population>
        <group_list>
          <group group_id="O1">
            <title>OPC-61815 Injection 16 mg</title>
            <description>Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 16 mg.</description>
          </group>
          <group group_id="O2">
            <title>Tolvaptan Tablet 15mg</title>
            <description>Once daily for 5 days tolvaptan 15-mg tablet will be orally administered, followed immediately by 1-hour intravenous administration of placebo.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Subjects Who Achieve Resolution of Pulmonary Rales and Third Cardiac Sound</title>
          <description>Percentage of subjects in whom the symptom was present at baseline and disappeared after IMP administration was provided.&#xD;
The presence of pulmonary rales was checked by auscultation.&#xD;
The presence of cardiac third sound was checked by auscultation.</description>
          <population>Full Analysis Set: subjects who received at least one dose of IMP and had at least one postbaseline weight measurement were included in the full analysis. &quot;Number Analyzed&quot; = number of subjects with baseline symptoms.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="149"/>
                <count group_id="O2" value="145"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Pulmonary Rales</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="35"/>
                    <count group_id="O2" value="19"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="74.3"/>
                    <measurement group_id="O2" value="78.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Third Cardiac Sound</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="41"/>
                    <count group_id="O2" value="42"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="31.7"/>
                    <measurement group_id="O2" value="31.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Improvement Rate for New York Heart Association (NYHA) Classification</title>
        <description>NYHA classification assesses the severity of heart failure based on subjective symptoms as follows.&#xD;
Class I: No limitations of physical activity. Ordinary physical activity caused no undue fatigue, palpitation, dyspnea or anginal pain.&#xD;
Class II: Slight limitation of physical activity, comfortable at rest. Ordinary physical activity resulted in fatigue, palpitation, dyspnea or anginal pain.&#xD;
Class III: Marked limitation of physical activity, comfortable at rest. Less than ordinary physical activity caused fatigue, palpitation, dyspnea or anginal pain.&#xD;
Class IV: Inability to carry on any physical activity without discomfort. heart failure or anginal syndrome may have been present even at rest. If any physical activity was undertaken, discomfort was increased.&#xD;
Of the subjects with Class II or higher at baseline, the percentage of subjects whose NYHA classification stage at the time of final IMP administration improved by 1 or more grades was provided.</description>
        <time_frame>Baseline, Day 6</time_frame>
        <population>Full Analysis Set: subjects who received at least one dose of IMP and had at least one postbaseline weight measurement were included in the full analysis. &quot;Overall Number of Participants Analyzed&quot; = number of subjects with a baseline of class II or more.</population>
        <group_list>
          <group group_id="O1">
            <title>OPC-61815 Injection 16 mg</title>
            <description>Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 16 mg.</description>
          </group>
          <group group_id="O2">
            <title>Tolvaptan Tablet 15mg</title>
            <description>Once daily for 5 days tolvaptan 15-mg tablet will be orally administered, followed immediately by 1-hour intravenous administration of placebo.</description>
          </group>
        </group_list>
        <measure>
          <title>Improvement Rate for New York Heart Association (NYHA) Classification</title>
          <description>NYHA classification assesses the severity of heart failure based on subjective symptoms as follows.&#xD;
Class I: No limitations of physical activity. Ordinary physical activity caused no undue fatigue, palpitation, dyspnea or anginal pain.&#xD;
Class II: Slight limitation of physical activity, comfortable at rest. Ordinary physical activity resulted in fatigue, palpitation, dyspnea or anginal pain.&#xD;
Class III: Marked limitation of physical activity, comfortable at rest. Less than ordinary physical activity caused fatigue, palpitation, dyspnea or anginal pain.&#xD;
Class IV: Inability to carry on any physical activity without discomfort. heart failure or anginal syndrome may have been present even at rest. If any physical activity was undertaken, discomfort was increased.&#xD;
Of the subjects with Class II or higher at baseline, the percentage of subjects whose NYHA classification stage at the time of final IMP administration improved by 1 or more grades was provided.</description>
          <population>Full Analysis Set: subjects who received at least one dose of IMP and had at least one postbaseline weight measurement were included in the full analysis. &quot;Overall Number of Participants Analyzed&quot; = number of subjects with a baseline of class II or more.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="136"/>
                <count group_id="O2" value="120"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="44.9"/>
                    <measurement group_id="O2" value="42.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Treatment-emergent adverse events (TEAEs) were collected from the start of IMP administration up to 15 days</time_frame>
      <desc>Subjects who received at least one dose of IMP were included in the safety analysis.</desc>
      <group_list>
        <group group_id="E1">
          <title>OPC-61815 Injection 16 mg</title>
          <description>Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 16 mg.</description>
        </group>
        <group group_id="E2">
          <title>Tolvaptan Tablet 15mg</title>
          <description>Once daily for 5 days tolvaptan 15-mg tablet will be orally administered, followed immediately by 1-hour intravenous administration of placebo.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA Ver. 23.0</default_vocab>
        <default_assessment>Non-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="0" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="145"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="145"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="145"/>
              </event>
              <event>
                <sub_title>Cardiac failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="145"/>
              </event>
              <event>
                <sub_title>Cardiac failure acute</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="145"/>
              </event>
              <event>
                <sub_title>Coronary artery stenosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="145"/>
              </event>
              <event>
                <sub_title>Sinus node dysfunction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="145"/>
              </event>
              <event>
                <sub_title>Ventricular tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="145"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Gastric antral vascular ectasia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="145"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="145"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="145"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperkalaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="145"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>General infarction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="145"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>2</frequency_threshold>
