<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/NCT02970669</url>
  </required_header>
  <id_info>
    <org_study_id>CLCZ696BUS14</org_study_id>
    <nct_id>NCT02970669</nct_id>
  </id_info>
  <brief_title>Study on the Effects of Sacubitril/Valsartan on Physical Activity and Sleep in Heart Failure With Reduced Ejection Fraction Patients.</brief_title>
  <acronym>AWAKE-HF</acronym>
  <official_title>Multicenter, Randomized, Double-blind, Double Dummy, Parallel Group, Active-controlled 8-week Study and 8-week Open Label Extension to Evaluate the Effect of Initiation of Sacubitril/Valsartan on Objective Measures of Waking Activity and Sleep, as Health-related Quality of Life Functions in Subjects With Heart Failure and Reduced Ejection Fraction (AWAKE-HF).</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Novartis</source>
  <brief_summary>
    <textblock>
      The purpose of this study was to investigate the effects of initiation of&#xD;
      sacubitril/valsartan vs enalapril treatment on objective measures of both waking activity and&#xD;
      sleep in subjects with heart failure with reduced ejection fraction.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 16, 2016</start_date>
  <completion_date type="Actual">March 19, 2018</completion_date>
  <primary_completion_date type="Actual">March 19, 2018</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>Yes</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Ratio of Mean Activity Counts Collected During the Most Active 30 Minutes of the Subject's Day Between Week 8 and Baseline</measure>
    <time_frame>Baseline, week 8</time_frame>
    <description>The primary endpoint is the ratio in mean activity counts collected during the most active 30 minutes of the subject's day between the final randomized treatment phase measurement (mean of endpoint data collected each day during week 8) and baseline phase (mean of endpoint data collected each day during week -1), as measured by wrist-worn accelerometer collected actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day). A ratio &gt; 1 indicates an increase in mean activity counts from baseline to week 8.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 1</measure>
    <time_frame>Baseline, Week 1</time_frame>
    <description>Change in mean activity counts during most active 30 minutes of day from baseline phase (mean of data collected during week -1) to week 1 (mean of data collected during week 1), as measured by actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 9 and 16</measure>
    <time_frame>Baseline (Sacubitril/Valsartan: week -1/ Enalapril: week 8), week 9 and 16</time_frame>
    <description>Change in mean activity counts during most active 30 minutes of day from baseline phase (mean of data collected during week -1 for Sacubitril/Valsartan and mean of data collected during week 8 for Enalapril) to week 9 and 16 (mean of data collected during weeks 9 and 16), as measured by actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 8</measure>
    <time_frame>Baseline, Week 8</time_frame>
    <description>Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1) to the final randomized treatment phase measurement (mean of data collected during week 8), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 1</measure>
    <time_frame>Baseline, Week 1</time_frame>
    <description>Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1) to week 1 (mean of data collected during week 1), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 9 and 16</measure>
    <time_frame>Baseline (Sacubitril/Valsartan: week -1 / Enalapril: week 8), week 9 and 16</time_frame>
    <description>Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1 for Sacubitril/Valsartan and mean of data collected during week 8 for Enalapril) to week 9 and 16 (mean of data collected during week 9 and 16), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">140</enrollment>
  <condition>Heart Failure, Reduced Ejection Fraction</condition>
  <arm_group>
    <arm_group_label>Enalapril</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Double blind treatment epoch: Patients randomized to this arm received 1 tablet of enalapril and 1 tablet of matching placebo sacubitril/valsartan twice daily for 8 weeks. All Patients began the study on Dose Level 1 (i.e. 2.5 mg enalapril BID). Patients may have been sequentially up-titrated to achieve desired dose of Dose Level 3 (i.e. 10 mg enalapril BID). Patients not tolerating dose escalation could have been titrated down to next lower dose level.&#xD;
Open-label treatment epoch: All patients entering this epoch (8 weeks) were given sacubitril/valsartan 49/51 mg BID (Dose Level 2) unless they completed the double-blind treatment epoch on enalapril Dose Level 1. Instead, these patients entered open-label epoch on Dose Level 1 of sacubitril/valsartan. Patients may have been sequentially up-titrated to achieve desired dose of Dose Level 3 of sacubitril/valsartan. Patients not tolerating dose escalation could have been titrated down to next lower dose level.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sacubitril/Valsartan</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Double blind treatment epoch: Patients randomized to this arm received 1 tablet of sacubitril/valsartan and 1 tablet of matching placebo enalapril twice daily for 8 weeks. All Patients began the study on Dose Level 1 (i.e. 24/26 mg sacubitril/valsartan BID). Patients may have sequentially been up-titrated to achieve desired dose of Dose Level 3 (i.e. 97/103 mg sacubitril/valsartan BID). Patients not tolerating dose escalation could have been titrated down to next lower dose level.&#xD;
