<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/NCT04491136</url>
  </required_header>
  <id_info>
    <org_study_id>CLCZ696BCN04</org_study_id>
    <nct_id>NCT04491136</nct_id>
  </id_info>
  <brief_title>Effective Study of ARNI on Ventricular Arrhythmia in HFrEF Patients With ICD or CRT-D (RHYTHM)</brief_title>
  <acronym>RHYTHM</acronym>
  <official_title>A Multicenter, Interventional, Open-label and Single-arm Study to Investigate the Effect of ARNI on Ventricular Arrhythmia in HFrEF Patients With ICD or CRT-D</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Novartis</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to generate effectiveness data of ARNI, in the Chinese HFrEF&#xD;
      patients with implanted ICD or CRT-D. This will be a multicenter, interventional, open-label,&#xD;
      and prospective single-arm study to evaluate the effect of ARNI on VAs in approximately 219&#xD;
      HFrEF patients receiving ICD or CRT-D in China.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The rationale of this study is to compare the effect of ACEI/ARB with the effect of ARNI on&#xD;
      VA events for HFrEF patients with ICD or CRT-D, thus a multicenter, interventional,&#xD;
      open-label, and prospective single-arm study was considered.&#xD;
&#xD;
      Study design:This will be a multicenter, interventional, open-label, and prospective&#xD;
      single-arm study to evaluate the effect of ARNI on VAs in approximately 219 HFrEF patients&#xD;
      receiving ICD or CRT-D in China.&#xD;
&#xD;
      After the patient is informed and asked to sign an informed consent form, baseline data will&#xD;
      be collected. Device data of patients will be collected for 12 months. ACEI/ARB will be given&#xD;
      to the patient for 6 months. Dosage of ACEI/ARB will be based on investigator's discretion&#xD;
      and up titrated after 2-4 weeks to the maximum dosage the patients can tolerate and according&#xD;
      to product label.After 6 months, patients using ACEI need to undergo a 36-hr washout period&#xD;
      (36-hr washout period is not needed for patients using ARB at month 6). Patients will then&#xD;
      receive ARNI (sponsored by Novartis only for this study) while the dosage of ARNI will be&#xD;
      according to investigator's discretion and up titrated to the maximum dosage the patient can&#xD;
      tolerate or 200 mg bid as per guideline.All patients will be followed up for 6 months for&#xD;
      each treatment. After patients finalize the trial, the investigator will evaluate all&#xD;
      patients and produce a report.&#xD;
&#xD;
      Primary objective of this study is to assess the proportion of patients with VA events over 6&#xD;
      months of ACEI/ARB and 6 months of ARNI treatment.&#xD;
&#xD;
      Secondary Objectives include:To assess numbers of occurrences of VA events and ICD or CRT-D&#xD;
      shocks over 6 months of ACEI/ARB and 6 months of ARNI treatment; To compare the changes in&#xD;
      LVEF and NYHA level between ACEI/ARB and ARNI treatment; To compare the changes in the&#xD;
      NT-proBNP level between ACEI/ARB and ARNI treatments; To compare the healthcare resource&#xD;
      utilization of HF patients during ACEI/ARB and ARNI treatments;&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 11, 2020</start_date>
  <completion_date type="Actual">June 8, 2023</completion_date>
  <primary_completion_date type="Actual">June 8, 2023</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of patients with VA, ICD and ATP events over 6 months of ACEI/ARB and 6 months of ARNI treatment</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Paired proportion of patients by occurrence of at least one Ventricular arrhythmia (VA), Implantable cardioverter defibrillator (ICD ) &amp; Antitachycardia pacing (ATP) event over 6 months of Angiotensin-converting enzyme inhibitor/Angiotensin receptor blockers(ACEI/ARB) &amp; Angiotensin receptor neprilysin inhibitor (ARNI) treatment respectively. VA events defined as: NSVT(Non-sustained ventricular tachycardia), SVT(Sustained ventricular tachycardia),PVC(Premature ventricular contraction), SVT is defined as: tachycardia with haemodynamic disorder or lasting for ≥30 seconds. NSVT is defined as: different ICD devices. PVC is defined as: early ventricular depolarization as determined by device.&#xD;
ICD events: Ventricular tachycardia occurrence in implantable cardioverter defibrillator (ICD) patients may result in shock delivery &amp; is associated with increased morbidity &amp; mortality.&#xD;
ATP events: Anti-tachycardia pacing is defined as a low-energy alternative to high-energy biphasic shocks.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Numbers of NSVT, SVT, PVC, ICD shock and ATP experienced by patients</measure>