        <default_vocab>MedDRA Ver. 23.0</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="61" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="57" subjects_at_risk="145"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="145"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="145"/>
              </event>
              <event>
                <sub_title>Ventricular tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="145"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="145"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="145"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="145"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="145"/>
              </event>
              <event>
                <sub_title>Thirst</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="16" subjects_at_risk="145"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood potassium increased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="145"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="145"/>
              </event>
              <event>
                <sub_title>Hyperkalaemia</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="145"/>
              </event>
              <event>
                <sub_title>Hypernatraemia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="145"/>
              </event>
              <event>
                <sub_title>Hyperuricaemia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="145"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Renal impairment</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="145"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Eczema</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="145"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="145"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="149"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="145"/>
              </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>Director of Clinical Trials</name_or_title>
      <organization>Otsuka Pharmaceutical Co., LTD.</organization>
      <phone>+81-3-6361-7366</phone>
      <email>CL_OPCJ_RDA_Team@otsuka.jp</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/NCT03772041
org study id: 263-102-00003
secondary id: JapicCTI-184234
nct id: NCT03772041
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
To confirm the non-inferiority of OPC-61815 16-mg injection to tolvaptan 15-mg tablet using
      as the primary endpoint the change in body weight following 5-day intravenous administration
      of OPC-61815 16-mg injection or 5-day oral administration of tolvaptan 15-mg tablet to CHF
      patients with volume overload despite having received diuretics other than vasopressin
      antagonists
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Change From Baseline in Body Weight
time frame: Baseline, Day 6
description: Change in body weight from baseline (before investigational medicinal product [IMP] administration on Day 1) at time of final IMP administration (day after final IMP administration). A negative change from baseline indicates improvement.
measure: Improvement Rate for Lower Limb Edema and Pulmonary Congestion
time frame: Baseline, Day 6
description: The improvement rate was defined as the percentage of subjects in whom the symptom was present at baseline and it markedly improved or improved after IMP administration. Improvement category is a 4-point scale below:
Markedly improved
Improved
Unchanged
Deteriorated
measure: Change From Baseline in Jugular Venous Distension and Hepatomegaly
time frame: Baseline, Day 6
description: Jugular Venous Distension: the presence of Jugular Venous Distension was checked, and if present, the height (in cm) from the sternal angle to the highest point of pulsation in the internal Jugular vein was measured with the subject in a semi-upright position. A negative change from baseline indicates improvement.
Hepatomegaly: the presence of a palpable liver was checked, and if present, the width (distance from the right costal arch of the right chest, in cm) was measured. A negative change from baseline indicates improvement.
measure: Percentage of Subjects Who Achieve Resolution of Pulmonary Rales and Third Cardiac Sound
time frame: Baseline, Day 6
description: Percentage of subjects in whom the symptom was present at baseline and disappeared after IMP administration was provided.
The presence of pulmonary rales was checked by auscultation.
The presence of cardiac third sound was checked by auscultation.
measure: Improvement Rate for New York Heart Association (NYHA) Classification
time frame: Baseline, Day 6
description: NYHA classification assesses the severity of heart failure based on subjective symptoms as follows.
Class I: No limitations of physical activity. Ordinary physical activity caused no undue fatigue, palpitation, dyspnea or anginal pain.
Class II: Slight limitation of physical activity, comfortable at rest. Ordinary physical activity resulted in fatigue, palpitation, dyspnea or anginal pain.
Class III: Marked limitation of physical activity, comfortable at rest. Less than ordinary physical activity caused fatigue, palpitation, dyspnea or anginal pain.
Class IV: Inability to carry on any physical activity without discomfort. heart failure or anginal syndrome may have been present even at rest. If any physical activity was undertaken, discomfort was increased.
Of the subjects with Class II or higher at baseline, the percentage of subjects whose NYHA classification stage at the time of final IMP administration improved by 1 or more grades was provided.
arm group label: OPC-61815 injection 16 mg
arm group type: Experimental
description: Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 16 mg
arm group label: Tolvaptan tablet 15mg
arm group type: Active Comparator
description: Once daily for 5 days tolvaptan 15-mg tablet will be orally administered, followed immediately by 1-hour intravenous administration of placebo
intervention type: Drug
intervention name: OPC-61815
description: Once daily for 5 days placebo tablet will be orally administered, followed immediately by intravenous administration of OPC-61815 at 16 mg
arm group label: OPC-61815 injection 16 mg
intervention type: Drug
intervention name: Tolvaptan Tab 15 MG
description: Once daily for 5 days tolvaptan 15-mg tablet will be orally administered, followed immediately by 1-hour intravenous administration of placebo
arm group label: Tolvaptan tablet 15mg
criteria: 
gender: All
minimum age: 20 Years
maximum age: 85 Years
healthy volunteers: No
last name: Osamu Sato
role: Study Director
affiliation: Otsuka Pharmaceutical Co., Ltd.
facility: 
country: Japan
responsible party type: Sponsor
mesh term: Heart Failure
mesh term: Tolvaptan
sharing ipd: Yes
ipd description: Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal.
ipd time frame: Data will be available after marketing approval in global markets, or beginning 1-3 years following article Publication. There is no end date to the availability of the data.
ipd access criteria: Otsuka will share data on an Otsuka-owned remotely accessible data sharing platform with Python and R analytical software. Research requests should be directed to https://clinical-trials.otsuka.com/contact-us
ipd url: https://clinical-trials.otsuka.com/contact-us
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 