Open-label treatment epoch: All patients entering this epoch (8 weeks) were given sacubitril/valsartan 49/51 mg BID (Dose Level 2) unless they completed the double-blind treatment epoch on Dose Level 1. Instead, these patients entered open-label epoch on Dose Level 1. Patients may sequentially have been up-titrated to achieve desired dose of Dose Level 3. Patients not tolerating dose escalation could have been titrated down to next lower dose level.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>sacubitril/valsartan (LCZ696)</intervention_name>
    <description>sacubitril/valsartan tablet taken orally.</description>
    <arm_group_label>Enalapril</arm_group_label>
    <arm_group_label>Sacubitril/Valsartan</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>enalapril</intervention_name>
    <description>Enalapril tablet taken orally.</description>
    <arm_group_label>Enalapril</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>matching placebo sacubitril/valsartan (LCZ696)</intervention_name>
    <description>matching placebo sacubitril/valsartan tablet taken orally</description>
    <arm_group_label>Enalapril</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>matching placebo enalapril</intervention_name>
    <description>matching placebo enalapril tablet taken orally</description>
    <arm_group_label>Sacubitril/Valsartan</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Key Inclusion Criteria:&#xD;
&#xD;
          -  Written informed consent must be obtained before any assessment is performed.&#xD;
&#xD;
          -  Men and women between 18 and 80 years of age&#xD;
&#xD;
          -  Subjects diagnosed with NYHA class II or III heart failure and with reduced ejection&#xD;
             (HFrEF).&#xD;
&#xD;
        (Reduced ejection is defined as left ventricular EF ≤ 40%. LVEF ≤40% may be determined via&#xD;
        any local measurement within the past 6 months prior to signing consent, using&#xD;
        echocardiography, multi gated acquisition scan (MUGA), CT scanning, MRI or ventricular&#xD;
        angiography provided no subsequent study documenting an EF of &gt;40%. If the EF measurement&#xD;
        is expressed as a value range, the average of the range endpoint values should be used as&#xD;
        the EF).&#xD;
&#xD;
          -  Subjects must be a candidate for treatment with sacubitril/valsartan as per USPI.&#xD;
&#xD;
          -  Subjects must be living in a traditional residence, apartment, or non-communal adult&#xD;
             home where they can move about freely and frequently and are primarily responsible for&#xD;
             scheduling their sleep and daily activities.&#xD;
&#xD;
        Key Exclusion Criteria:&#xD;
&#xD;
          -  Subjects with a history of hypersensitivity to any of the study drugs, including&#xD;
             history of hypersensitivity to drugs of similar chemical classes, or allergy to ACEIs,&#xD;
             ARBs, or NEP inhibitors as well as known or suspected contraindications to the study&#xD;
             drugs.&#xD;
&#xD;
          -  Subjects with a history of angioedema drug related or otherwise&#xD;
&#xD;
          -  Subjects with symptomatic hypotension or systolic blood pressure &lt;100 mmHg at&#xD;
             screening or &lt;95 mmHg at randomization&#xD;
&#xD;
          -  Subjects with any conditions in skin or upper extremities which would limit the&#xD;
             ability to tolerate a wrist-worn actigraphy device on the non-dominant arm for 24&#xD;
             hours/day for the duration of the study.&#xD;
&#xD;
          -  Subjects who are non-ambulatory or use mobility assistive devices such as motorized&#xD;
             devices, wheelchairs, or walkers. The use of canes for stability while ambulating is&#xD;
             acceptable.&#xD;
&#xD;
          -  Subjects with physical activity impairment primarily due to conditions other than&#xD;
             heart failure such as:&#xD;
&#xD;
          -  Exertional angina inflammatory or degenerative joint disease -gout&#xD;
&#xD;
          -  peripheral vascular disease&#xD;
&#xD;
          -  neurologic disease affecting activity or mobility&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Novartis Pharmaceuticals</last_name>
    <role>Study Director</role>
    <affiliation>Novartis Pharmaceuticals</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Fort Payne</city>
        <state>Alabama</state>
        <zip>35967</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Beverly Hills</city>
        <state>California</state>
        <zip>90211</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Stockton</city>
        <state>California</state>
        <zip>95204</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>West Hills</city>
        <state>California</state>
        <zip>91307</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Doral</city>
        <state>Florida</state>
        <zip>33126</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Inverness</city>
        <state>Florida</state>
        <zip>34452</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Ormond Beach</city>
        <state>Florida</state>
        <zip>32174</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Port Orange</city>
        <state>Florida</state>
        <zip>32127</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Lutherville</city>
        <state>Maryland</state>
