EntrestoTM (LCZ696) In Advanced Heart Failure (LIFE Study)

NCT ID: NCT02816736

Last Updated: 2021-12-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 365 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-03-02
• Study Completion Date: 2020-09-29

Brief Summary

The primary objective of the study is to determine whether, in patients with symptomatic, advanced heart failure due to left ventricular systolic dysfunction, treatment with LCZ696 for 24 weeks will improve Pro-B-type Natriuretic Peptide (NT-proBNP) levels, which reflect hemodynamic and clinical status, compared to treatment with valsartan.

Detailed Description

Patients with advanced heart failure with reduced ejection fraction (HFrEF) have extremely high morbidity and mortality with 1 year outcomes of death and hospitalization of approximately 50%. For the most advanced heart failure patients, the evidence base for medical treatment is limited with consensus guidelines recommending consideration for either cardiac transplant or ventricular assist device, or palliative care.

The PARADIGM-HF trial showed that LCZ696, which consists of the neprilysin inhibitor sacubitril and the ARB valsartan, improved morbidity and mortality in patients with chronic HFrEF in comparison to enalapril. However, limited experience with advanced heart failure patients was gained from patients enrolled in the trial. Because the information on the effects of sacubitril/valsartan in patients with NYHA class IV heart failure is limited, the updated 2016 ACC/AHA/HFSA guidelines for the treatment of heart failure do not yet endorse the use of sacubitril/valsartan in patients with NYHA class IV heart failure. Accordingly, experience is needed on the use of, and outcomes with LCZ696 in patients unable to tolerate target doses of angiotensin-converting enzyme inhibitor (ACEI)/ angiotensin receptor blocker (ARB).

This study will be a randomized, double-blinded trial of advanced heart failure subjects with 1:1 randomization to either LCZ696 (sacubitril and valsartan) or valsartan. Study drug will be administered in a double-dummy fashion, in which subjects take active (LCZ696 or valsartan) and placebo. Approximately 400 subjects will be randomized into the study.

Subjects will have an initial screening evaluation, including baseline laboratory tests as well as an assessment of left ventricular (LV) ejection fraction, at which time preliminary subject eligibility will be determined. The LV ejection fraction may have been obtained within the prior 12 months by 2-D echocardiogram, LV angiogram or radionuclide scintigraphy. Willing subjects meeting entry criteria will be consented. Those who meet all entry criteria and are interested in study participation will be enrolled.

Enrolled subjects will complete baseline assessments and undergo a run-in period of 3-7 days with LCZ696 50 mg (equivalent to Entresto™ 24/26 mg) po BID (taken by mouth twice a day) prior to randomization. For subjects taking an ACEI, the ACEI will be withheld for ≥ 36 hours prior to first dose of LCZ696.

Subjects who tolerate the run-in period with LCZ696 will be randomized 1:1 to LCZ696 or valsartan.

Study treatment will be titrated to the target dose of 200 mg LCZ696 (equivalent to Entresto™ 97/103 mg) as two 100 mg LCZ696 and 2 placebo tablets po BID or valsartan 160 mg (two 80 mg valsartan and 2 placebo tablets) po BID.*

Randomized subjects will receive the first dose of study drug as follows:

• For subjects not previously taking ACEI or ARB, previously taking ACEI or ARB at a low dose*, or subjects who have an eGFR < 30 mL/min/1.73m², the starting dose of valsartan will be 40 mg po BID and the starting dose of LCZ696 will be 50 mg po BID.
• For subjects taking an ARB at greater than low dose†, the starting dose of valsartan will be 80 mg po BID and the starting dose of LCZ696 will be 100 mg po BID.*
• For subjects taking an ACEI at greater than low dose†, the ACEI will be withheld for ≥ 36 hours prior to randomization. The starting dose of valsartan will be 80 mg po BID and the starting dose of LCZ696 will be 100 mg po BID.*

• At Investigator discretion, study drug may be started at the low dose (LCZ696/placebo 50 mg po BID or valsartan/placebo 40 mg po BID) if there are any concerns regarding tolerability at the 100 mg / 80 mg dose.)

