<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/NCT04495712</url>
  </required_header>
  <id_info>
    <org_study_id>ICDAD-1</org_study_id>
    <secondary_id>VA 02-2704</secondary_id>
    <nct_id>NCT04495712</nct_id>
  </id_info>
  <brief_title>Antiarrhythmic Effects of Spironolactone in Patients With ICDs</brief_title>
  <acronym>SPIRIT</acronym>
  <official_title>Antiarrhythmic Effects of Spironolactone in Patients With ICDs</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>VA Office of Research and Development</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>VA Office of Research and Development</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will test whether spironolactone, an approved drug for among other things&#xD;
      hypertension, will reduce the risk of severe arrhythmias in patients with implanted&#xD;
      defibrillators. Half the patients in the study will get spironolactone and half will get a&#xD;
      placebo. Neither the patients or their providers will know if they are getting spironolactone&#xD;
      or placebo.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Objectives: This study is designed to determine whether spironolactone at a dose of 25 mg per&#xD;
      day in patients with implanted cardioverter defibrillators (ICD) will 1) Reduce the incidence&#xD;
      of ventricular tachycardia (VT) and ventricular fibrillation (VF), 2) Improve health related&#xD;
      quality of life, 3) Reduce the need for hospitalization, and 4) Change ventricular&#xD;
      refractoriness.&#xD;
&#xD;
      Plan: The study was a randomized double blind placebo controlled multi-center trial. Patients&#xD;
      were randomized to either 25 mg per day of spironolactone or placebo and followed for 2 years&#xD;
      each. The primary endpoint is time to the first episode of VT/VF. Secondary endpoints will&#xD;
      include changes in health related quality of life, frequency of hospitalization, and in a&#xD;
      subset of patients the effect of spironolactone on the ventricular effective refractory&#xD;
      period measured through the ICD 3 months after starting the study medication. All data&#xD;
      analyses will be conducted on intent to treat basis.&#xD;
&#xD;
      Methods: Patients were recruited at the Portland VA ICD clinics, the Seattle VA ICD clinics,&#xD;
      Oregon Health and Sciences University ICD clinics and the Little Rock, Arkansas VA ICD&#xD;
      clinics. Randomization and drug preparation were done by the Portland VA Medical Center&#xD;
      research pharmacy. For safety purposes serum potassium will be measured at 1, 2, 3, 6, 12,&#xD;
      18, and 24 months. Patients will undergo ICD interrogation to document the occurrence of ICD&#xD;
      therapy for VT or VF and will be screened for potential drug side effects every 3 months&#xD;
      during the study. Health related quality of life will be measured at baseline, 3, 6, 12, 18,&#xD;
      and 24 months using Short Form Health Survey adapted for veterans (SF36V) Veterans Health&#xD;
      Study Version, the Patients Concerns Assessment, and the Kansas City Cardiomyopathy&#xD;
      Questionnaire. Hospitalizations will be tracked throughout the study. In the subset of&#xD;
      patient enrolled at the Portland VA the ventricular effective refractory period will be&#xD;
      measured via single extra stimuli pacing through the ICD at 3 months after randomization.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 28, 2004</start_date>
  <completion_date type="Actual">May 28, 2008</completion_date>
  <primary_completion_date type="Actual">May 28, 2008</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>
    <intervention_model_description>This was a prospective, double-blind, randomized trial that assigned patients to receive either spironolactone 25 mg/day or a placebo.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>All participants, providers, investigators, and outcome assessors were blinded to treatment assignment. The pharmacy maintained a key to randomization that was not broken until the study was completed and all outcomes had been assessed.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Time to First Appropriate Implantable Cardioverter Defibrillator (ICD) Therapy</measure>
    <time_frame>through study completion, an average of 35 months</time_frame>
    <description>Time to first documented ICD therapy for ventricular tachycardia or ventricular fibrillation after randomization</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>All Cause Hospitalization</measure>
    <time_frame>through study completion, an average of 35 months</time_frame>
    <description>Number of patients hospitalized for any reason during study follow-up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ventricular Refractoriness</measure>
    <time_frame>measured 3 months after randomization</time_frame>
    <description>The right ventricular effective refractory period (ERP) will be measured at 3 month in patients enrolled at the Portland VA Medical Center by single extra stimuli via their implanted defibrillator. The ERP is defined as the shortest paced beat coupling interval that fails to produce ventricular capture after a baseline stable pacing train.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Short Form Health Survey Adapted for Veterans (SF36V)</measure>
    <time_frame>12 months after enrollment</time_frame>
    <description>Short Form Health Survey adapted for veterans (SF36V) is a 36 item questionnaire that measures general physical and mental health [17]. The SF36V is a reliable and valid questionnaire, containing eight constructs of health status: physical functioning (PF), role limitations due to physical problems (RP), bodily pain (BP), general health perceptions (GH), energy/vitality (VT), social functioning (SF), role limitations due to emotional problems (RE), and mental health (MH). These eight dimensions can be summarized numerically into two scores, the physical component summary (PCS) and the mental component summary (MCS). Range 0-100 higher score is better Health Related Quality of Life (HRQOL). We are reporting the Mental Component Summary score at 12 months here.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient Concerns Assessment (PCA)</measure>
