<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/NCT04458285</url>
  </required_header>
  <id_info>
    <org_study_id>20191025</org_study_id>
    <nct_id>NCT04458285</nct_id>
  </id_info>
  <brief_title>Efficacy and Safety of Sacubitril/Valsartan in Maintenance Hemodialysis Patients With Heart Failure</brief_title>
  <acronym>ESARHD-HF</acronym>
  <official_title>A Multi-center, Randomized, Open-label, Active-controlled, 12-week Study to Evaluate the Efficacy and Safety of Sacubitril/Valsartan in Maintenance Hemodialysis Patients With Heart Failure</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Guangdong Provincial People's Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Guangdong Provincial People's Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Sacubitril/valsartan reduces the risk of cardiovascular mortality among patients with heart&#xD;
      failure with reduced ejection fraction, and has been recently indicated as a new treatment&#xD;
      option with a strong level of recommendation (class I, level of evidence B) in the main&#xD;
      international guidelines. Cardiovascular disease (CVD) is the most common cause of death in&#xD;
      end stage renal disease (ESRD) patients undergoing hemodialysis (HD). Hence, treatments to&#xD;
      improve mortality and specifically cardiovascular outcomes in this population are greatly&#xD;
      needed. So far, no data available about the efficacy and safety of sacubitril/valsartan in&#xD;
      ESRD patients undergoing hemodialysis, although this medication was noted to be effective and&#xD;
      comparably well tolerable in those with estimated glomerular filtration rate(eGFR) 20 to 60&#xD;
      mL/min/1.73 m2 in the United Kingdom Heart and Renal Protection-III trial.&#xD;
&#xD;
      The purpose of this open label, randomized controlled study with prospective data collection&#xD;
      is to assess the efficacy and safety of sacubitril/valsartan in maintenance hemodialysis&#xD;
      patients with heart failure.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">January 1, 2020</start_date>
  <completion_date type="Anticipated">December 31, 2020</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Left ventricular ejection fraction (LVEF)</measure>
    <time_frame>12 weeks</time_frame>
    <description>Change from baseline in left ventricular ejection fraction (LVEF) between baseline and end of study</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>N terminal pro B type natriuretic peptide (NT-prpBNP)</measure>
    <time_frame>12 weeks</time_frame>
    <description>Blood samples will be collected for analysis of concentration of N terminal pro B type natriuretic peptide (NT-proBNP) every 2 weeks.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Left ventricular end diastolic volume (LVEDV)</measure>
    <time_frame>12 weeks</time_frame>
    <description>LVEDV is measured as baseline and after 12 weeks follow-up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Left atrial volume (LAV)</measure>
    <time_frame>12 weeks</time_frame>
    <description>LAV is measured as baseline and after 12 weeks follow-up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The ratio of mitral early diastolic blood flow peak and mitral annulus velocity (E/E')</measure>
    <time_frame>12 weeks</time_frame>
    <description>E/E' is measured as baseline and after 12 weeks follow-up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pulmonary Artery Pressure</measure>
    <time_frame>12 weeks</time_frame>
    <description>Pulmonary Artery Pressure is measured as baseline and after 12 weeks follow-up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Concentration of high-sensitivity serum troponin T</measure>
    <time_frame>12 weeks</time_frame>
    <description>Blood samples will be collected for analysis of concentration of serum troponin every 4 weeks.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>NYHA functional classification</measure>
    <time_frame>12 weeks</time_frame>
    <description>NYHA functional classification is assessed from baseline and 12 weeks follow-up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Minnesota Heart Failure Quality of Life Questionnaire (LiHFe)</measure>
    <time_frame>12 weeks</time_frame>
    <description>Change in health status is assessed using the disease-specific Minnesota Heart Failure Quality of Life Questionnaire.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Systolic and diastolic blood pressure</measure>
    <time_frame>12 weeks</time_frame>
    <description>Systolic and diastolic blood pressure will be measured every 2 weeks.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Concentration of postassium</measure>
    <time_frame>12 weeks</time_frame>
    <description>Blood samples will be collected for analysis of concentration of postassium every 2 weeks.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Electrocardiogram(ECG)</measure>
    <time_frame>12 weeks</time_frame>
    <description>ECG QT Interval analysis was performed at baseline and 12 weeks follow-up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Estimated glomerular filtration rate(eGFR)</measure>
