Heart FailurePhase 4RHYTHMNCT04491136

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

A Phase 4 study testing ACEI/ARB and ARNI in people with Heart Failure, run by Novartis Pharmaceuticals at 23 sites in China.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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Trial summary

The purpose of this study was to generate effectiveness data of Angiotensin receptor neprilysin inhibitor (ARNI), in the Chinese Heart failure with reduced ejection fraction (HFrEF) patients with implantable cardioverted defibrillator (ICD) or Cardiac resynchronization therapy-defibrillator (CRT-D). Read more about this study

Who is it for?: Ages 18 to 80 years
Conditions the study is for: Heart Failure
What is being tested?: ACEI/ARB and ARNI
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 201 participants
Where: 23 sitesChina
Study dates: 11 Nov 2020to 8 Jun 2023
Phase: Phase 4
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 80 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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

Who cannot join

History of hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes.
Patient received target dose (≥200 mg/d) of ARNI for 2 weeks continuously within the 6-week period prior to study enrollment.
Participation in other clinical studies 3 months prior to participating study.
Advanced cancer or other significant comorbidities with life expectancy of <1 year.
Previous history of angioedema associated with ACEI/ARB treatment, hereditary or idiopathic angioedema.
Patients with renal artery stenosis history.

Show all 12Show fewer

Current stage D HF patients requiring vasoactive drugs.
Symptomatic hypotension < 100/60 mmHg at visit 1 (screening) or Symptomatic hypotension < 90/60 mmHg in anti-hypertension drug treatment at visit 1 (screening).
Serum potassium >5.4 mmol/L at visit 1 (screening).
Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 as measured at visit 1 (screening).
Pregnant or nursing (lactating) women.
Other exclusion depend on investigator's discretion.

Trial locations and contacts

23 sites in 1 country.

City, postcode or hospital

23 sites in 1 country

China23 sites

Novartis Investigative Site
Beijing, Beijing Municipality, 100034
Novartis Investigative Site
Beijing, Beijing Municipality, 100044
Novartis Investigative Site
Changsha, Hunan, 410011
Novartis Investigative Site
Chengdu, Sichuan, 610031
Novartis Investigative Site
Chengdu, Sichuan, 610041
Novartis Investigative Site
Dalian, Liaoning, 116011
Novartis Investigative Site
Fuzhou, Fujian, 350001
Novartis Investigative Site
Guangzhou, Guangdong, 510000
Novartis Investigative Site
Hangzhou, Zhejiang, 310014
Novartis Investigative Site
Hefei, Anhui, 230001
Novartis Investigative Site
Nanjing, Jiangsu, 210000
Novartis Investigative Site
Nantong, Jiangsu, 226000
Novartis Investigative Site
Qingdao, 266000
Novartis Investigative Site
Shanghai, Shanghai Municipality, 200032
Novartis Investigative Site
Shanghai, Shanghai Municipality, 200433
Novartis Investigative Site
Shenyang, Liaoning, 110011
Novartis Investigative Site
Shenzhen, Guangdong, 518057
Novartis Investigative Site
Tianjin, 300000
Novartis Investigative Site
Ürümqi, Xinjiang, 830054
Novartis Investigative Site
Wuxi, Jiangsu, 214023
Novartis Investigative Site
Xian, Shanxi, 710061
Novartis Investigative Site
Xuzhou, Jiangsu, 221000
Novartis Investigative Site
Zhengzhou, Henan, 450000

Other trials in China

About this study

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

Read the detailed description

The rationale of this study was to compare the effect of angiotensin-converting enzyme inhibitor (ACEI) / Angiotensin receptor blockers (ARB) with the effect of ARNI on ventricular arrhythmia (VA) events for HFrEF patients with ICD or CRT-D, thus a multicenter, interventional, open-label, and prospective single-arm study was considered.

ACEI/ARB was given to the patient for 6 months. After 6 months, patients using ACEI needed to undergo a 36-hr washout period (36-hr washout period was not needed for patients using ARB at month 6). Patients then received ARNI (sponsored by Novartis only for this study).