        <zip>21093</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>East Brunswick</city>
        <state>New Jersey</state>
        <zip>08816</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Ridgewood</city>
        <state>New Jersey</state>
        <zip>07450</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Columbia</city>
        <state>South Carolina</state>
        <zip>29203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Greenville</city>
        <state>South Carolina</state>
        <zip>29615</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Lancaster</city>
        <state>South Carolina</state>
        <zip>29720</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Allen</city>
        <state>Texas</state>
        <zip>75002-3688</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>McKinney</city>
        <state>Texas</state>
        <zip>75013</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>New Braunfels</city>
        <state>Texas</state>
        <zip>78130</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>San Marcos</city>
        <state>Texas</state>
        <zip>78666</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Sherman</city>
        <state>Texas</state>
        <zip>75092</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Tomball</city>
        <state>Texas</state>
        <zip>77375</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Midlothian</city>
        <state>Virginia</state>
        <zip>23114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Tacoma</city>
        <state>Washington</state>
        <zip>98405</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://www.novctrd.com/ctrdweb/patientsummary/patientsummaries?patientSummaryId=471</url>
    <description>A Plain Language Trial Summary is available on novartisclinicaltrials.com</description>
  </link>
  <verification_date>October 2021</verification_date>
  <study_first_submitted>November 17, 2016</study_first_submitted>
  <study_first_submitted_qc>November 17, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 22, 2016</study_first_posted>
  <results_first_submitted>March 14, 2019</results_first_submitted>
  <results_first_submitted_qc>March 14, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">April 8, 2019</results_first_posted>
  <last_update_submitted>October 6, 2021</last_update_submitted>
  <last_update_submitted_qc>October 6, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 7, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Heart failure with reduced left ventricular ejection fraction (LVEF)</keyword>
  <keyword>Cardiac dysfunction</keyword>
  <keyword>Heart muscle dysfunction</keyword>
  <keyword>Left ventricular (LV) dilation</keyword>
  <keyword>Left ventricular hypertrophy</keyword>
  <keyword>HF</keyword>
  <keyword>AHF</keyword>
  <keyword>CHF</keyword>
  <keyword>acute heart failure</keyword>
  <keyword>chronic heart failure</keyword>
  <keyword>congestive heart failure</keyword>
  <keyword>congestive cardiac failure</keyword>
  <keyword>Heart failure</keyword>
  <keyword>HReEF</keyword>
  <keyword>Physical Activity</keyword>
  <keyword>Actigraphy</keyword>
  <keyword>Home sleep test</keyword>
  <keyword>wake</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
    <mesh_term>Heart Failure, Systolic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Valsartan</mesh_term>
    <mesh_term>Enalapril</mesh_term>
    <mesh_term>Enalaprilat</mesh_term>
    <mesh_term>Sacubitril and valsartan sodium hydrate drug combination</mesh_term>
  </intervention_browse>
  <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 13, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/69/NCT02970669/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>April 10, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/69/NCT02970669/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>140 subjects from 23 sites in the US were randomized. The study consisted of a 2-week baseline period , followed by an 8-week double-blind treatment period ( randomized to sacubitril/valsartan or enalapril, in a 1:1 ratio), followed by an 8-week open label extension period during which all patients were treated with sacubitril/valsartan.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Enalapril</title>
          <description>Double blind treatment epoch: Patients randomized to this arm received 1 tablet of enalapril and 1 tablet of matching placebo sacubitril/valsartan twice daily for 8 weeks. All Patients began the study on Dose Level 1 (i.e. 2.5 mg enalapril BID). Patients may have been sequentially up-titrated to achieve desired dose of Dose Level 3 (i.e. 10 mg enalapril BID). Patients not tolerating dose escalation could have been titrated down to next lower dose level.&#xD;
Open-label treatment epoch: All patients entering this epoch (8 weeks) were given sacubitril/valsartan 49/51 mg BID (Dose Level 2) unless they completed the double-blind treatment epoch on enalapril Dose Level 1. Instead, these patients entered open-label epoch on Dose Level 1 of sacubitril/valsartan. Patients may have been sequentially up-titrated to achieve desired dose of Dose Level 3 of sacubitril/valsartan. Patients not tolerating dose escalation could have been titrated down to next lower dose level.</description>
        </group>
        <group group_id="P2">
          <title>Sacubitril/Valsartan</title>