    <time_frame>12 weeks</time_frame>
    <description>Change in estimated glomerular filtration rate(eGFR)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Angioedema</measure>
    <time_frame>12 weeks</time_frame>
    <description>Incidence of Angioedema during the study period 12 weeks.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Concentration of alanine aminotransferase or aspartate aminotransferase</measure>
    <time_frame>12 weeks</time_frame>
    <description>Blood samples will be collected for analysis of concentration of alanine aminotransferase or aspartate aminotransferase every 2 weeks.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Neprilysin</measure>
    <time_frame>12 weeks</time_frame>
    <description>The concentration of Neprilysis is measured by Human Neprilysin ELISA Kit as baseline and after 12 weeks follow-up.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">118</enrollment>
  <condition>Hemodialysis Complication</condition>
  <condition>Heart Failure</condition>
  <arm_group>
    <arm_group_label>Sacubitril/valsartan</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients in experimental group will receive sacubitril/valsartan with the recommended starting dose: 50mg twice daily (if previous angiotensin converting enzyme inhibitor(ACEI), ensure 36-hour washout period), after 2-4 weeks, the dose will be doubled to the target maintenance dose of 100mg twice daily(if tolerated) for 12 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Valsartan</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients in active comparator group will receive Valsartan with an dose of 80 mg once daily.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sacubitril / Valsartan Oral Tablet [Entresto]</intervention_name>
    <description>Patients in experimental group will receive sacubitril/valsartan with the recommended starting dose: 50mg twice daily (if previous ACEI, ensure 36-hour washout period), after 2-4 weeks, the dose will be doubled to the target maintenance dose of 100mg twice daily(if tolerated) for 12 weeks.</description>
    <arm_group_label>Sacubitril/valsartan</arm_group_label>
    <other_name>LCZ696 100 mg tablet</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Valsartan 80mg Tablet</intervention_name>
    <description>Patients in active comparator group will receive Valsartan with an dose of 80 mg once daily.</description>
    <arm_group_label>Valsartan</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Written informed consent obtained before any study assessment is performed.&#xD;
&#xD;
          -  End stage renal disease (ESRD) patients (eGFR&lt;15ml/min/1.73m² as measured by the&#xD;
             Chronic Kidney Disease Epidemiology Collaboration formula at screening) who have been&#xD;
             receiving hemodialysis 3 times a week for at least 12 weeks before registration.&#xD;
&#xD;
          -  Chronic heart failure (NYHA class ≥ II) with reduced ejection fraction, defined as&#xD;
             known LVEF ≤ 50%.&#xD;
&#xD;
          -  Mean sitting systolic blood pressure(msSBP)≥110 mmHg.&#xD;
&#xD;
          -  Use of angiotensin-converting enzyme inhibitors/angiotensin receptor blocker for at&#xD;
             least 2 weeks.&#xD;
&#xD;
          -  Good compliance.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Acute renal failure with hemodialysis.&#xD;
&#xD;
          -  Isolated right heart failure owing to pulmonary disease, primary cause of dyspnea due&#xD;
             to noncardiac, non-HF causes such as acute or chronic respiratory disorders.&#xD;
&#xD;
          -  Systolic blood pressure lower than 100 mmHg at screening (&lt;95 mmHg at the&#xD;
             randomization visit).&#xD;
&#xD;
          -  Previous history of intolerance to recommended target doses of angiotensin receptor&#xD;
             blockers.&#xD;
&#xD;
          -  Significant laboratory abnormalities at screening interfering with assessment of study&#xD;
             drug safety or efficacy (such as serum potassium&gt;5.5 or &lt;3.5mmol/L, serum&#xD;
             sodium&lt;130mmol/L or alanine aminotransferase or aspartate aminotransferase&gt;2 times the&#xD;
             upper limit of the normal range)&#xD;
&#xD;
          -  History of hypersensitivity to any of the study drugs or their excipients or to drugs&#xD;
             of similar chemical classes.&#xD;
&#xD;
          -  History of angioedema.&#xD;
&#xD;
          -  Any medications that have potential for drug-drug interaction with LCZ696 will not be&#xD;
             allowed during the study.&#xD;
&#xD;
          -  Pregnant female.&#xD;
&#xD;
          -  Use of sacubitril/valsartan prior to week-2.&#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>Shuangxin Liu, Doctor</last_name>
    <role>Principal Investigator</role>
    <affiliation>Guangdong Provincial People's Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Faye Jiang, Doctor</last_name>
    <phone>(+86)020-83525210</phone>
    <email>gdphgcp@gdph.org.cn</email>
  </overall_contact>
  <location>
    <facility>
      <name>Guangdong Provincial People's Hospital</name>
      <address>
