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

Sponsor
Duke University (Other)
Overall Status
Completed
CT.gov ID
NCT02816736
Collaborator
National Heart, Lung, and Blood Institute (NHLBI) (NIH)
365
Enrollment
38
Locations
2
Arms
42.9
Actual Duration (Months)
9.6
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

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 DiseaseIntervention/TreatmentPhase
Phase 4

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
365 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 :
Mar 2, 2017
Actual Primary Completion Date :
Sep 15, 2020
Actual Study Completion Date :
Sep 29, 2020

Arms and Interventions

ArmIntervention/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. * 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.
Other Names:
  • 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. * 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).
    Other Names:
  • 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.)

    Outcome Measures

    Primary Outcome Measures

    1. Change in NT-proBNP [Baseline, 2, 4, 8, 12, and 24 weeks]

      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.

    Secondary Outcome Measures

    1. Composite Endpoint of the Effects of LCZ696 (Number of Days) [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, 1B or 1-4), or undergoing transplant not implanted with an LVAD not maintained or started on continuous inotropic therapy for ≥ 7 days not hospitalized twice for HF (following the index admission) The days alive and out of hospital will end on the day of the second HF readmission, if applicable.

    2. Tolerability - Target Dose [Randomization through 24 weeks]

      Tolerability as measured by number of subjects achieving a target dose of 0% (stopped study drug early or was never started on study drug), 25%, 50% or 100% of valsartan or LCZ696 (based on last dose of study drug taken prior to end of study)

    3. Tolerability - Hypotension [Randomization through 24 weeks]

      Tolerability as measured by number of subjects developing hypotension (SBP ≤ 85 mmHg) with symptoms

    4. Tolerability - Renal Function [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 [Randomization through 24 weeks]

      Tolerability as measured by number of subjects developing moderate (>/= 5.5 mmol/L-5.9 mmol/L) or severe (>/= 6 mmol/L) hyperkalemia

    Other Outcome Measures

    1. Time to Death [Randomization through 24 weeks]

      Time to death through 24 weeks

    2. Time to First Heart Failure (HF) Hospitalization [Randomization through 24 weeks]

      Time to first HF hospitalization through 24 weeks

    3. Time to Death and First Heart Failure (HF) Hospitalization [Randomization through 24 weeks]

      Time to death and first HF hospitalization through 24 weeks

    4. Total Number of Heart Failure (HF) Hospitalizations [Randomization through 24 weeks]

      Total number of HF hospitalization admissions through 24 weeks

    5. Inotropic Therapy [Randomization through 24 weeks]

      Number of subjects on continuous inotropic therapy >/= 7 days after discharge from the index hospitalization through 24 weeks

    6. Number of Subjects Listed for Transplant (Status 1A, 1B or 1-4), Transplanted or Implanted With an LVAD [Randomization through 24 weeks]

      Number of subjects listed for transplant (status 1A, 1B or 1-4), transplanted or implanted with an LVAD through 24 weeks.

    7. Change in eGFR and Cystatin C Levels [Randomization through 24 weeks]

      Change in eGFR and cystatin C levels compared to baseline. Renal function will be assessed at baseline, 4, 8, 12, and 24 weeks

    8. Unanticipated IV Diuretic Use [Randomization through 24 weeks]

      Number of subjects with unanticipated use of IV diuretics (outpatient, ER or inpatient) through 24 weeks.

    9. Change in AUC in the Kansas City Cardiomyopathy Questionnaire (KCCQ) [Randomization through 24 weeks]

      Difference in AUC of the KCCQ at 4, 12 and 24 weeks

    10. Change in AUC for the Ratio of NT-proBNP/BNP [Randomization through 24 weeks]

      The change in AUC for the ratio of NT-proBNP/BNP from baseline to weeks 2, 4, 8, 12 and 24 weeks

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 85 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Advanced HFrEF defined as including ALL

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

    3. 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

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

    5. Systolic blood pressure ≥ 90 mmHg

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

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

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

    9. ≥ 1 hospitalization for heart failure in the past 6 months (not including the index hospitalization for inpatient participants)

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

    11. 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)

    12. 6 min walk test distance < 300 m (within the past 3 months)

