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

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ClinicalTrials.gov Identifier: NCT02816736
Recruitment Status : Recruiting
First Posted : June 29, 2016
Last Update Posted : June 18, 2019
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Duke University

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.

Condition or disease Intervention/treatment Phase
Heart Failure Drug: LCZ696 Drug: valsartan Drug: LCZ696 placebo Drug: valsartan placebo Phase 4

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: EntrestoTM (LCZ696) In Advanced Heart Failure (LIFE Study)
Actual Study Start Date : March 2, 2017
Estimated Primary Completion Date : August 31, 2020
Estimated Study Completion Date : September 21, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure
Drug Information available for: Valsartan

Arm Intervention/treatment
Active Comparator: 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
Drug: 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.

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.

Other Name: Entresto

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.)

Active Comparator: 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
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.

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).

Other Name: Diovan

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.)




Primary Outcome Measures :
  1. Change in NT-proBNP [ Time Frame: Baseline, 2, 4, 8, 12, and 24 weeks ]
    The Core laboratory at Vermont will determine NT-proBNP levels to determine the proportional change from baseline in the AUC at 4, 8, 12, and 24 weeks.


Secondary Outcome Measures :
  1. Composite endpoint of the effects of LCZ696 (number of days) [ Time Frame: Randomization through 24 weeks ]

    Composite endpoint of effects of LCZ696 compared to valsartan over 24 weeks will be compared based upon the number of days subjects are

    • alive and out of hospital
    • not listed for transplant (Status 1A or 1B)
    • not implanted with an LVAD (or scheduled for implant within 2 weeks)
    • not maintained or started on continuous inotropic therapy for ≥ 7 days
    • not hospitalized twice for HF (following the index admission)

  2. Tolerability - target dose [ Time Frame: Randomization through 24 weeks ]
    Tolerability as measured by number of subjects achieving a target dose of 25%, 50% or 100% of valsartan or LCZ696

  3. Tolerability - hypotension [ Time Frame: Randomization through 24 weeks ]
    Tolerability as measured by number of subjects developing hypotension (SBP ≤ 85 mmHg) with symptoms

  4. Tolerability - renal function [ Time Frame: Randomization through 24 weeks ]
    Tolerability as measured by number of subjects developing worsening renal function (eGFR < 20 ml/min/1.73 m²)

  5. Tolerability - hyperkalemia [ Time Frame: Randomization through 24 weeks ]
    Tolerability as measured by number of subjects developing moderate (> 5.5 mmol/L) or severe (> 6 mmol/L) hyperkalemia

  6. Tolerability - inotropic therapy [ Time Frame: Randomization through 24 weeks ]
    Tolerability as measured by number of days on inotropic therapy following discharge for the index hospitalization

  7. Tolerability - use of IV diuretics [ Time Frame: Randomization through 24 weeks ]
    Tolerability as measured by number of subjects with unanticipated use of IV diuretics (outpatient, ER or inpatient)

  8. Tolerability - change in eGFR and cystatin C levels [ Time Frame: Randomization through 24 weeks ]
    Tolerability as measured by change in eGFR and cystatin C levels compared to baseline. Renal function will be assessed at baseline, 2, 4, 8, 12, and 24 weeks.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02816736


Contacts
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Contact: Pamela Monds 919-668-8695 pamela.monds@duke.edu
Contact: Teresa Atwood 919-668-8841 Teresal.Atwood@duke.edu

  Show 39 Study Locations
Sponsors and Collaborators
Duke University
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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Principal Investigator: Kevin Anstrom Duke University Health System
Study Chair: Eugene Braunwald, MD Harvard University

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Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT02816736     History of Changes
Other Study ID Numbers: Pro00071722
5U01HL084904 ( U.S. NIH Grant/Contract )
First Posted: June 29, 2016    Key Record Dates
Last Update Posted: June 18, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Duke University:
Heart Failure
Heart Diseases
Cardiovascular Diseases
Valsartan
Entresto
Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases
Valsartan
LCZ 696
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action