Per package insert, the valsartan compounded in Entresto™ is more bioavailable than the valsartan in other marketed formulations. The dose equivalence for valsartan compounded in Entresto™ compared to valsartan prepared alone (Entresto™ dose = marketed valsartan dose) is as follows: 26 mg=40 mg, 51 mg=80 mg, 103 mg=160 mg.

† Low dose is defined as 24 hour dose of ≤ 10 mg lisinopril, ≤ 5 mg ramipril, ≤ 50 mg losartan, ≤ 10 mg olmesartan, or other dose equivalent.

Dose adjustments will be performed every 2 weeks by doubling the dose of LCZ696 or valsartan up to the target maximum dose. The doses of LCZ696 are 50 mg (one 50 mg active and 1 placebo tablet), 100 mg (one 100 mg active and 1 placebo tablet) and 200 mg (two 100 mg active and 2 placebo tablets). These doses are equivalent to 24/26 mg, 49/51 mg, and 97/103 mg commercial Entresto™, respectively. The doses of valsartan are 40mg (one 40 mg active and 1 placebo tablet), 80 mg (one 80 mg active and 1 placebo tablet), and 160 mg (two 80 mg active and 2 placebo tablets). The criteria for doubling the dose will be based on systolic blood pressure (a SBP > 90 mmHg is required for up titration), changes in renal function (maximum serum creatinine of 2.0 mg/dL), and the absence of symptoms of hypotension. For those not tolerating the current dose of study drug, the dose will be down-titrated to the previous tolerated dose. Subjects will return to clinic for follow-up visits at 2, 4, 8, 12, and 24 weeks after randomization.

Assessments at the follow-up visits include some or all of the following: interim medical history, review of medications, physical examination with the New York Heart Association (NYHA) class assessment, Kansas City Cardiomyopathy Questionnaire (KCCQ) quality of life questionnaire, local laboratory testing (creatinine, Blood Urea Nitrogen (BUN), electrolytes), Core laboratory testing (Cystatin C, BNP, NT-proBNP), adherence and tolerance assessment, and adverse event monitoring.

Follow-up phone calls will be made at 10, 16, and 20, weeks after randomization to assess dosing compliance, record the occurrence of applicable adverse events and events of interest, and remind the subject of the date and time of their next in-person visit.

A final phone visit is conducted approximately 2 weeks after study visit 10 (26 weeks after randomization) to assess clinical stability and any applicable adverse events.

During the consent process, subjects will be asked if interested in donating samples and data for research purposes via a biorepository and/or genetic study. Based on site and IRB preference, this optional part of the study may be incorporated into the main consent or may be a separate consent and Institutional Review Board (IRB) application.

Conditions

Heart Failure

Keywords

Heart Failure; Heart Diseases; Cardiovascular Diseases; Valsartan; Entresto

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

LCZ696 (Entresto) + placebo

LCZ696 50 mg, 100 mg, or 200 mg orally twice daily for 24 weeks, plus valsartan placebo (to match 40 mg, 80 mg, or 160 mg) orally twice daily for 24 weeks

Group Type: ACTIVE_COMPARATOR

LCZ696

Intervention Type: DRUG

Subjects previously taking no or low-dose ACEI or ARB, or who have an eGFR < 30 mL/min/1.73m²: starting dose of LCZ696 = 50 mg po BID.

Subjects taking an ARB at greater than low dose: starting dose of LCZ696 = 100 mg po BID.

Subjects taking an ACEI at greater than low dose: starting dose of LCZ696 = 100 mg po BID.

• At Investigator discretion, study drug may be started at the low dose if there are any concerns regarding tolerability.

Dose adjustments will be performed every 2 weeks by doubling the dose of LCZ696 up to the target max dose of 200 mg po BID as tolerated.