          <description>Double blind treatment epoch: Patients randomized to this arm received 1 tablet of sacubitril/valsartan and 1 tablet of matching placebo enalapril twice daily for 8 weeks. All Patients began the study on Dose Level 1 (i.e. 24/26 mg sacubitril/valsartan BID). Patients may have sequentially been up-titrated to achieve desired dose of Dose Level 3 (i.e. 97/103 mg sacubitril/valsartan BID). Patients not tolerating dose escalation could have been titrated down to next lower dose level.&#xD;
Open-label treatment epoch: All patients entering this epoch (8 weeks) were given sacubitril/valsartan 49/51 mg BID (Dose Level 2) unless they completed the double-blind treatment epoch on Dose Level 1. Instead, these patients entered open-label epoch on Dose Level 1. Patients may sequentially have been up-titrated to achieve desired dose of Dose Level 3. Patients not tolerating dose escalation could have been titrated down to next lower dose level.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Double-blind Period</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="70"/>
                <participants group_id="P2" count="70"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="62"/>
                <participants group_id="P2" count="64"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Study terminated by sponsor</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <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="0"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Open-label Period</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="62"/>
                <participants group_id="P2" count="64"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="58"/>
                <participants group_id="P2" count="62"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Enalapril</title>
          <description>Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan</description>
        </group>
        <group group_id="B2">
          <title>Sacubitril/Valsartan</title>
          <description>Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan</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="70"/>
            <count group_id="B2" value="70"/>
            <count group_id="B3" value="140"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="64.2" lower_limit="26" upper_limit="81"/>
                    <measurement group_id="B2" value="62.3" lower_limit="45" upper_limit="80"/>
                    <measurement group_id="B3" value="63.3" lower_limit="26" upper_limit="81"/>
                  </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="14"/>
                    <measurement group_id="B2" value="18"/>
                    <measurement group_id="B3" value="32"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="56"/>
                    <measurement group_id="B2" value="52"/>
                    <measurement group_id="B3" value="108"/>
                  </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>
              <category_list>
                <category>
                  <title>Caucasian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="60"/>
                    <measurement group_id="B2" value="48"/>
                    <measurement group_id="B3" value="108"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="13"/>
                    <measurement group_id="B3" value="21"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Other</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Ratio of Mean Activity Counts Collected During the Most Active 30 Minutes of the Subject's Day Between Week 8 and Baseline</title>
        <description>The primary endpoint is the ratio in mean activity counts collected during the most active 30 minutes of the subject's day between the final randomized treatment phase measurement (mean of endpoint data collected each day during week 8) and baseline phase (mean of endpoint data collected each day during week -1), as measured by wrist-worn accelerometer collected actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day). A ratio &gt; 1 indicates an increase in mean activity counts from baseline to week 8.</description>
        <time_frame>Baseline, week 8</time_frame>
        <population>Full Analysis Set</population>
        <group_list>
          <group group_id="O1">
            <title>Enalapril</title>
            <description>Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan</description>
          </group>
          <group group_id="O2">
            <title>Sacubitril/Valsartan</title>
            <description>Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan</description>
          </group>
        </group_list>
        <measure>
          <title>Ratio of Mean Activity Counts Collected During the Most Active 30 Minutes of the Subject's Day Between Week 8 and Baseline</title>
          <description>The primary endpoint is the ratio in mean activity counts collected during the most active 30 minutes of the subject's day between the final randomized treatment phase measurement (mean of endpoint data collected each day during week 8) and baseline phase (mean of endpoint data collected each day during week -1), as measured by wrist-worn accelerometer collected actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day). A ratio &gt; 1 indicates an increase in mean activity counts from baseline to week 8.</description>
          <population>Full Analysis Set</population>
          <units>Ratio</units>
          <param>Geometric Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="60"/>
                <count group_id="O2" value="64"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.0411" lower_limit="0.9938" upper_limit="1.0906"/>