Conditions: Heart Failure
Being tested: ACEI/ARB, ARNI
Keywords: LCZ696, sacubitril/valsartan, Heart Failure, Heart failure with reduced ejection fraction, HFrEF, Ventricular arrhythmias, Implanted Device, Healthcare resource utilization
Medical subject headings: Heart Failure

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

ACEI/ARBDrug
Oral ACE/ARB drug according to the investigator's discretion for the first 6 months in this study
ARNIDrug
Also called Entresto
Oral sacubitril/valsartan at the dosage of investigators discretion, whit a target dose of 200mg bid for the next 6 months of this study

Study groups in NCT04491136
Study group	Role	What they receive
ACEI/ARB treatment for 6 months/ARNI treatment the next 6 months	Experimental	Patients received angiotensin-converting enzyme inhibitor/angiotensin receptor blockers treatment the first 6 months. The following 6 months patients received angiotensin receptor neprilysin inhibitor treatment. Receives: Drug: ACEI/ARB; Drug: ARNI

What is being measured

The primary outcome is the main question the study is designed to answer.

Proportion of Paired Patients With Ventricular Arrhythmia (VA) Events
VA events were measured through devices to determine sustained ventricular tachycardia (SVT), non-sustained ventricular tachycardia (NSVT) and premature ventricular contraction (PVC).
SVT was defined as tachycardia lasting for ≥30 seconds or with hemodynamic disorder as determined by Holter and/or device.
NSVT was defined as recorded by Holter and/or device. PVC was defined as an early ventricular depolarization as determined by the device, and/or detected by Holter.
PVC data were not available for patients with single -lumen implantation type
Measured: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
Proportion of Paired Patients Who Experienced at Least One ICD or CRT-D Shock and ATP Event
Once VA events were detected, implantable cardioverter defibrillator (ICD) could treat with high-energy shocks or Anti-tachycardia pacing (ATP). ATP consists of one or more trains of pacing stimuli, expressed as a percentage of the tachycardia cycle length for a given RR interval, from the onset of the preceding R wave.
Patients with sustained VA events would receive ICD or cardiac resynchronization therapy-defibrillator (CRT-D) shock therapy.
Measured: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)

Secondary outcomes (5)

Pairwise Number of SVT, NSVT, PVC, ICD or CRT-D Shocks and ATP Events 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.
PVC data were not available for patients with single-lumen implantation type
Measured: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
Left Ventricular Ejection Fraction
To compare the changes in Left Ventricular Ejection Fraction (LVEF) between ACEI/ARB and ARNI treatments.
LVEF is a measurement expressed as a percentage of how much blood in the left ventricle is pumped out with each contraction of the heart.
Measured: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
New York Heart Association Classification
To compare the changes in New York Heart Association (NYHA) level between ACEI/ARB and ARNI treatments.
NYHA classification is a subjective physician's assessment of heart failure patient's functional capacity and symptomatic status.
Class I - No limitation of physical activity. Class II - Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath). Class III - Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV - Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases.
Measured: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
N-Terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Level
To compare the changes in the N-Terminal prohormone of Brain Natriuretic Peptide(NT-proBNP) level between ACEI/ARB and ARNI treatments.
NT-proBNP are small proteins produced in large amounts when the heart senses it needs to work harder, such as in heart failure.
Measured: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
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
Measured: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

11 Nov 20208 Jun 2023

First posted29 Jul 2020
Study start11 Nov 2020
Primary completion8 Jun 2023
Study completion8 Jun 2023

Why it stopped: Company decision

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Other trials for Heart FailureStudies of the same condition, open and under way.
More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 4
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrolment: 201 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT04491136
Sponsor's protocol ID: CLCZ696BCN04
Acronym: RHYTHM
Status last verified: May 2025
First submitted: 22 Jun 2020
Last updated: 16 May 2025
Results posted: Yes, on ClinicalTrials.gov
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: Yes: 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.