The doses of LCZ696 are 50mg (one low-dose (50mg) tablet), 100mg (one high-dose (100mg) tablet), and 200mg (two high-dose (100mg) tablets.) These doses are equivalent to 24/26 mg, 49/51 mg, and 97/103 mg commercial Entresto™, respectively.

valsartan placebo

Intervention Type: DRUG

Valsartan placebo tablets will be supplied to match the low-dose (40mg) and high-dose (80mg) active valsartan tablets. Dosing for valsartan placebo will mirror dosing for active LCZ696 (the same number of low or high-dose tablets will be given.)

valsartan + placebo

valsartan 40 mg, 80 mg, or 160 mg orally twice daily for 24 weeks, plus LCZ696 placebo (to match 50 mg, 100 mg, or 200 mg) orally twice daily for 24 weeks

Group Type: ACTIVE_COMPARATOR

valsartan

Intervention Type: DRUG

Subjects previously taking no or low-dose ACEI or ARB, or who have an eGFR < 30 mL/min/1.73m²: the starting dose of valsartan = 40 mg po BID.

Subjects taking an ARB at greater than low dose: starting dose of valsartan = 80 mg po BID.

Subjects taking an ACEI at greater than low dose: starting dose of valsartan = 80 mg po BID.

• At Investigator discretion, study drug may be started at the low dose if there are any concerns regarding tolerability.

Dose adjustments will be performed every 2 weeks by doubling the dose of valsartan up to the target maximum dose of 160 mg po BID, as tolerated.

The doses of valsartan are 40mg (one low-dose (40mg) tablet), 80mg (one high-dose (80mg) tablet), and 160mg (two high-dose (80mg) tablets).

LCZ696 placebo

Intervention Type: DRUG

LCZ696 placebo tablets will be supplied to match the low-dose (50mg) and high-dose (100mg) active LCZ696 tablets. Dosing for LCZ696 placebo will mirror dosing for active valsartan (the same number of low or high-dose tablets will be given.)

Interventions

LCZ696

Subjects previously taking no or low-dose ACEI or ARB, or who have an eGFR < 30 mL/min/1.73m²: starting dose of LCZ696 = 50 mg po BID.

Subjects taking an ARB at greater than low dose: starting dose of LCZ696 = 100 mg po BID.

Subjects taking an ACEI at greater than low dose: starting dose of LCZ696 = 100 mg po BID.

• At Investigator discretion, study drug may be started at the low dose if there are any concerns regarding tolerability.

Dose adjustments will be performed every 2 weeks by doubling the dose of LCZ696 up to the target max dose of 200 mg po BID as tolerated.

The doses of LCZ696 are 50mg (one low-dose (50mg) tablet), 100mg (one high-dose (100mg) tablet), and 200mg (two high-dose (100mg) tablets.) These doses are equivalent to 24/26 mg, 49/51 mg, and 97/103 mg commercial Entresto™, respectively.

Intervention Type: DRUG

valsartan

Subjects previously taking no or low-dose ACEI or ARB, or who have an eGFR < 30 mL/min/1.73m²: the starting dose of valsartan = 40 mg po BID.

Subjects taking an ARB at greater than low dose: starting dose of valsartan = 80 mg po BID.

Subjects taking an ACEI at greater than low dose: starting dose of valsartan = 80 mg po BID.

• At Investigator discretion, study drug may be started at the low dose if there are any concerns regarding tolerability.

Dose adjustments will be performed every 2 weeks by doubling the dose of valsartan up to the target maximum dose of 160 mg po BID, as tolerated.

The doses of valsartan are 40mg (one low-dose (40mg) tablet), 80mg (one high-dose (80mg) tablet), and 160mg (two high-dose (80mg) tablets).

Intervention Type: DRUG

LCZ696 placebo

LCZ696 placebo tablets will be supplied to match the low-dose (50mg) and high-dose (100mg) active LCZ696 tablets. Dosing for LCZ696 placebo will mirror dosing for active valsartan (the same number of low or high-dose tablets will be given.)