                    <measurement group_id="O2" value="0.9844" lower_limit="0.9411" upper_limit="1.0297"/>
                  </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>0.0895</p_value>
            <method>ANCOVA</method>
            <method_desc>model for a log-scaled response with treatment group as a class variable and the baseline value in logarithmic scale as a continuous covariate.</method_desc>
            <param_type>Ratio of Geometric Means (SacVal/Ena)</param_type>
            <param_value>0.9456</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.8863</ci_lower_limit>
            <ci_upper_limit>1.0088</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 1</title>
        <description>Change in mean activity counts during most active 30 minutes of day from baseline phase (mean of data collected during week -1) to week 1 (mean of data collected during week 1), as measured by actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day).</description>
        <time_frame>Baseline, Week 1</time_frame>
        <population>Full Analysis Set</population>
        <group_list>
          <group group_id="O1">
            <title>Enalapril</title>
            <description>Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan</description>
          </group>
          <group group_id="O2">
            <title>Sacubitril/Valsartan</title>
            <description>Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 1</title>
          <description>Change in mean activity counts during most active 30 minutes of day from baseline phase (mean of data collected during week -1) to week 1 (mean of data collected during week 1), as measured by actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day).</description>
          <population>Full Analysis Set</population>
          <units>counts</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="54"/>
                <count group_id="O2" value="59"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="171.3" spread="440.9"/>
                    <measurement group_id="O2" value="464.9" spread="421.8"/>
                  </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>0.6316</p_value>
            <method>ANCOVA</method>
            <method_desc>model with treatment group as a class variable and the baseline value as a continuous covariate.</method_desc>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>293.6</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-916.5</ci_lower_limit>
            <ci_upper_limit>1503.8</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 9 and 16</title>
        <description>Change in mean activity counts during most active 30 minutes of day from baseline phase (mean of data collected during week -1 for Sacubitril/Valsartan and mean of data collected during week 8 for Enalapril) to week 9 and 16 (mean of data collected during weeks 9 and 16), as measured by actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day).</description>
        <time_frame>Baseline (Sacubitril/Valsartan: week -1/ Enalapril: week 8), week 9 and 16</time_frame>
        <population>Full Analysis Set</population>
        <group_list>
          <group group_id="O1">
            <title>Enalapril</title>
            <description>Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan</description>
          </group>
          <group group_id="O2">
            <title>Sacubitril/Valsartan</title>
            <description>Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 9 and 16</title>
          <description>Change in mean activity counts during most active 30 minutes of day from baseline phase (mean of data collected during week -1 for Sacubitril/Valsartan and mean of data collected during week 8 for Enalapril) to week 9 and 16 (mean of data collected during weeks 9 and 16), as measured by actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day).</description>
          <population>Full Analysis Set</population>
          <units>counts</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="62"/>
                <count group_id="O2" value="64"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 9 (change from Baseline)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="54"/>
                    <count group_id="O2" value="58"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-198.8" spread="5245.5"/>
                    <measurement group_id="O2" value="-402.9" spread="5857.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 16 (change from Baseline)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="51"/>
                    <count group_id="O2" value="55"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-455.1" spread="4966.7"/>
                    <measurement group_id="O2" value="46.9" spread="4811.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 8</title>
        <description>Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1) to the final randomized treatment phase measurement (mean of data collected during week 8), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer).</description>
        <time_frame>Baseline, Week 8</time_frame>
        <population>Full Analysis Set</population>
        <group_list>
          <group group_id="O1">
            <title>Enalapril</title>
            <description>Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan</description>
          </group>
          <group group_id="O2">
            <title>Sacubitril/Valsartan</title>
            <description>Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 8</title>