    13. Age ≥18 years and ≤ 85 years

    14. 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

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Cedars-Sinai Heart InstituteBeverly HillsCaliforniaUnited States90211
    2Sutter Health Mills-Peninsula Health ServicesSacramentoCaliforniaUnited States95816
    3San Diego Cardiac CenterSan DiegoCaliforniaUnited States92123
    4MedStar Washington Hospital CenterWashingtonDistrict of ColumbiaUnited States20010
    5Piedmont Heart InstituteAtlantaGeorgiaUnited States30309
    6Emory University School of MedicineAtlantaGeorgiaUnited States30322
    7Advocate Christ Medical CenterOak LawnIllinoisUnited States60453
    8St. Vincent Medical GroupIndianapolisIndianaUnited States46260
    9Ochsner Clinic FoundationNew OrleansLouisianaUnited States70121
    10Johns Hopkins HospitalBaltimoreMarylandUnited States21287
    11Tufts Medical CenterBostonMassachusettsUnited States02111
    12Massachusetts General HospitalBostonMassachusettsUnited States02114
    13Brigham and Women's HospitalBostonMassachusettsUnited States02115
    14University of Michigan Health SystemAnn ArborMichiganUnited States48109
    15Mayo ClinicRochesterMinnesotaUnited States55905
    16Washington UniversitySaint LouisMissouriUnited States63110
    17Saint Louis University HospitalSaint LouisMissouriUnited States63117
    18Mount Sinai HospitalNew YorkNew YorkUnited States10029
    19Stony Brook University Medical CenterStony BrookNew YorkUnited States11794
    20Charlotte-Mecklenburg Hospital AuthorityCharlotteNorth CarolinaUnited States28203
    21Duke University Medical CenterDurhamNorth CarolinaUnited States27705
    22The Christ HospitalCincinnatiOhioUnited States45219
    23Case Western Medical CenterClevelandOhioUnited States44106
    24Metro Health SystemClevelandOhioUnited States44109
    25Cleveland ClinicClevelandOhioUnited States44195
    26The Ohio State University Medical CenterColumbusOhioUnited States43210
    27Integris Baptist Medical CenterOklahoma CityOklahomaUnited States73112
    28Oregon Health and Science UniversityPortlandOregonUnited States97239
    29University of PennsylvaniaPhiladelphiaPennsylvaniaUnited States19104
    30Thomas Jefferson University HospitalPhiladelphiaPennsylvaniaUnited States19107
    31Allegheny General HospitalPittsburghPennsylvaniaUnited States15212
    32Geisinger Medical CenterWilkes-BarrePennsylvaniaUnited States18711
    33Vanderbilt University Medical CenterNashvilleTennesseeUnited States37232
    34Houston Methodist Research InstituteHoustonTexasUnited States77030
    35University of Utah School of MedicineSalt Lake CityUtahUnited States84132
    36Inova Heart and Vascular InsitituteFalls ChurchVirginiaUnited States22042
    37Sentara Norfolk General HospitalNorfolkVirginiaUnited States23507
    38University of Washington Medical CenterSeattleWashingtonUnited States98195

    Sponsors and Collaborators

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

    Investigators

    • Principal Investigator: Kevin Anstrom, Duke Health
    • Study Chair: Eugene Braunwald, MD, Harvard University

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Duke University
    ClinicalTrials.gov Identifier:
    NCT02816736
    Other Study ID Numbers:
    • Pro00071722
    • 5U01HL084904
    First Posted:
    Jun 29, 2016
    Last Update Posted:
    Dec 3, 2021
    Last Verified:
    Dec 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Duke University
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group TitleLCZ696 (Entresto) + PlaceboValsartan + Placebo
    Arm/Group DescriptionLCZ696 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 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. 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.)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 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). 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.)
    Period Title: Overall Study
    STARTED179186
    COMPLETED164166
    NOT COMPLETED1520

    Baseline Characteristics

    Arm/Group TitleLCZ696 (Entresto) + PlaceboValsartan + PlaceboTotal
    Arm/Group DescriptionLCZ696 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 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. 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.)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 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). 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.)Total of all reporting groups
    Overall Participants179186365
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    60.0
    (13.7)
    58.8
    (13.0)
    59.4
    (13.3)
    Sex: Female, Male (Count of Participants)
    Female
    53
    29.6%
    50
    26.9%
    103
    28.2%
    Male
    126
    70.4%
    136
    73.1%
    262
    71.8%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    7
    3.9%
    13
    7%
    20
    5.5%
    Not Hispanic or Latino
    172
    96.1%
    173
    93%
    345
    94.5%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    1
    0.5%
    1
    0.3%
    Asian
    2
    1.1%
    2
    1.1%
    4
    1.1%
    Native Hawaiian or Other Pacific Islander
    2
    1.1%
    0
    0%
    2
    0.5%
    Black or African American
    67
    37.4%
    68
    36.6%
    135
    37%
    White
    107
    59.8%
    115
    61.8%
    222
    60.8%
    More than one race
    1
    0.6%
    0
    0%
    1
    0.3%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Region of Enrollment (Count of Participants)
    United States
    179
    100%
    186
    100%
    365
    100%