        <city>Guangzhou</city>
        <state>Guangdong</state>
        <zip>510080</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Shuangxin Liu, Doctor</last_name>
      <phone>(+86)13543456446</phone>
      <email>13543456446@139.com</email>
    </contact>
    <investigator>
      <last_name>Shuangxin Liu, Doctor</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Li Zhang, Doctor</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Zhonglin Feng, Master</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Sijia Li, Master</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Zhuo Li, Master</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Feng Wen, Doctor</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Lei Fu, Master</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Jianchao Ma, Doctor</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <reference>
    <citation>McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077. Epub 2014 Aug 30.</citation>
    <PMID>25176015</PMID>
  </reference>
  <reference>
    <citation>Haynes R, Judge PK, Staplin N, Herrington WG, Storey BC, Bethel A, Bowman L, Brunskill N, Cockwell P, Hill M, Kalra PA, McMurray JJV, Taal M, Wheeler DC, Landray MJ, Baigent C. Effects of Sacubitril/Valsartan Versus Irbesartan in Patients With Chronic Kidney Disease. Circulation. 2018 Oct 9;138(15):1505-1514. doi: 10.1161/CIRCULATIONAHA.118.034818.</citation>
    <PMID>30002098</PMID>
  </reference>
  <reference>
    <citation>Velazquez EJ, Morrow DA, DeVore AD, Duffy CI, Ambrosy AP, McCague K, Rocha R, Braunwald E; PIONEER-HF Investigators. Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure. N Engl J Med. 2019 Feb 7;380(6):539-548. doi: 10.1056/NEJMoa1812851. Epub 2018 Nov 11. Erratum In: N Engl J Med. 2019 Mar 14;380(11):1090.</citation>
    <PMID>30415601</PMID>
  </reference>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>June 26, 2020</study_first_submitted>
  <study_first_submitted_qc>July 2, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 7, 2020</study_first_posted>
  <last_update_submitted>October 4, 2020</last_update_submitted>
  <last_update_submitted_qc>October 4, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 6, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Guangdong Provincial People's Hospital</investigator_affiliation>
    <investigator_full_name>ShuangXin Liu</investigator_full_name>
    <investigator_title>Chief Physician</investigator_title>
  </responsible_party>
  <keyword>Sacubitril/valsartan</keyword>
  <keyword>valsartan</keyword>
  <keyword>Hemodialysis</keyword>
  <keyword>Heart failure</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Valsartan</mesh_term>
    <mesh_term>Sacubitril and valsartan sodium hydrate drug combination</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT04458285
org study id: 20191025
nct id: NCT04458285
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Sacubitril/valsartan reduces the risk of cardiovascular mortality among patients with heart
      failure with reduced ejection fraction, and has been recently indicated as a new treatment
      option with a strong level of recommendation (class I, level of evidence B) in the main
      international guidelines. Cardiovascular disease (CVD) is the most common cause of death in
      end stage renal disease (ESRD) patients undergoing hemodialysis (HD). Hence, treatments to
      improve mortality and specifically cardiovascular outcomes in this population are greatly
      needed. So far, no data available about the efficacy and safety of sacubitril/valsartan in
      ESRD patients undergoing hemodialysis, although this medication was noted to be effective and
      comparably well tolerable in those with estimated glomerular filtration rate(eGFR) 20 to 60
      mL/min/1.73 m2 in the United Kingdom Heart and Renal Protection-III trial.

      The purpose of this open label, randomized controlled study with prospective data collection
      is to assess the efficacy and safety of sacubitril/valsartan in maintenance hemodialysis
      patients with heart failure.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Left ventricular ejection fraction (LVEF)
time frame: 12 weeks
description: Change from baseline in left ventricular ejection fraction (LVEF) between baseline and end of study
measure: N terminal pro B type natriuretic peptide (NT-prpBNP)
time frame: 12 weeks
description: Blood samples will be collected for analysis of concentration of N terminal pro B type natriuretic peptide (NT-proBNP) every 2 weeks.
measure: Left ventricular end diastolic volume (LVEDV)
time frame: 12 weeks
description: LVEDV is measured as baseline and after 12 weeks follow-up.
measure: Left atrial volume (LAV)
time frame: 12 weeks
description: LAV is measured as baseline and after 12 weeks follow-up.
measure: The ratio of mitral early diastolic blood flow peak and mitral annulus velocity (E/E')
time frame: 12 weeks
description: E/E' is measured as baseline and after 12 weeks follow-up.
measure: Pulmonary Artery Pressure
time frame: 12 weeks
description: Pulmonary Artery Pressure is measured as baseline and after 12 weeks follow-up.