    <time_frame>12 months</time_frame>
    <description>Patient Concerns Assessment (PCA) is a symptom checklist that measures physical symptoms and fears that are common after ICD implantation. The PCA is a disease-specific instrument for ICD QOL, symptoms, and distress, with a reliability of ( = 0.88). Range 0-44, a higher score reflects more concerns and fears.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Kansas City Cardiomyopathy Questionnaire (KCCQ)</measure>
    <time_frame>through study completion, an average of 35 months</time_frame>
    <description>Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item reliable and valid questionnaire, which evaluates HRQOL in heart failure. It quantifies, in a disease-specific fashion, physical limitations, symptoms, quality of life, social interference and self-efficacy. KCCQ provides the calculation of 2 main scores, the overall score and the clinical summary score, which includes functional status, social limitation and quality of life domains scores. Range 0-100, higher scores represent higher HRQOL.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">90</enrollment>
  <condition>Ventricular Arrhythmias</condition>
  <arm_group>
    <arm_group_label>Spironolactone</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients randomized to active therapy with spironolactone</description>
  </arm_group>
  <arm_group>
    <arm_group_label>placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>patients randomized to placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>spironolactone</intervention_name>
    <description>aldosterone blocker</description>
    <arm_group_label>Spironolactone</arm_group_label>
    <other_name>Aldactone</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>placebo</intervention_name>
    <description>identical in appearance to spironolactone study drug</description>
    <arm_group_label>placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        -Patients were considered eligible for enrollment only if they had received&#xD;
&#xD;
          -  an ICD therapy, either a shock or antitachycardia pacing (ATP),&#xD;
&#xD;
          -  VT/VF in the previous 2 years or&#xD;
&#xD;
          -  received an ICD for secondary prevention of sustained VT/VF in the previous 6 months.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        -Important exclusion criteria were&#xD;
&#xD;
          -  an indication for spironolactone based on the RALES trial (EF of &lt;35% and -New York&#xD;
             Heart Association (NYHA) class III or IV),&#xD;
&#xD;
          -  unstable angina,&#xD;
&#xD;
          -  primary hepatic failure,&#xD;
&#xD;
          -  known intolerance to spironolactone,&#xD;
&#xD;
          -  a serum creatinine concentration of &gt;2.5 mg/dL,&#xD;
&#xD;
          -  a serum potassium concentration of &gt;5.0 mmol/L, and&#xD;
&#xD;
          -  a life expectancy of &lt;2 years.&#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>Merritt Raitt, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>VA Portland Health Care System, Portland, OR</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>VA Portland Health Care System, Portland, OR</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <results_reference>
    <citation>Zarraga IG, Dougherty CM, MacMurdy KS, Raitt MH. The effect of spironolactone on ventricular tachyarrhythmias in patients with implantable cardioverter-defibrillators. Circ Arrhythm Electrophysiol. 2012 Aug 1;5(4):739-47. doi: 10.1161/CIRCEP.112.970566. Epub 2012 Jul 7.</citation>
    <PMID>22773022</PMID>
  </results_reference>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>July 28, 2020</study_first_submitted>
  <study_first_submitted_qc>July 28, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 3, 2020</study_first_posted>
  <results_first_submitted>August 19, 2020</results_first_submitted>
  <results_first_submitted_qc>August 19, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">September 4, 2020</results_first_posted>
  <last_update_submitted>October 7, 2020</last_update_submitted>
  <last_update_submitted_qc>October 7, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 9, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Anti-Arrhythmia Agents</keyword>
  <keyword>Ventricular Fibrillation</keyword>
  <keyword>Ventricular Tachycardia</keyword>
  <keyword>Defibrillators, Implantable</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Arrhythmias, Cardiac</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Spironolactone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Patients did not give permission for data sharing</ipd_description>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Spironolactone</title>
          <description>Patients randomized to active therapy with spironolactone&#xD;
spironolactone: aldosterone blocker</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>patients randomized to placebo&#xD;
placebo: identical in appearance to spironolactone study drug</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="44"/>
                <participants group_id="P2" count="46"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="44"/>
                <participants group_id="P2" count="46"/>
              </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>Spironolactone</title>
          <description>Patients randomized to active therapy with spironolactone&#xD;
spironolactone: aldosterone blocker</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>patients randomized to placebo&#xD;