          <description>Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1) to the final randomized treatment phase measurement (mean of data collected during week 8), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer).</description>
          <population>Full Analysis Set</population>
          <units>counts/minute</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="64"/>
                <count group_id="O2" value="65"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.339" spread="0.752"/>
                    <measurement group_id="O2" value="2.377" spread="0.746"/>
                  </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>0.0570</p_value>
            <method>ANCOVA</method>
            <method_desc>model with treatment group as a class variable and the baseline value as a continuous covariate.</method_desc>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>2.038</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.062</ci_lower_limit>
            <ci_upper_limit>4.138</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 1</title>
        <description>Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1) to week 1 (mean of data collected during week 1), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer).</description>
        <time_frame>Baseline, Week 1</time_frame>
        <population>Full Analysis Set</population>
        <group_list>
          <group group_id="O1">
            <title>Enalapril</title>
            <description>Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan</description>
          </group>
          <group group_id="O2">
            <title>Sacubitril/Valsartan</title>
            <description>Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 1</title>
          <description>Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1) to week 1 (mean of data collected during week 1), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer).</description>
          <population>Full Analysis Set</population>
          <units>counts/minute</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="59"/>
                <count group_id="O2" value="63"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.169" spread="0.696"/>
                    <measurement group_id="O2" value="2.647" spread="0.674"/>
                  </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>0.0121</p_value>
            <method>ANCOVA</method>
            <method_desc>model with treatment group as a class variable and the baseline value as a continuous covariate.</method_desc>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>2.478</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.553</ci_lower_limit>
            <ci_upper_limit>4.403</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 9 and 16</title>
        <description>Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1 for Sacubitril/Valsartan and mean of data collected during week 8 for Enalapril) to week 9 and 16 (mean of data collected during week 9 and 16), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer).</description>
        <time_frame>Baseline (Sacubitril/Valsartan: week -1 / Enalapril: week 8), week 9 and 16</time_frame>
        <population>Full Analysis Set</population>
        <group_list>
          <group group_id="O1">
            <title>Enalapril</title>
            <description>Double-blind Treatment Period (Week 1 - Week 8): Enalapril Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan</description>
          </group>
          <group group_id="O2">
            <title>Sacubitril/Valsartan</title>
            <description>Double-blind Treatment Period (Week 1 - Week 8): Sacubitril/Valsartan Open-label Treatment Period (Week 9 - Week 16): Sacubitril/Valsartan</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 9 and 16</title>
          <description>Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1 for Sacubitril/Valsartan and mean of data collected during week 8 for Enalapril) to week 9 and 16 (mean of data collected during week 9 and 16), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer).</description>
          <population>Full Analysis Set</population>
          <units>counts/minute</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="62"/>
                <count group_id="O2" value="64"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 9 (change from Baseline)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="52"/>
                    <count group_id="O2" value="56"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.158" spread="5.150"/>
                    <measurement group_id="O2" value="3.230" spread="7.269"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 16 (change from Baseline)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="56"/>
                    <count group_id="O2" value="60"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.066" spread="5.367"/>
                    <measurement group_id="O2" value="1.489" spread="5.642"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>8 weeks in Randomized Treatment Period (Week 1 - Week 8). 8 Weeks in Open-Label Extension Period (Week 9 - Week 16)</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Enalapril (Randomized Treatment Period)</title>
          <description>Week 1 to Week 8: Enalapril</description>
        </group>
        <group group_id="E2">
          <title>Sacubitril/Valsartan (Randomized Treatment Period)</title>
          <description>Week 1 to Week 8: Sacubitril/Valsartan</description>
        </group>
        <group group_id="E3">