measure: Concentration of high-sensitivity serum troponin T
time frame: 12 weeks
description: Blood samples will be collected for analysis of concentration of serum troponin every 4 weeks.
measure: NYHA functional classification
time frame: 12 weeks
description: NYHA functional classification is assessed from baseline and 12 weeks follow-up.
measure: Minnesota Heart Failure Quality of Life Questionnaire (LiHFe)
time frame: 12 weeks
description: Change in health status is assessed using the disease-specific Minnesota Heart Failure Quality of Life Questionnaire.
measure: Systolic and diastolic blood pressure
time frame: 12 weeks
description: Systolic and diastolic blood pressure will be measured every 2 weeks.
measure: Concentration of postassium
time frame: 12 weeks
description: Blood samples will be collected for analysis of concentration of postassium every 2 weeks.
measure: Electrocardiogram(ECG)
time frame: 12 weeks
description: ECG QT Interval analysis was performed at baseline and 12 weeks follow-up.
measure: Estimated glomerular filtration rate(eGFR)
time frame: 12 weeks
description: Change in estimated glomerular filtration rate(eGFR)
measure: Incidence of Angioedema
time frame: 12 weeks
description: Incidence of Angioedema during the study period 12 weeks.
measure: Concentration of alanine aminotransferase or aspartate aminotransferase
time frame: 12 weeks
description: Blood samples will be collected for analysis of concentration of alanine aminotransferase or aspartate aminotransferase every 2 weeks.
measure: Neprilysin
time frame: 12 weeks
description: The concentration of Neprilysis is measured by Human Neprilysin ELISA Kit as baseline and after 12 weeks follow-up.
arm group label: Sacubitril/valsartan
arm group type: Experimental
description: Patients in experimental group will receive sacubitril/valsartan with the recommended starting dose: 50mg twice daily (if previous angiotensin converting enzyme inhibitor(ACEI), ensure 36-hour washout period), after 2-4 weeks, the dose will be doubled to the target maintenance dose of 100mg twice daily(if tolerated) for 12 weeks.
arm group label: Valsartan
arm group type: Active Comparator
description: Patients in active comparator group will receive Valsartan with an dose of 80 mg once daily.
intervention type: Drug
intervention name: Sacubitril / Valsartan Oral Tablet [Entresto]
description: Patients in experimental group will receive sacubitril/valsartan with the recommended starting dose: 50mg twice daily (if previous ACEI, ensure 36-hour washout period), after 2-4 weeks, the dose will be doubled to the target maintenance dose of 100mg twice daily(if tolerated) for 12 weeks.
arm group label: Sacubitril/valsartan
other name: LCZ696 100 mg tablet
intervention type: Drug
intervention name: Valsartan 80mg Tablet
description: Patients in active comparator group will receive Valsartan with an dose of 80 mg once daily.
arm group label: Valsartan
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Shuangxin Liu, Doctor
role: Principal Investigator
affiliation: Guangdong Provincial People's Hospital
last name: Faye Jiang, Doctor
phone: (+86)020-83525210
email: gdphgcp@gdph.org.cn
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
country: China
citation: McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077. Epub 2014 Aug 30.
PMID: 25176015
citation: Haynes R, Judge PK, Staplin N, Herrington WG, Storey BC, Bethel A, Bowman L, Brunskill N, Cockwell P, Hill M, Kalra PA, McMurray JJV, Taal M, Wheeler DC, Landray MJ, Baigent C. Effects of Sacubitril/Valsartan Versus Irbesartan in Patients With Chronic Kidney Disease. Circulation. 2018 Oct 9;138(15):1505-1514. doi: 10.1161/CIRCULATIONAHA.118.034818.
PMID: 30002098
citation: Velazquez EJ, Morrow DA, DeVore AD, Duffy CI, Ambrosy AP, McCague K, Rocha R, Braunwald E; PIONEER-HF Investigators. Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure. N Engl J Med. 2019 Feb 7;380(6):539-548. doi: 10.1056/NEJMoa1812851. Epub 2018 Nov 11. Erratum In: N Engl J Med. 2019 Mar 14;380(11):1090.
PMID: 30415601
responsible party type: Principal Investigator
investigator affiliation: Guangdong Provincial People's Hospital
investigator full name: ShuangXin Liu
investigator title: Chief Physician
mesh term: Heart Failure
mesh term: Valsartan
mesh term: Sacubitril and valsartan sodium hydrate drug combination
sharing ipd: No