placebo: identical in appearance to spironolactone study drug</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="44"/>
            <count group_id="B2" value="46"/>
            <count group_id="B3" value="90"/>
          </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="44"/>
                    <count group_id="B2" value="46"/>
                    <count group_id="B3" value="90"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="66.6" spread="10.9"/>
                    <measurement group_id="B2" value="66.5" spread="9.3"/>
                    <measurement group_id="B3" value="66.5" spread="10.0"/>
                  </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="44"/>
                    <count group_id="B2" value="46"/>
                    <count group_id="B3" value="90"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="44"/>
                    <measurement group_id="B2" value="42"/>
                    <measurement group_id="B3" value="86"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="4"/>
                  </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>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="44"/>
                    <count group_id="B2" value="46"/>
                    <count group_id="B3" value="90"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="44"/>
                    <measurement group_id="B2" value="46"/>
                    <measurement group_id="B3" value="90"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Time to First Appropriate Implantable Cardioverter Defibrillator (ICD) Therapy</title>
        <description>Time to first documented ICD therapy for ventricular tachycardia or ventricular fibrillation after randomization</description>
        <time_frame>through study completion, an average of 35 months</time_frame>
        <population>all enrolled patients</population>
        <group_list>
          <group group_id="O1">
            <title>Spironolactone</title>
            <description>Patients randomized to active therapy with spironolactone&#xD;
spironolactone: aldosterone blocker</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>patients randomized to placebo&#xD;
placebo: identical in appearance to spironolactone study drug</description>
          </group>
        </group_list>
        <measure>
          <title>Time to First Appropriate Implantable Cardioverter Defibrillator (ICD) Therapy</title>
          <description>Time to first documented ICD therapy for ventricular tachycardia or ventricular fibrillation after randomization</description>
          <population>all enrolled patients</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="44"/>
                <count group_id="O2" value="46"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.8" lower_limit="0" upper_limit="37.2"/>
                    <measurement group_id="O2" value="12.3" lower_limit="0.3" upper_limit="38.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.71</p_value>
            <method>Log Rank</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>All Cause Hospitalization</title>
        <description>Number of patients hospitalized for any reason during study follow-up.</description>
        <time_frame>through study completion, an average of 35 months</time_frame>
        <population>all randomized patients</population>
        <group_list>
          <group group_id="O1">
            <title>Spironolactone</title>
            <description>Patients randomized to active therapy with spironolactone&#xD;
spironolactone: aldosterone blocker</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>patients randomized to placebo&#xD;
placebo: identical in appearance to spironolactone study drug</description>
          </group>
        </group_list>
        <measure>
          <title>All Cause Hospitalization</title>
          <description>Number of patients hospitalized for any reason during study follow-up.</description>
          <population>all randomized patients</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="44"/>
                <count group_id="O2" value="46"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="28"/>
                    <measurement group_id="O2" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.07</p_value>
            <method>Log Rank</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Ventricular Refractoriness</title>
        <description>The right ventricular effective refractory period (ERP) will be measured at 3 month in patients enrolled at the Portland VA Medical Center by single extra stimuli via their implanted defibrillator. The ERP is defined as the shortest paced beat coupling interval that fails to produce ventricular capture after a baseline stable pacing train.</description>
        <time_frame>measured 3 months after randomization</time_frame>
        <population>Patients randomized at the Portland VA Hospital that consented to testing</population>
        <group_list>
          <group group_id="O1">
            <title>Spironolactone</title>
            <description>Patients randomized to active therapy with spironolactone&#xD;
spironolactone: aldosterone blocker</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>patients randomized to placebo&#xD;
placebo: identical in appearance to spironolactone study drug</description>
          </group>
        </group_list>
        <measure>
          <title>Ventricular Refractoriness</title>
          <description>The right ventricular effective refractory period (ERP) will be measured at 3 month in patients enrolled at the Portland VA Medical Center by single extra stimuli via their implanted defibrillator. The ERP is defined as the shortest paced beat coupling interval that fails to produce ventricular capture after a baseline stable pacing train.</description>
          <population>Patients randomized at the Portland VA Hospital that consented to testing</population>