    Outcome Measures

    1. Primary Outcome
    TitleChange in NT-proBNP
    DescriptionThe 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.
    Time FrameBaseline, 2, 4, 8, 12, and 24 weeks

    Outcome Measure Data

    Analysis Population Description
    All randomized patients with baseline and at least one post-baseline NTpro BNP value present were included. Population was further reduced due to impact of COVID-19 by removing patients with inadequate follow-up after Feb 29th, 2020.
    Arm/Group TitleLCZ696 (Entresto) + PlaceboValsartan + Placebo
    Arm/Group DescriptionLCZ696 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 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. 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.)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 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). 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.)
    Measure Participants155158
    Mean (Standard Deviation) [unitless]
    0.14
    (0.65)
    0.19
    (0.50)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection LCZ696 (Entresto) + Placebo, Valsartan + Placebo
    Comments AUC was normalized for time; With the log-scale, the value of 0 indicates, on average, no change in NTproBNP from baseline.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.45
    Comments
    MethodRegression, Linear
    Comments
    Method of EstimationEstimation Parameterratio of the AUCs
    Estimated Value0.95
    Confidence Interval (2-Sided) 95%
    0.84 to 1.08
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    TitleComposite Endpoint of the Effects of LCZ696 (Number of Days)
    DescriptionComposite 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, 1B or 1-4), or undergoing transplant not implanted with an LVAD not maintained or started on continuous inotropic therapy for ≥ 7 days not hospitalized twice for HF (following the index admission) The days alive and out of hospital will end on the day of the second HF readmission, if applicable.
    Time FrameRandomization through 24 weeks

    Outcome Measure Data

    Analysis Population Description
    Population was reduced due to impact of COVID-19 by removing patients with inadequate follow-up after Feb 29th, 2020.
    Arm/Group TitleLCZ696 (Entresto) + PlaceboValsartan + Placebo
    Arm/Group DescriptionLCZ696 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 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. 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.)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 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). 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.)
    Measure Participants167168
    Mean (95% Confidence Interval) [days]
    108.58
    119.8
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection LCZ696 (Entresto) + Placebo, Valsartan + Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.15
    Comments
    Methodgeneral linear model
    Comments
    Method of EstimationEstimation ParameterMean Difference (Net)
    Estimated Value-11.22
    Confidence Interval (2-Sided) 95%
    -26.4 to 3.97
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    TitleTolerability - Target Dose
    DescriptionTolerability as measured by number of subjects achieving a target dose of 0% (stopped study drug early or was never started on study drug), 25%, 50% or 100% of valsartan or LCZ696 (based on last dose of study drug taken prior to end of study)
    Time FrameRandomization through 24 weeks

    Outcome Measure Data

    Analysis Population Description
    Population was reduced due to impact of COVID-19 by removing patients with inadequate follow-up after Feb 29th, 2020.
    Arm/Group TitleLCZ696 (Entresto) + PlaceboValsartan + Placebo
    Arm/Group DescriptionLCZ696 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 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. 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.)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 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). 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.)
    Measure Participants167168
    Not on study drug (0%)
    49
    27.4%
    37
    19.9%
    Low dose (25%)
    28
    15.6%
    41
    22%
    Mid dose (50%)
    33
    18.4%
    30
    16.1%
    High dose (100%)
    57
    31.8%
    60
    32.3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection LCZ696 (Entresto) + Placebo, Valsartan + Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.51
    Comments
    Methodordinal logistic regression
    Comments
    Method of EstimationEstimation ParameterOdds Ratio (OR)
    Estimated Value1.14
    Confidence Interval (2-Sided) 95%
    0.78 to 1.68
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    TitleTolerability - Hypotension
    DescriptionTolerability as measured by number of subjects developing hypotension (SBP ≤ 85 mmHg) with symptoms
    Time FrameRandomization through 24 weeks