Intervention Type: DRUG

valsartan placebo

Valsartan placebo tablets will be supplied to match the low-dose (40mg) and high-dose (80mg) active valsartan tablets. Dosing for valsartan placebo will mirror dosing for active LCZ696 (the same number of low or high-dose tablets will be given.)

Intervention Type: DRUG

Other Intervention Names

Entresto; Diovan

Eligibility Criteria

Inclusion Criteria

1. Advanced HFrEF defined as including ALL

1. LVEF≤ 35% documented during the preceding 12 months

2. NYHA class IV symptomatology, defined as chronic dyspnea or fatigue at rest or on minimal exertion in the previous 3 months, or patients who require chronic inotropic therapy

3. Minimum of 3 months GDMT for HF and/or intolerant to therapy

2. Systolic blood pressure ≥ 90 mmHg

3. Serum NT-proBNP ≥ 800 pg/mL OR BNP ≥ 250 pg/mL (most recent - less than 3 months old)

4. Any one or more of the following objective findings of advanced HF including:

1. Current inotropic therapy or use of inotropes in the past 6 months

2. ≥ 1 hospitalization for heart failure in the past 6 months (not including the index hospitalization for inpatient participants)

3. LVEF ≤ 25% (within the past 12 months)

4. Peak VO2 < 55% predicted or peak VO2 ≤ 16 for men or ≤ 14 for women (Respiratory Exchange Ratio (RER) ≥ 1.05) (within the past 12 months)

5. 6 min walk test distance < 300 m (within the past 3 months)

5. Age ≥18 years and ≤ 85 years

6. Signed Informed Consent form

Exclusion Criteria

1. Currently taking Entresto™

2. History of hypersensitivity or intolerance (unmodifiable) to Entresto™, an ACEI or ARB as well as known or suspected contraindications (including hereditary angioedema) to the study drugs.

3. Estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73 m2 at baseline

4. Co-morbid conditions that may interfere with completing the study protocol (e.g. recent history of drug or alcohol abuse) or cause death within 1 year

5. Symptomatic hypotension at randomization or systolic blood pressure < 90 mmHg

6. Serum potassium > 5.5 mmol/L

7. Severe liver dysfunction (Childs-Pugh Class C)

8. Acute coronary syndrome within 4 weeks as defined by electrocardiographic (ECG) changes and biomarkers of myocardial necrosis (e.g. troponin) in an appropriate clinical setting (chest discomfort or anginal equivalent)

9. Planned or recent (≤ 4 weeks) PCI, coronary artery bypass grafting, or biventricular pacing

10. Currently hospitalized and listed status 1A, 1B or 1-4 for heart transplant

11. Current or scheduled for LVAD implantation within 30 days of study enrollment

12. Active infection (current use of oral or IV antimicrobial agents)

13. Primary hypertrophic or infiltrative cardiomyopathy, acute myocarditis, constrictive pericarditis or tamponade

14. Complex congenital heart disease

15. Concomitant use of aliskiren in patients with diabetes or renal impairment (eGFR <60 mL/min/1.73 m²)

16. Known pregnancy or anticipated pregnancy within the next 6 months or breastfeeding mothers

17. Enrollment in any other investigational clinical trial within 30 days prior to screening

18. Inability to comply with study procedures

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Duke University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Kevin Anstrom