          <units>milliseconds</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="294.2" spread="40.8"/>
                    <measurement group_id="O2" value="278.3" spread="24.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.42</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Short Form Health Survey Adapted for Veterans (SF36V)</title>
        <description>Short Form Health Survey adapted for veterans (SF36V) is a 36 item questionnaire that measures general physical and mental health [17]. The SF36V is a reliable and valid questionnaire, containing eight constructs of health status: physical functioning (PF), role limitations due to physical problems (RP), bodily pain (BP), general health perceptions (GH), energy/vitality (VT), social functioning (SF), role limitations due to emotional problems (RE), and mental health (MH). These eight dimensions can be summarized numerically into two scores, the physical component summary (PCS) and the mental component summary (MCS). Range 0-100 higher score is better Health Related Quality of Life (HRQOL). We are reporting the Mental Component Summary score at 12 months here.</description>
        <time_frame>12 months after enrollment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Spironolactone</title>
            <description>Patients randomized to active therapy with spironolactone&#xD;
spironolactone: aldosterone blocker</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>patients randomized to placebo&#xD;
placebo: identical in appearance to spironolactone study drug</description>
          </group>
        </group_list>
        <measure>
          <title>Short Form Health Survey Adapted for Veterans (SF36V)</title>
          <description>Short Form Health Survey adapted for veterans (SF36V) is a 36 item questionnaire that measures general physical and mental health [17]. The SF36V is a reliable and valid questionnaire, containing eight constructs of health status: physical functioning (PF), role limitations due to physical problems (RP), bodily pain (BP), general health perceptions (GH), energy/vitality (VT), social functioning (SF), role limitations due to emotional problems (RE), and mental health (MH). These eight dimensions can be summarized numerically into two scores, the physical component summary (PCS) and the mental component summary (MCS). Range 0-100 higher score is better Health Related Quality of Life (HRQOL). We are reporting the Mental Component Summary score at 12 months here.</description>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="44"/>
                <count group_id="O2" value="46"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="54.87" spread="22.50"/>
                    <measurement group_id="O2" value="63.31" spread="20.35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Patient Concerns Assessment (PCA)</title>
        <description>Patient Concerns Assessment (PCA) is a symptom checklist that measures physical symptoms and fears that are common after ICD implantation. The PCA is a disease-specific instrument for ICD QOL, symptoms, and distress, with a reliability of ( = 0.88). Range 0-44, a higher score reflects more concerns and fears.</description>
        <time_frame>12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Spironolactone</title>
            <description>Patients randomized to active therapy with spironolactone&#xD;
spironolactone: aldosterone blocker</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>patients randomized to placebo&#xD;
placebo: identical in appearance to spironolactone study drug</description>
          </group>
        </group_list>
        <measure>
          <title>Patient Concerns Assessment (PCA)</title>
          <description>Patient Concerns Assessment (PCA) is a symptom checklist that measures physical symptoms and fears that are common after ICD implantation. The PCA is a disease-specific instrument for ICD QOL, symptoms, and distress, with a reliability of ( = 0.88). Range 0-44, a higher score reflects more concerns and fears.</description>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="44"/>
                <count group_id="O2" value="46"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.15" spread="12.28"/>
                    <measurement group_id="O2" value="18.42" spread="10.06"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Kansas City Cardiomyopathy Questionnaire (KCCQ)</title>
        <description>Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item reliable and valid questionnaire, which evaluates HRQOL in heart failure. It quantifies, in a disease-specific fashion, physical limitations, symptoms, quality of life, social interference and self-efficacy. KCCQ provides the calculation of 2 main scores, the overall score and the clinical summary score, which includes functional status, social limitation and quality of life domains scores. Range 0-100, higher scores represent higher HRQOL.</description>
        <time_frame>through study completion, an average of 35 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Spironolactone</title>
            <description>Patients randomized to active therapy with spironolactone&#xD;
spironolactone: aldosterone blocker</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>patients randomized to placebo&#xD;
placebo: identical in appearance to spironolactone study drug</description>
          </group>
        </group_list>
        <measure>
          <title>Kansas City Cardiomyopathy Questionnaire (KCCQ)</title>
          <description>Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item reliable and valid questionnaire, which evaluates HRQOL in heart failure. It quantifies, in a disease-specific fashion, physical limitations, symptoms, quality of life, social interference and self-efficacy. KCCQ provides the calculation of 2 main scores, the overall score and the clinical summary score, which includes functional status, social limitation and quality of life domains scores. Range 0-100, higher scores represent higher HRQOL.</description>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="44"/>
