EntrestoTM (LCZ696) In Advanced Heart Failure (LIFE Study)
Condition: Heart Failure
MeSH terms: Heart Failure
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): LCZ696; valsartan; LCZ696 placebo; valsartan placebo
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 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.)
Other intervention name(s): Entresto; Diovan
Intervention MeSH terms: Valsartan; Sacubitril and valsartan sodium hydrate drug combination
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Heart Failure; Heart Diseases; Cardiovascular Diseases; Valsartan; Entresto