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

RecruitingPhase 4
The Effects of Ferric Derisomaltose in Patients With Acute Heart Failure and Iron Deficiency on Exercise Capacity and Quality of Life(COREVIVE-HFrEF)
Heart Failure With Reduced Ejection Fraction, Iron Deficiency
Not yet recruitingPhase 2
A Study of Bimagrumab in Participants With HFpEF
Heart Failure, Diastolic, Diastolic Heart Failure
Recruiting
Evaluation of a French Hospital Discharge Therapeutic Education Program by Nurses for Heart Failure Patient (EduSor)
Heart Failure
Active, not recruiting
Assessment of Combined CCM and ICD Device in HFrEF
Heart Failure, Heart Failure With Reduced Ejection Fraction
Not yet recruiting
RELIEVE-HFrEF TRIAL: REducing Lung congestIon Symptoms Using the v-wavE Shunt in adVancEd Heart Failure With Reduced EF
Heart Failure and Reduced Ejection Fraction, Heart Failure Chronic

All Heart Failure trials

Study at a glance

From the registry record, last updated by the sponsor on 16 May 2025. Recruitment status is as the sponsor reported it: confirm with the study team.

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
ClinicalTrials.gov ID: NCT04491136
Acronym / sponsor ID: RHYTHM / CLCZ696BCN04
Conditions: Heart Failure
Keywords: LCZ696, sacubitril/valsartan, Heart Failure, Heart failure with reduced ejection fraction, HFrEF, Ventricular arrhythmias, Implanted Device, Healthcare resource utilization
Phase: Phase 4
Study type: Interventional
Recruitment status: TerminatedReason stopped: Company decision
Enrolment: 201 participants (actual)
Lead sponsor: Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
Study start: 11 Nov 2020 (actual)
Primary completion: 8 Jun 2023 (actual)
Study completion: 8 Jun 2023 (actual)
First posted: 29 Jul 2020 (actual)
Results: Posted 17 Oct 2024

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Number of arms: 1

Arm	Type	Receives
ACEI/ARB treatment for 6 months/ARNI treatment the next 6 months	Experimental	Drug: ACEI/ARB, Drug: ARNIPatients received angiotensin-converting enzyme inhibitor/angiotensin receptor blockers treatment the first 6 months. The following 6 months patients received angiotensin receptor neprilysin inhibitor treatment.

Who may qualify

Ages: 18 to 80 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (5 listed)

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

Key exclusion criteria (12 listed)

History of hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes.
Patient received target dose (≥200 mg/d) of ARNI for 2 weeks continuously within the 6-week period prior to study enrollment.
Participation in other clinical studies 3 months prior to participating study.
Advanced cancer or other significant comorbidities with life expectancy of <1 year.
Previous history of angioedema associated with ACEI/ARB treatment, hereditary or idiopathic angioedema.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
ACEI/ARBOral ACE/ARB drug according to the investigator's discretion for the first 6 months in this study	Drug	ACEI/ARB treatment for 6 months/ARNI treatment the next 6 months
ARNIAlso: EntrestoOral sacubitril/valsartan at the dosage of investigators discretion, whit a target dose of 200mg bid for the next 6 months of this study	Drug	ACEI/ARB treatment for 6 months/ARNI treatment the next 6 months

Primary outcome

Proportion of Paired Patients With Ventricular Arrhythmia (VA) Events
Time frame: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
VA events were measured through devices to determine sustained ventricular tachycardia (SVT), non-sustained ventricular tachycardia (NSVT) and premature ventricular contraction (PVC). SVT was defined as tachycardia lasting for ≥30 seconds or with hemodynamic disorder as determined by Holter and/or device. NSVT was defined as recorded by Holter and/or device. PVC was defined as an early ventricular depolarization as determined by the device, and/or detected by Holter. PVC data were not available for patients with single -lumen implantation type
Proportion of Paired Patients Who Experienced at Least One ICD or CRT-D Shock and ATP Event
Time frame: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
Once VA events were detected, implantable cardioverter defibrillator (ICD) could treat with high-energy shocks or Anti-tachycardia pacing (ATP). ATP consists of one or more trains of pacing stimuli, expressed as a percentage of the tachycardia cycle length for a given RR interval, from the onset of the preceding R wave. Patients with sustained VA events would receive ICD or cardiac resynchronization therapy-defibrillator (CRT-D) shock therapy.