                <count group_id="O2" value="46"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="57.35" spread="28.59"/>
                    <measurement group_id="O2" value="68.67" spread="22.55"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>life of the study mean 35 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Spironolactone</title>
          <description>Patients randomized to active therapy with spironolactone&#xD;
spironolactone: aldosterone blocker</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>patients randomized to placebo&#xD;
placebo: identical in appearance to spironolactone study drug</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="46"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="39" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="37" subjects_at_risk="46"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>hospitalization</sub_title>
                <description>hospitalization for any cause</description>
                <counts group_id="E1" subjects_affected="38" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="35" subjects_at_risk="46"/>
              </event>
              <event>
                <sub_title>death</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="46"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>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="44" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="46" subjects_at_risk="46"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>congestive heart failure</sub_title>
                <counts group_id="E1" subjects_affected="34" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="33" subjects_at_risk="46"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Gynecomastia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="46"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Any gastrointestinal issue</sub_title>
                <counts group_id="E1" subjects_affected="25" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="22" subjects_at_risk="46"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Prerenal azotemia</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="44"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="46"/>
              </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>
    <limitations_and_caveats>A limitation of this study was its small sample size. If a 35% relative risk reduction in the primary end point were assumed, the sample size of this trial would have given it 76% power with a type I error rate of 0.05.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Merritt Raitt MD</name_or_title>
      <organization>VA Portland Health Care System</organization>
      <phone>503-220-8262 ext 57571</phone>
      <email>merritt.raitt@va.gov</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04495712
org study id: ICDAD-1
secondary id: VA 02-2704
nct id: NCT04495712
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This study will test whether spironolactone, an approved drug for among other things
      hypertension, will reduce the risk of severe arrhythmias in patients with implanted
      defibrillators. Half the patients in the study will get spironolactone and half will get a
      placebo. Neither the patients or their providers will know if they are getting spironolactone
      or placebo.
Objectives: This study is designed to determine whether spironolactone at a dose of 25 mg per
      day in patients with implanted cardioverter defibrillators (ICD) will 1) Reduce the incidence
      of ventricular tachycardia (VT) and ventricular fibrillation (VF), 2) Improve health related
      quality of life, 3) Reduce the need for hospitalization, and 4) Change ventricular
      refractoriness.

      Plan: The study was a randomized double blind placebo controlled multi-center trial. Patients
      were randomized to either 25 mg per day of spironolactone or placebo and followed for 2 years
      each. The primary endpoint is time to the first episode of VT/VF. Secondary endpoints will
      include changes in health related quality of life, frequency of hospitalization, and in a
      subset of patients the effect of spironolactone on the ventricular effective refractory
      period measured through the ICD 3 months after starting the study medication. All data
      analyses will be conducted on intent to treat basis.

      Methods: Patients were recruited at the Portland VA ICD clinics, the Seattle VA ICD clinics,
      Oregon Health and Sciences University ICD clinics and the Little Rock, Arkansas VA ICD
      clinics. Randomization and drug preparation were done by the Portland VA Medical Center
      research pharmacy. For safety purposes serum potassium will be measured at 1, 2, 3, 6, 12,
      18, and 24 months. Patients will undergo ICD interrogation to document the occurrence of ICD
      therapy for VT or VF and will be screened for potential drug side effects every 3 months
      during the study. Health related quality of life will be measured at baseline, 3, 6, 12, 18,
      and 24 months using Short Form Health Survey adapted for veterans (SF36V) Veterans Health
      Study Version, the Patients Concerns Assessment, and the Kansas City Cardiomyopathy
      Questionnaire. Hospitalizations will be tracked throughout the study. In the subset of
      patient enrolled at the Portland VA the ventricular effective refractory period will be
      measured via single extra stimuli pacing through the ICD at 3 months after randomization.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: This was a prospective, double-blind, randomized trial that assigned patients to receive either spironolactone 25 mg/day or a placebo.