          <title>Enalapril (Open-Label Extension Period)</title>
          <description>Week 9 - 16: Sacubitril/Valsartan</description>
        </group>
        <group group_id="E4">
          <title>Sacubitril/Valsartan (Open-Label Extension Period)</title>
          <description>Week 9 - 16: Sacubitril/Valsartan</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (20.1)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="64"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="64"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Angina pectoris</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="64"/>
              </event>
              <event>
                <sub_title>Cardiac failure congestive</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="64"/>
              </event>
              <event>
                <sub_title>Ischaemic cardiomyopathy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="64"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Complication associated with device</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="64"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="64"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="64"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="64"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="64"/>
              </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="1" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="64"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Cerebrovascular accident</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="64"/>
              </event>
              <event>
                <sub_title>Incoherent</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="64"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Acute respiratory failure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="64"/>
              </event>
              <event>
                <sub_title>Chronic obstructive pulmonary disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="64"/>
              </event>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="64"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Peripheral arterial occlusive disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="64"/>
              </event>
              <event>
                <sub_title>Peripheral coldness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="64"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (20.1)</default_vocab>
        <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="26" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="11" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="11" subjects_at_risk="64"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="64"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="64"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="5" subjects_at_risk="64"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="64"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="70"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="69"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="62"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="64"/>
              </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>The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Study Director</name_or_title>
      <organization>Novartis Pharmaceuticals</organization>
      <phone>862-778-8300</phone>
      <email>Novartis.email@novartis.com</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/NCT02970669
org study id: CLCZ696BUS14
nct id: NCT02970669
lead sponsor: 
The purpose of this study was to investigate the effects of initiation of
      sacubitril/valsartan vs enalapril treatment on objective measures of both waking activity and
      sleep in subjects with heart failure with reduced ejection fraction.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Other
masking: Double (Participant, Investigator)
measure: Ratio of Mean Activity Counts Collected During the Most Active 30 Minutes of the Subject's Day Between Week 8 and Baseline
time frame: Baseline, week 8
description: The primary endpoint is the ratio in mean activity counts collected during the most active 30 minutes of the subject's day between the final randomized treatment phase measurement (mean of endpoint data collected each day during week 8) and baseline phase (mean of endpoint data collected each day during week -1), as measured by wrist-worn accelerometer collected actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day). A ratio > 1 indicates an increase in mean activity counts from baseline to week 8.
measure: Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 1
time frame: Baseline, Week 1
description: Change in mean activity counts during most active 30 minutes of day from baseline phase (mean of data collected during week -1) to week 1 (mean of data collected during week 1), as measured by actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day).
measure: Change in Mean Activity Counts During Most Active 30 Minutes of Day From Baseline to Week 9 and 16
time frame: Baseline (Sacubitril/Valsartan: week -1/ Enalapril: week 8), week 9 and 16
description: Change in mean activity counts during most active 30 minutes of day from baseline phase (mean of data collected during week -1 for Sacubitril/Valsartan and mean of data collected during week 8 for Enalapril) to week 9 and 16 (mean of data collected during weeks 9 and 16), as measured by actigraphy (total counts per 30 min period collected during the most active 30 minutes of each day).