5 secondary outcomes

Pairwise Number of SVT, NSVT, PVC, ICD or CRT-D Shocks and ATP Events Experienced by Patients
Time frame: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
Left Ventricular Ejection Fraction
Time frame: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
New York Heart Association Classification
Time frame: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
N-Terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Level
Time frame: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
Number of Hospitalizations for Arrhythmia or HF Related Hospitalizations
Time frame: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)

Results and safety

Results posted to the registry on 17 Oct 2024, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
ACEI/ARB Followed by ARNI	201	122

Primary outcome: Proportion of Paired Patients With Ventricular Arrhythmia (VA) Events

Time frame: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment). Count of participants. Unit: Participants

Measure	ACEI/ARB n = 76	ARNI n = 76
At least one SVT occurred	13	12
At least one NSVT occurred	23	21
At least one PVC occurred	40	38

ACEI/ARB vs ARNI: p >0.9999, McNemar
ACEI/ARB vs ARNI: p = 0.7905, McNemar
ACEI/ARB vs ARNI: p = 0.6250, McNemar

Population analysed: Efficacy analysis set (EAS): Patients in the safety set who received at least one dose of ARNI and completed 12 months of complete treatment and follow-up or withdrew early after receiving at least one dose of ARNI. Only subjects who had this measurement index successfully paired (ACEI/ARB treatment and ARNI treatment) were included in the analysis.

Primary outcome: Proportion of Paired Patients Who Experienced at Least One ICD or CRT-D Shock and ATP Event

Time frame: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment). Count of participants. Unit: Participants

Measure	ACEI/ARB n = 87	ARNI n = 87
Occurrence of at least one ICD or CRT-D shock	3	2
Occurrence of at least one ATP event	15	8

ACEI/ARB vs ARNI: p >0.9999, McNemar
ACEI/ARB vs ARNI: p = 0.0654, McNemar

5 secondary outcomes are reported in the full results.

Adverse events

Time frame: Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment. Patients were followed up for 6 months for each treatment, up to a maximum duration of 13 months. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
ACEI/ARB	38 of 201 (18.9%)	99 of 201 (49.3%)	3 of 201
ARNI	19 of 140 (13.6%)	58 of 140 (41.4%)	0 of 140

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 16 May 2025.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
A Plain Language Trial Summary is available on www.novctrd.comLink provided by the sponsor.
Individual participant dataSharing planned: Yes. 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.

Related trials for Heart Failure

RecruitingPhase 4
The Effects of Ferric Derisomaltose in Patients With Acute Heart Failure and Iron Deficiency on Exercise Capacity and Quality of Life(COREVIVE-HFrEF)
Heart Failure With Reduced Ejection Fraction, Iron Deficiency
Not yet recruitingPhase 2
A Study of Bimagrumab in Participants With HFpEF
Heart Failure, Diastolic, Diastolic Heart Failure
Recruiting
Evaluation of a French Hospital Discharge Therapeutic Education Program by Nurses for Heart Failure Patient (EduSor)
Heart Failure
Active, not recruiting
Assessment of Combined CCM and ICD Device in HFrEF
Heart Failure, Heart Failure With Reduced Ejection Fraction
Not yet recruiting
RELIEVE-HFrEF TRIAL: REducing Lung congestIon Symptoms Using the v-wavE Shunt in adVancEd Heart Failure With Reduced EF
Heart Failure and Reduced Ejection Fraction, Heart Failure Chronic

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Novartis Pharmaceuticals study director

Novartis Pharmaceuticals

23 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing ACEI/ARB and ARNI in people with Heart Failure, run by Novartis Pharmaceuticals at 23 sites in China.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 16 May 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 23 sites in China. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 17 Oct 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Proportion of Paired Patients With Ventricular Arrhythmia (VA) Events (time frame: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04491136.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 May 2025.