    <time_frame>baseline, 6 month, 12 month</time_frame>
    <description>To assess the number of occurrences of Ventricular arrhythmia (VA) events and Implantable cardioverter defibrillator (ICD) or Cardiac resynchronization therapy-defibrillator (CRT-D) shocks over 6 months of ACEI/ARB and 6 months of ARNI treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>LVEF (%)</measure>
    <time_frame>baseline, 6 month, 12 month</time_frame>
    <description>To compare the changes in Left Ventricular Ejection Fraction (LVEF) between ACEI/ARB and ARNI treatments</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>NYHA level</measure>
    <time_frame>baseline, 6 month, 12 month</time_frame>
    <description>To compare the changes in New York Heart Association (NYHA) level between ACEI/ARB and ARNI treatments</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>NT-proBNP (pg/mL) level</measure>
    <time_frame>baseline, 6 month, 12 month</time_frame>
    <description>To compare the changes in the N-Terminal prohormone of Brain Natriuretic Peptide(NT-proBNP) level between ACEI/ARB and ARNI treatments</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of hospitalizations for arrhythmia or HF related hospitalizations</measure>
    <time_frame>baseline, 6 month, 12 month</time_frame>
    <description>To compare the healthcare resource utilization of Heart Failure (HF) patients during ACEI/ARB and ARNI treatments</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">177</enrollment>
  <condition>Heart Failure</condition>
  <arm_group>
    <arm_group_label>ACEI/ARB treatment in 6 months/ARNI treatment in next 6 months</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Angiotensin-converting enzyme inhibitor/Angiotensin receptor blockers treatment in the first 6 months&#xD;
Angiotensin receptor neprilysin inhibitor treatment in next 6 months</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ACEI/ARB</intervention_name>
    <description>initative ACE/ARB drug for 6 months in this study</description>
    <arm_group_label>ACEI/ARB treatment in 6 months/ARNI treatment in next 6 months</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ARNI</intervention_name>
    <description>initative ARNI drug for next 6 months in this study</description>
    <arm_group_label>ACEI/ARB treatment in 6 months/ARNI treatment in next 6 months</arm_group_label>
    <other_name>Entresto</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Key Inclusion criteria:&#xD;
&#xD;
          1. Male or female patients ≥18 and ≤80 years of age&#xD;
&#xD;
          2. Implanted with an ICD or CRT-D within 2 weeks&#xD;
&#xD;
          3. NYHA functional class II - IV&#xD;
&#xD;
          4. LVEF ≤40% (measured by echocardiography)&#xD;
&#xD;
          5. Signed informed consent must be obtained prior to participation in the study.&#xD;
&#xD;
        Key Exclusion criteria&#xD;
&#xD;
          1. History of hypersensitivity to any of the study treatments or its excipients or to&#xD;
             drugs of similar chemical classes.&#xD;
&#xD;
          2. Patient received target dose (≥200 mg/d) of ARNI for 2 weeks continuously within the&#xD;
             6-week period prior to study enrollment.&#xD;
&#xD;
          3. Participation in other clinical studies 3 months prior to participating study.&#xD;
&#xD;
          4. Advanced cancer or other significant comorbidities with life expectancy of &lt;1 year.&#xD;
&#xD;
          5. Previous history of angioedema associated with ACEI/ARB treatment, hereditary or&#xD;
             idiopathic angioedema.&#xD;
&#xD;
          6. Patients with renal artery stenosis history.&#xD;
&#xD;
          7. Current stage D HF patients requiring vasoactive drugs.&#xD;
&#xD;
          8. Symptomatic hypotension &lt; 100/60 mmHg at visit 1 (screening) or Symptomatic&#xD;
             hypotension &lt; 90/60 mmHg in anti-hypertension drug treatment at visit 1 (screening).&#xD;
&#xD;
          9. Serum potassium &gt;5.4 mmol/L at visit 1 (screening).&#xD;
&#xD;
         10. Estimated glomerular filtration rate (eGFR) &lt; 30 mL/min/1.73m2 as measured at visit 1&#xD;
             (screening).&#xD;
&#xD;
         11. Pregnant or nursing (lactating) women.&#xD;
&#xD;
         12. Other exclusion depend on investigator's discretion.&#xD;
&#xD;
        Other protocol- defined inclusion/exclusion criteria may apply&#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>Hefei</city>
        <state>An Hui</state>
        <zip>230001</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Bei Jing</city>
        <state>Bei Jing</state>
        <zip>100034</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Beijing</city>
        <state>Beijing</state>
        <zip>100044</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Fuzhou</city>
        <state>Fujian</state>
