EntrestoTM (LCZ696) In Advanced Heart Failure (LIFE Study)
Condition: Heart Failure
MeSH terms: Heart Failure
Intervention: LCZ696; valsartan; LCZ696 placebo; valsartan placebo
Intervention description: 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.; 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 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 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 MeSH terms: Valsartan; Sacubitril and valsartan sodium hydrate drug combination
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 365.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: Heart Failure; Heart Diseases; Cardiovascular Diseases; Valsartan; Entresto

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.
    

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