measure: Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 8
time frame: Baseline, Week 8
description: Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1) to the final randomized treatment phase measurement (mean of data collected during week 8), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer).
measure: Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 1
time frame: Baseline, Week 1
description: Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1) to week 1 (mean of data collected during week 1), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer).
measure: Change in Mean Activity (Counts Per Minute) During Sleep From Baseline to Week 9 and 16
time frame: Baseline (Sacubitril/Valsartan: week -1 / Enalapril: week 8), week 9 and 16
description: Change in mean activity (counts per minute) during sleep from baseline phase (mean of data collected during week -1 for Sacubitril/Valsartan and mean of data collected during week 8 for Enalapril) to week 9 and 16 (mean of data collected during week 9 and 16), as measured by actigraphy (activity counts per minute during daily sleep period, wrist-worn accelerometer).
arm group label: Enalapril
arm group type: Active Comparator
description: Double blind treatment epoch: Patients randomized to this arm received 1 tablet of enalapril and 1 tablet of matching placebo sacubitril/valsartan twice daily for 8 weeks. All Patients began the study on Dose Level 1 (i.e. 2.5 mg enalapril BID). Patients may have been sequentially up-titrated to achieve desired dose of Dose Level 3 (i.e. 10 mg enalapril BID). Patients not tolerating dose escalation could have been titrated down to next lower dose level.
Open-label treatment epoch: All patients entering this epoch (8 weeks) were given sacubitril/valsartan 49/51 mg BID (Dose Level 2) unless they completed the double-blind treatment epoch on enalapril Dose Level 1. Instead, these patients entered open-label epoch on Dose Level 1 of sacubitril/valsartan. Patients may have been sequentially up-titrated to achieve desired dose of Dose Level 3 of sacubitril/valsartan. Patients not tolerating dose escalation could have been titrated down to next lower dose level.
arm group label: Sacubitril/Valsartan
arm group type: Experimental
description: Double blind treatment epoch: Patients randomized to this arm received 1 tablet of sacubitril/valsartan and 1 tablet of matching placebo enalapril twice daily for 8 weeks. All Patients began the study on Dose Level 1 (i.e. 24/26 mg sacubitril/valsartan BID). Patients may have sequentially been up-titrated to achieve desired dose of Dose Level 3 (i.e. 97/103 mg sacubitril/valsartan BID). Patients not tolerating dose escalation could have been titrated down to next lower dose level.
Open-label treatment epoch: All patients entering this epoch (8 weeks) were given sacubitril/valsartan 49/51 mg BID (Dose Level 2) unless they completed the double-blind treatment epoch on Dose Level 1. Instead, these patients entered open-label epoch on Dose Level 1. Patients may sequentially have been up-titrated to achieve desired dose of Dose Level 3. Patients not tolerating dose escalation could have been titrated down to next lower dose level.
intervention type: Drug
intervention name: sacubitril/valsartan (LCZ696)
description: sacubitril/valsartan tablet taken orally.
arm group label: Enalapril
arm group label: Sacubitril/Valsartan
intervention type: Drug
intervention name: enalapril
description: Enalapril tablet taken orally.
arm group label: Enalapril
intervention type: Drug
intervention name: matching placebo sacubitril/valsartan (LCZ696)
description: matching placebo sacubitril/valsartan tablet taken orally
arm group label: Enalapril
intervention type: Drug
intervention name: matching placebo enalapril
description: matching placebo enalapril tablet taken orally
arm group label: Sacubitril/Valsartan
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Novartis Pharmaceuticals
role: Study Director
affiliation: Novartis Pharmaceuticals
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country: United States
url: https://www.novctrd.com/ctrdweb/patientsummary/patientsummaries?patientSummaryId=471
description: A Plain Language Trial Summary is available on novartisclinicaltrials.com
responsible party type: Sponsor
mesh term: Heart Failure
mesh term: Heart Failure, Systolic
mesh term: Valsartan
mesh term: Enalapril
mesh term: Enalaprilat
mesh term: Sacubitril and valsartan sodium hydrate drug combination
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 