        <zip>350001</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Shenzhen</city>
        <state>Guangdong</state>
        <zip>518057</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Zhengzhou</city>
        <state>Henan</state>
        <zip>450000</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Nanjing</city>
        <state>Jiangsu</state>
        <zip>210000</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Nantong</city>
        <state>Jiangsu</state>
        <zip>226000</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Wu XI</city>
        <state>Jiangsu</state>
        <zip>214023</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Xuzhou</city>
        <state>Jiangsu</state>
        <zip>221000</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Dalian</city>
        <state>Liaoning</state>
        <zip>116011</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Shenyang</city>
        <state>Liaoning</state>
        <zip>110011</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Shanghai</city>
        <state>Shanghai</state>
        <zip>200032</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Shanghai</city>
        <state>Shanghai</state>
        <zip>200433</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Xian</city>
        <state>Shanxi</state>
        <zip>710061</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Chengdu</city>
        <state>Sichuan</state>
        <zip>610031</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Hangzhou</city>
        <state>Zhejiang</state>
        <zip>310014</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Guangzhou</city>
        <zip>510000</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Tianjin</city>
        <zip>300000</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>June 22, 2020</study_first_submitted>
  <study_first_submitted_qc>July 28, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 29, 2020</study_first_posted>
  <last_update_submitted>July 26, 2023</last_update_submitted>
  <last_update_submitted_qc>July 26, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 27, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>LCZ696</keyword>
  <keyword>sacubitril/valsartan</keyword>
  <keyword>Heart Failure</keyword>
  <keyword>Heart failure with reduced ejection fraction</keyword>
  <keyword>HFrEF</keyword>
  <keyword>Ventricular arrhythmias</keyword>
  <keyword>Implanted Device</keyword>
  <keyword>Healthcare resource utilization</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
    <mesh_term>Arrhythmias, Cardiac</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sacubitril and valsartan sodium hydrate drug combination</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.&#xD;
This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.</ipd_description>
  </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/NCT04491136
org study id: CLCZ696BCN04
nct id: NCT04491136
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
The purpose of this study is to generate effectiveness data of ARNI, in the Chinese HFrEF
      patients with implanted ICD or CRT-D. This will be a multicenter, interventional, open-label,
      and prospective single-arm study to evaluate the effect of ARNI on VAs in approximately 219
      HFrEF patients receiving ICD or CRT-D in China.
The rationale of this study is to compare the effect of ACEI/ARB with the effect of ARNI on
      VA events for HFrEF patients with ICD or CRT-D, thus a multicenter, interventional,
      open-label, and prospective single-arm study was considered.

      Study design:This will be a multicenter, interventional, open-label, and prospective
      single-arm study to evaluate the effect of ARNI on VAs in approximately 219 HFrEF patients
      receiving ICD or CRT-D in China.

      After the patient is informed and asked to sign an informed consent form, baseline data will
      be collected. Device data of patients will be collected for 12 months. ACEI/ARB will be given
      to the patient for 6 months. Dosage of ACEI/ARB will be based on investigator's discretion
      and up titrated after 2-4 weeks to the maximum dosage the patients can tolerate and according
      to product label.After 6 months, patients using ACEI need to undergo a 36-hr washout period
      (36-hr washout period is not needed for patients using ARB at month 6). Patients will then
      receive ARNI (sponsored by Novartis only for this study) while the dosage of ARNI will be
      according to investigator's discretion and up titrated to the maximum dosage the patient can
      tolerate or 200 mg bid as per guideline.All patients will be followed up for 6 months for
      each treatment. After patients finalize the trial, the investigator will evaluate all
      patients and produce a report.

