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

NCT02816736 | Completed Phase 4 Results DMC FDA Drug

• 2 other identifiers: Pro000717225U01HL084904
• Study Type: interventional
• Target: 365
• Locations: 1 country
• Sites: 38

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.

Conditions

Heart Failure

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Change in NT-proBNP

  The proportional change from baseline in the AUC for NT-proBNP levels measured at 2, 4, 8, 12, and 24 weeks. AUC was normalized for time and divided by the baseline value of NTproBNP so it has no unitshas no units. With the log-scale, the value of 0 indicates, on average, no change in NTproBNP from baseline. A value \> 0 indicates an increase in log NT Pro BNP relative to baseline and a value \< 0 indicates a decrease in log NT Pro BNP relative to baseline.

  Baseline, 2, 4, 8, 12, and 24 weeks

Secondary Outcomes (5)

• Composite Endpoint of the Effects of LCZ696 (Number of Days)

  Randomization through 24 weeks

• Tolerability - Target Dose

  Randomization through 24 weeks

• Tolerability - Hypotension

  Randomization through 24 weeks

• Tolerability - Renal Function

  Randomization through 24 weeks

• Tolerability - Hyperkalemia

  Randomization through 24 weeks

Other Outcomes (10)

• Time to Death

  Randomization through 24 weeks

• Time to First Heart Failure (HF) Hospitalization

  Randomization through 24 weeks

• Time to Death and First Heart Failure (HF) Hospitalization

  Randomization through 24 weeks

Study Arms (2)

LCZ696 (Entresto) + placebo

ACTIVE COMPARATOR

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

Drug: LCZ696; Drug: valsartan placebo

valsartan + placebo

ACTIVE COMPARATOR

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

Drug: valsartan; Drug: LCZ696 placebo

Interventions

LCZ696 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.

Also known as: Entresto

LCZ696 (Entresto) + placebo

valsartan 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).

Also known as: Diovan

valsartan + placebo

LCZ696 placebo 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.)

valsartan + placebo

valsartan placebo 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.)

LCZ696 (Entresto) + placebo

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Advanced HFrEF defined as including ALL
• LVEF≤ 35% documented during the preceding 12 months
• 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
• Minimum of 3 months GDMT for HF and/or intolerant to therapy
• Systolic blood pressure ≥ 90 mmHg
• Serum NT-proBNP ≥ 800 pg/mL OR BNP ≥ 250 pg/mL (most recent - less than 3 months old)
• Any one or more of the following objective findings of advanced HF including:
• Current inotropic therapy or use of inotropes in the past 6 months
• ≥ 1 hospitalization for heart failure in the past 6 months (not including the index hospitalization for inpatient participants)
• LVEF ≤ 25% (within the past 12 months)
• 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)
• min walk test distance \< 300 m (within the past 3 months)
• Age ≥18 years and ≤ 85 years
• Signed Informed Consent form

You may not qualify if:

• Currently taking Entresto™
• 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.
• Estimated glomerular filtration rate (eGFR) \< 20 mL/min/1.73 m2 at baseline
• 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
• Symptomatic hypotension at randomization or systolic blood pressure \< 90 mmHg
• Serum potassium \> 5.5 mmol/L
• Severe liver dysfunction (Childs-Pugh Class C)
• 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)
• Planned or recent (≤ 4 weeks) PCI, coronary artery bypass grafting, or biventricular pacing
• Currently hospitalized and listed status 1A, 1B or 1-4 for heart transplant
• Current or scheduled for LVAD implantation within 30 days of study enrollment
• Active infection (current use of oral or IV antimicrobial agents)
• Primary hypertrophic or infiltrative cardiomyopathy, acute myocarditis, constrictive pericarditis or tamponade
• Complex congenital heart disease
• Concomitant use of aliskiren in patients with diabetes or renal impairment (eGFR \<60 mL/min/1.73 m²)

Sponsors & Collaborators

• Duke University: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (38)

Cedars-Sinai Heart Institute

Beverly Hills, California, 90211, United States

Location

Sutter Health Mills-Peninsula Health Services

Sacramento, California, 95816, United States

Location

San Diego Cardiac Center

San Diego, California, 92123, United States

Location

MedStar Washington Hospital Center

Washington D.C., District of Columbia, 20010, United States

Location

Piedmont Heart Institute

Atlanta, Georgia, 30309, United States

Location

Emory University School of Medicine

Atlanta, Georgia, 30322, United States

Location

Advocate Christ Medical Center

Oak Lawn, Illinois, 60453, United States

Location

St. Vincent Medical Group

Indianapolis, Indiana, 46260, United States

Location

Ochsner Clinic Foundation

New Orleans, Louisiana, 70121, United States

Location

Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Tufts Medical Center

Boston, Massachusetts, 02111, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

University of Michigan Health System

Ann Arbor, Michigan, 48109, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Washington University

St Louis, Missouri, 63110, United States

Location

Saint Louis University Hospital

St Louis, Missouri, 63117, United States

Location

Mount Sinai Hospital

New York, New York, 10029, United States

Location

Stony Brook University Medical Center

Stony Brook, New York, 11794, United States

Location

Charlotte-Mecklenburg Hospital Authority

Charlotte, North Carolina, 28203, United States

Location

Duke University Medical Center

Durham, North Carolina, 27705, United States

Location

The Christ Hospital

Cincinnati, Ohio, 45219, United States

Location

Case Western Medical Center

Cleveland, Ohio, 44106, United States

Location

Metro Health System

Cleveland, Ohio, 44109, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

The Ohio State University Medical Center

Columbus, Ohio, 43210, United States

Location

Integris Baptist Medical Center

Oklahoma City, Oklahoma, 73112, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Thomas Jefferson University Hospital

Philadelphia, Pennsylvania, 19107, United States

Location

Allegheny General Hospital

Pittsburgh, Pennsylvania, 15212, United States

Location

Geisinger Medical Center

Wilkes-Barre, Pennsylvania, 18711, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

Houston Methodist Research Institute

Houston, Texas, 77030, United States

Location

University of Utah School of Medicine

Salt Lake City, Utah, 84132, United States

Location

Inova Heart and Vascular Insititute

Falls Church, Virginia, 22042, United States

Location

Sentara Norfolk General Hospital

Norfolk, Virginia, 23507, United States

Location

University of Washington Medical Center

Seattle, Washington, 98195, United States

Location

Related Publications (3)

• 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.

  PMID: 35772853 DERIVED

• 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.

  PMID: 34730769 DERIVED

• 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.

  PMID: 32641226 DERIVED

MeSH Terms

Conditions

Heart Failure; Heart Diseases; Cardiovascular Diseases

Interventions

sacubitril and valsartan sodium hydrate drug combination; Valsartan

Intervention Hierarchy (Ancestors)

Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Valine; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential

Results Point of Contact

• Title: Kevin J. Anstrom, Ph.D., Director of Biostatistics
• Organization: Duke Clinical Research Institute

kevin.anstrom@duke.edu

919-668-8902

Study Officials

• Kevin Anstrom

  Duke Health

  PRINCIPAL INVESTIGATOR

• Eugene Braunwald, MD

  Harvard University

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 13, 2016
• First Posted: June 29, 2016
• Study Start: March 2, 2017
• Primary Completion: September 15, 2020
• Study Completion: September 29, 2020
• Last Updated: December 3, 2021
• Results First Posted: December 3, 2021

Record last verified: 2021-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (38)