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: All participants, providers, investigators, and outcome assessors were blinded to treatment assignment. The pharmacy maintained a key to randomization that was not broken until the study was completed and all outcomes had been assessed.
measure: Time to First Appropriate Implantable Cardioverter Defibrillator (ICD) Therapy
time frame: through study completion, an average of 35 months
description: Time to first documented ICD therapy for ventricular tachycardia or ventricular fibrillation after randomization
measure: All Cause Hospitalization
time frame: through study completion, an average of 35 months
description: Number of patients hospitalized for any reason during study follow-up.
measure: Ventricular Refractoriness
time frame: measured 3 months after randomization
description: The right ventricular effective refractory period (ERP) will be measured at 3 month in patients enrolled at the Portland VA Medical Center by single extra stimuli via their implanted defibrillator. The ERP is defined as the shortest paced beat coupling interval that fails to produce ventricular capture after a baseline stable pacing train.
measure: Short Form Health Survey Adapted for Veterans (SF36V)
time frame: 12 months after enrollment
description: Short Form Health Survey adapted for veterans (SF36V) is a 36 item questionnaire that measures general physical and mental health [17]. The SF36V is a reliable and valid questionnaire, containing eight constructs of health status: physical functioning (PF), role limitations due to physical problems (RP), bodily pain (BP), general health perceptions (GH), energy/vitality (VT), social functioning (SF), role limitations due to emotional problems (RE), and mental health (MH). These eight dimensions can be summarized numerically into two scores, the physical component summary (PCS) and the mental component summary (MCS). Range 0-100 higher score is better Health Related Quality of Life (HRQOL). We are reporting the Mental Component Summary score at 12 months here.
measure: Patient Concerns Assessment (PCA)
time frame: 12 months
description: Patient Concerns Assessment (PCA) is a symptom checklist that measures physical symptoms and fears that are common after ICD implantation. The PCA is a disease-specific instrument for ICD QOL, symptoms, and distress, with a reliability of ( = 0.88). Range 0-44, a higher score reflects more concerns and fears.
measure: Kansas City Cardiomyopathy Questionnaire (KCCQ)
time frame: through study completion, an average of 35 months
description: Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item reliable and valid questionnaire, which evaluates HRQOL in heart failure. It quantifies, in a disease-specific fashion, physical limitations, symptoms, quality of life, social interference and self-efficacy. KCCQ provides the calculation of 2 main scores, the overall score and the clinical summary score, which includes functional status, social limitation and quality of life domains scores. Range 0-100, higher scores represent higher HRQOL.
arm group label: Spironolactone
arm group type: Active Comparator
description: Patients randomized to active therapy with spironolactone
arm group label: placebo
arm group type: Placebo Comparator
description: patients randomized to placebo
intervention type: Drug
intervention name: spironolactone
description: aldosterone blocker
arm group label: Spironolactone
other name: Aldactone
intervention type: Drug
intervention name: placebo
description: identical in appearance to spironolactone study drug
arm group label: placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Merritt Raitt, MD
role: Principal Investigator
affiliation: VA Portland Health Care System, Portland, OR
facility: 
country: United States
citation: Zarraga IG, Dougherty CM, MacMurdy KS, Raitt MH. The effect of spironolactone on ventricular tachyarrhythmias in patients with implantable cardioverter-defibrillators. Circ Arrhythm Electrophysiol. 2012 Aug 1;5(4):739-47. doi: 10.1161/CIRCEP.112.970566. Epub 2012 Jul 7.
PMID: 22773022
responsible party type: Sponsor
mesh term: Arrhythmias, Cardiac
mesh term: Spironolactone
sharing ipd: No
ipd description: Patients did not give permission for data sharing
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: A limitation of this study was its small sample size. If a 35% relative risk reduction in the primary end point were assumed, the sample size of this trial would have given it 76% power with a type I error rate of 0.05.
point of contact: 