      Primary objective of this study is to assess the proportion of patients with VA events over 6
      months of ACEI/ARB and 6 months of ARNI treatment.

      Secondary Objectives include:To assess numbers of occurrences of VA events and ICD or CRT-D
      shocks over 6 months of ACEI/ARB and 6 months of ARNI treatment; To compare the changes in
      LVEF and NYHA level between ACEI/ARB and ARNI treatment; To compare the changes in the
      NT-proBNP level between ACEI/ARB and ARNI treatments; To compare the healthcare resource
      utilization of HF patients during ACEI/ARB and ARNI treatments;
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Proportion of patients with VA, ICD and ATP events over 6 months of ACEI/ARB and 6 months of ARNI treatment
time frame: Up to 12 months
description: Paired proportion of patients by occurrence of at least one Ventricular arrhythmia (VA), Implantable cardioverter defibrillator (ICD ) & Antitachycardia pacing (ATP) event over 6 months of Angiotensin-converting enzyme inhibitor/Angiotensin receptor blockers(ACEI/ARB) & Angiotensin receptor neprilysin inhibitor (ARNI) treatment respectively. VA events defined as: NSVT(Non-sustained ventricular tachycardia), SVT(Sustained ventricular tachycardia),PVC(Premature ventricular contraction), SVT is defined as: tachycardia with haemodynamic disorder or lasting for ≥30 seconds. NSVT is defined as: different ICD devices. PVC is defined as: early ventricular depolarization as determined by device.
ICD events: Ventricular tachycardia occurrence in implantable cardioverter defibrillator (ICD) patients may result in shock delivery & is associated with increased morbidity & mortality.
ATP events: Anti-tachycardia pacing is defined as a low-energy alternative to high-energy biphasic shocks.
measure: Numbers of NSVT, SVT, PVC, ICD shock and ATP experienced by patients
time frame: baseline, 6 month, 12 month
description: To assess the number of occurrences of Ventricular arrhythmia (VA) events and Implantable cardioverter defibrillator (ICD) or Cardiac resynchronization therapy-defibrillator (CRT-D) shocks over 6 months of ACEI/ARB and 6 months of ARNI treatment
measure: LVEF (%)
time frame: baseline, 6 month, 12 month
description: To compare the changes in Left Ventricular Ejection Fraction (LVEF) between ACEI/ARB and ARNI treatments
measure: NYHA level
time frame: baseline, 6 month, 12 month
description: To compare the changes in New York Heart Association (NYHA) level between ACEI/ARB and ARNI treatments
measure: NT-proBNP (pg/mL) level
time frame: baseline, 6 month, 12 month
description: To compare the changes in the N-Terminal prohormone of Brain Natriuretic Peptide(NT-proBNP) level between ACEI/ARB and ARNI treatments
measure: Number of hospitalizations for arrhythmia or HF related hospitalizations
time frame: baseline, 6 month, 12 month
description: To compare the healthcare resource utilization of Heart Failure (HF) patients during ACEI/ARB and ARNI treatments
arm group label: ACEI/ARB treatment in 6 months/ARNI treatment in next 6 months
arm group type: Experimental
description: Angiotensin-converting enzyme inhibitor/Angiotensin receptor blockers treatment in the first 6 months
Angiotensin receptor neprilysin inhibitor treatment in next 6 months
intervention type: Drug
intervention name: ACEI/ARB
description: initative ACE/ARB drug for 6 months in this study
arm group label: ACEI/ARB treatment in 6 months/ARNI treatment in next 6 months
intervention type: Drug
intervention name: ARNI
description: initative ARNI drug for next 6 months in this study
arm group label: ACEI/ARB treatment in 6 months/ARNI treatment in next 6 months
other name: Entresto
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Novartis Pharmaceuticals
role: Study Director
affiliation: Novartis Pharmaceuticals
facility: 
facility: 
facility: 
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facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
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facility: 
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facility: 
country: China
responsible party type: Sponsor
mesh term: Heart Failure
mesh term: Arrhythmias, Cardiac
mesh term: Sacubitril and valsartan sodium hydrate drug combination
sharing ipd: Yes
ipd description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.