Role: PRINCIPAL_INVESTIGATOR

Duke Health

Eugene Braunwald, MD

Role: STUDY_CHAIR

Harvard University

Locations

Cedars-Sinai Heart Institute

Beverly Hills, California, United States

Sutter Health Mills-Peninsula Health Services

Sacramento, California, United States

San Diego Cardiac Center

San Diego, California, United States

MedStar Washington Hospital Center

Washington D.C., District of Columbia, United States

Piedmont Heart Institute

Atlanta, Georgia, United States

Emory University School of Medicine

Atlanta, Georgia, United States

Advocate Christ Medical Center

Oak Lawn, Illinois, United States

St. Vincent Medical Group

Indianapolis, Indiana, United States

Ochsner Clinic Foundation

New Orleans, Louisiana, United States

Johns Hopkins Hospital

Baltimore, Maryland, United States

Tufts Medical Center

Boston, Massachusetts, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

University of Michigan Health System

Ann Arbor, Michigan, United States

Mayo Clinic

Rochester, Minnesota, United States

Washington University

St Louis, Missouri, United States

Saint Louis University Hospital

St Louis, Missouri, United States

Mount Sinai Hospital

New York, New York, United States

Stony Brook University Medical Center

Stony Brook, New York, United States

Charlotte-Mecklenburg Hospital Authority

Charlotte, North Carolina, United States

Duke University Medical Center

Durham, North Carolina, United States

The Christ Hospital

Cincinnati, Ohio, United States

Case Western Medical Center

Cleveland, Ohio, United States

Metro Health System

Cleveland, Ohio, United States

Cleveland Clinic

Cleveland, Ohio, United States

The Ohio State University Medical Center

Columbus, Ohio, United States

Integris Baptist Medical Center

Oklahoma City, Oklahoma, United States

Oregon Health and Science University

Portland, Oregon, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Thomas Jefferson University Hospital

Philadelphia, Pennsylvania, United States

Allegheny General Hospital

Pittsburgh, Pennsylvania, United States

Geisinger Medical Center

Wilkes-Barre, Pennsylvania, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Houston Methodist Research Institute

Houston, Texas, United States

University of Utah School of Medicine

Salt Lake City, Utah, United States

Inova Heart and Vascular Insititute

Falls Church, Virginia, United States

Sentara Norfolk General Hospital

Norfolk, Virginia, United States

University of Washington Medical Center

Seattle, Washington, United States

Countries

United States

References

Vader JM, Givertz MM, Starling RC, McNulty SE, Anstrom KJ, Desvigne-Nickens P, Hernandez AF, Braunwald E, Mann DL; LIFE Investigators. Tolerability of Sacubitril/Valsartan in Patients With Advanced Heart Failure: Analysis of the LIFE Trial Run-In. JACC Heart Fail. 2022 Jul;10(7):449-456. doi: 10.1016/j.jchf.2022.04.013.

Reference Type: DERIVED

PMID: 35772853 (View on PubMed)

Mann DL, Givertz MM, Vader JM, Starling RC, Shah P, McNulty SE, Anstrom KJ, Margulies KB, Kiernan MS, Mahr C, Gupta D, Redfield MM, Lala A, Lewis GD, DeVore AD, Desvigne-Nickens P, Hernandez AF, Braunwald E; LIFE Investigators. Effect of Treatment With Sacubitril/Valsartan in Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. JAMA Cardiol. 2022 Jan 1;7(1):17-25. doi: 10.1001/jamacardio.2021.4567.

Reference Type: DERIVED

PMID: 34730769 (View on PubMed)

Mann DL, Greene SJ, Givertz MM, Vader JM, Starling RC, Ambrosy AP, Shah P, McNulty SE, Mahr C, Gupta D, Redfield MM, Lala A, Lewis GD, Mohammed SF, Gilotra NA, DeVore AD, Gorodeski EZ, Desvigne-Nickens P, Hernandez AF, Braunwald E; LIFE Investigators. Sacubitril/Valsartan in Advanced Heart Failure With Reduced Ejection Fraction: Rationale and Design of the LIFE Trial. JACC Heart Fail. 2020 Oct;8(10):789-799. doi: 10.1016/j.jchf.2020.05.005. Epub 2020 Jun 10.

Reference Type: DERIVED

PMID: 32641226 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

5U01HL084904

Identifier Type: NIH

Identifier Source: secondary_id

View Link

Pro00071722

Identifier Type: -

Identifier Source: org_study_id