Effective Study of ARNI on Ventricular Arrhythmia in HFrEF Patients With ICD or CRT-D (RHYTHM) (RHYTHM)

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

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.

Study Overview

• Status: Terminated
• Conditions: Heart Failure
• Intervention / Treatment: Drug: ACEI/ARB; Drug: ARNI

Detailed Description

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;

• Study Type: Interventional
• Enrollment (Actual): 201
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Guangzhou, China, 510000
    • Novartis Investigative Site
  • Tianjin, China, 300000
    • Novartis Investigative Site
  • An Hui
    • Hefei, An Hui, China, 230001
      • Novartis Investigative Site
  • Bei Jing
    • Bei Jing, Bei Jing, China, 100034
      • Novartis Investigative Site
  • Beijing
    • Beijing, Beijing, China, 100044
      • Novartis Investigative Site
  • Fujian
    • Fuzhou, Fujian, China, 350001
      • Novartis Investigative Site
  • Guangdong
    • Shenzhen, Guangdong, China, 518057
      • Novartis Investigative Site
  • Henan
    • Zhengzhou, Henan, China, 450000
      • Novartis Investigative Site
  • Hunan
    • Changsha, Hunan, China, 410011
      • Novartis Investigative Site
  • Jiangsu
    • Nanjing, Jiangsu, China, 210000
      • Novartis Investigative Site
    • Nantong, Jiangsu, China, 226000
      • Novartis Investigative Site
    • Wu XI, Jiangsu, China, 214023
      • Novartis Investigative Site
    • Xuzhou, Jiangsu, China, 221000
      • Novartis Investigative Site
  • Liaoning
    • Dalian, Liaoning, China, 116011
      • Novartis Investigative Site
    • Shenyang, Liaoning, China, 110011
      • Novartis Investigative Site
  • Shandong
    • Qingdao, Shandong, China, 266003
      • Novartis Investigative Site
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Novartis Investigative Site
    • Shanghai, Shanghai, China, 200433
      • Novartis Investigative Site
  • Shanxi
    • Xian, Shanxi, China, 710061
      • Novartis Investigative Site
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Novartis Investigative Site
    • Chengdu, Sichuan, China, 610031
      • Novartis Investigative Site
  • Xinjiang
    • Wulumuqi, Xinjiang, China, 830054
      • Novartis Investigative Site
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310014
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion criteria:

1. Male or female patients ≥18 and ≤80 years of age
2. Implanted with an ICD or CRT-D within 2 weeks
3. NYHA functional class II - IV
4. LVEF ≤40% (measured by echocardiography)
5. Signed informed consent must be obtained prior to participation in the study.

Key Exclusion criteria

1. History of hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes.
2. Patient received target dose (≥200 mg/d) of ARNI for 2 weeks continuously within the 6-week period prior to study enrollment.
3. Participation in other clinical studies 3 months prior to participating study.
4. Advanced cancer or other significant comorbidities with life expectancy of <1 year.
5. Previous history of angioedema associated with ACEI/ARB treatment, hereditary or idiopathic angioedema.
6. Patients with renal artery stenosis history.
7. Current stage D HF patients requiring vasoactive drugs.
8. Symptomatic hypotension < 100/60 mmHg at visit 1 (screening) or Symptomatic hypotension < 90/60 mmHg in anti-hypertension drug treatment at visit 1 (screening).
9. Serum potassium >5.4 mmol/L at visit 1 (screening).
10. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 as measured at visit 1 (screening).
11. Pregnant or nursing (lactating) women.
12. Other exclusion depend on investigator's discretion.

Other protocol- defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ACEI/ARB treatment in 6 months/ARNI treatment in next 6 months; Angiotensin-converting enzyme inhibitor/Angiotensin receptor blockers treatment in the first 6 months Angiotensin receptor neprilysin inhibitor treatment in next 6 months	Drug: ACEI/ARB; initative ACE/ARB drug for 6 months in this study; Drug: ARNI; initative ARNI drug for next 6 months in this study; Other Names: Entresto

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with VA, ICD and ATP events over 6 months of ACEI/ARB and 6 months of ARNI treatment	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.	Up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Numbers of NSVT, SVT, PVC, ICD shock and ATP experienced by patients	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	baseline, 6 month, 12 month
LVEF (%)	To compare the changes in Left Ventricular Ejection Fraction (LVEF) between ACEI/ARB and ARNI treatments	baseline, 6 month, 12 month
NYHA level	To compare the changes in New York Heart Association (NYHA) level between ACEI/ARB and ARNI treatments	baseline, 6 month, 12 month
NT-proBNP (pg/mL) level	To compare the changes in the N-Terminal prohormone of Brain Natriuretic Peptide(NT-proBNP) level between ACEI/ARB and ARNI treatments	baseline, 6 month, 12 month
Number of hospitalizations for arrhythmia or HF related hospitalizations	To compare the healthcare resource utilization of Heart Failure (HF) patients during ACEI/ARB and ARNI treatments	baseline, 6 month, 12 month

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): November 11, 2020
• Primary Completion (Actual): June 8, 2023
• Study Completion (Actual): June 8, 2023

Study Registration Dates

• First Submitted: June 22, 2020
• First Submitted That Met QC Criteria: July 28, 2020
• First Posted (Actual): July 29, 2020

Study Record Updates

• Last Update Posted (Actual): February 21, 2024
• Last Update Submitted That Met QC Criteria: February 20, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Heart Failure; Heart failure with reduced ejection fraction; Ventricular arrhythmias; Healthcare resource utilization; LCZ696; HFrEF; sacubitril/valsartan; Implanted Device
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Heart Failure; Arrhythmias, Cardiac; Molecular Mechanisms of Pharmacological Action; Angiotensin Receptor Antagonists; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: CLCZ696BCN04

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No