    Outcome Measure Data

    Analysis Population Description
    Population was reduced due to impact of COVID-19 by removing patients with inadequate follow-up after Feb 29th, 2020.
    Arm/Group TitleLCZ696 (Entresto) + PlaceboValsartan + Placebo
    Arm/Group DescriptionLCZ696 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 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. 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.)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 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). 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.)
    Measure Participants167168
    Yes
    29
    16.2%
    20
    10.8%
    No
    138
    77.1%
    148
    79.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection LCZ696 (Entresto) + Placebo, Valsartan + Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.16
    Comments
    MethodRegression, Logistic
    Comments
    Method of EstimationEstimation ParameterOdds Ratio (OR)
    Estimated Value1.55
    Confidence Interval (2-Sided) 95%
    0.84 to 2.87
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    TitleTolerability - Renal Function
    DescriptionTolerability as measured by number of subjects developing worsening renal function (eGFR < 20 ml/min/1.73 m²)
    Time FrameRandomization through 24 weeks

    Outcome Measure Data

    Analysis Population Description
    Population was reduced due to impact of COVID-19 by removing patients with inadequate follow-up after Feb 29th, 2020.
    Arm/Group TitleLCZ696 (Entresto) + PlaceboValsartan + Placebo
    Arm/Group DescriptionLCZ696 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 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. 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.)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 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). 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.)
    Measure Participants167168
    Yes
    7
    3.9%
    7
    3.8%
    No
    160
    89.4%
    161
    86.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection LCZ696 (Entresto) + Placebo, Valsartan + Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.99
    Comments
    MethodRegression, Logistic
    Comments
    Method of EstimationEstimation ParameterOdds Ratio (OR)
    Estimated Value0.99
    Confidence Interval (2-Sided) 95%
    0.34 to 2.91
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    6. Secondary Outcome
    TitleTolerability - Hyperkalemia
    DescriptionTolerability as measured by number of subjects developing moderate (>/= 5.5 mmol/L-5.9 mmol/L) or severe (>/= 6 mmol/L) hyperkalemia
    Time FrameRandomization through 24 weeks

    Outcome Measure Data

    Analysis Population Description
    Population was reduced due to impact of COVID-19 by removing patients with inadequate follow-up after Feb 29th, 2020.
    Arm/Group TitleLCZ696 (Entresto) + PlaceboValsartan + Placebo
    Arm/Group DescriptionLCZ696 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 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. 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.)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 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). 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.)
    Measure Participants167168
    Yes
    28
    15.6%
    15
    8.1%
    No
    139
    77.7%
    153
    82.3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection LCZ696 (Entresto) + Placebo, Valsartan + Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.035
    Comments
    MethodRegression, Logistic
    Comments
    Method of EstimationEstimation ParameterOdds Ratio (OR)
    Estimated Value2.05
    Confidence Interval (2-Sided) 95%
    1.05 to 4.00
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    7. Other Pre-specified Outcome
    TitleTime to Death
    DescriptionTime to death through 24 weeks
    Time FrameRandomization through 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    8. Other Pre-specified Outcome
    TitleTime to First Heart Failure (HF) Hospitalization
    DescriptionTime to first HF hospitalization through 24 weeks
    Time FrameRandomization through 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    9. Other Pre-specified Outcome
    TitleTime to Death and First Heart Failure (HF) Hospitalization
    DescriptionTime to death and first HF hospitalization through 24 weeks
    Time FrameRandomization through 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    10. Other Pre-specified Outcome
    TitleTotal Number of Heart Failure (HF) Hospitalizations
    DescriptionTotal number of HF hospitalization admissions through 24 weeks
    Time FrameRandomization through 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    11. Other Pre-specified Outcome
    TitleInotropic Therapy
    DescriptionNumber of subjects on continuous inotropic therapy >/= 7 days after discharge from the index hospitalization through 24 weeks
    Time FrameRandomization through 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    12. Other Pre-specified Outcome
    TitleNumber of Subjects Listed for Transplant (Status 1A, 1B or 1-4), Transplanted or Implanted With an LVAD
    DescriptionNumber of subjects listed for transplant (status 1A, 1B or 1-4), transplanted or implanted with an LVAD through 24 weeks.
    Time FrameRandomization through 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    13. Other Pre-specified Outcome
    TitleChange in eGFR and Cystatin C Levels
    DescriptionChange in eGFR and cystatin C levels compared to baseline. Renal function will be assessed at baseline, 4, 8, 12, and 24 weeks
    Time FrameRandomization through 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    14. Other Pre-specified Outcome
    TitleUnanticipated IV Diuretic Use
    DescriptionNumber of subjects with unanticipated use of IV diuretics (outpatient, ER or inpatient) through 24 weeks.
    Time FrameRandomization through 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    15. Other Pre-specified Outcome
    TitleChange in AUC in the Kansas City Cardiomyopathy Questionnaire (KCCQ)
    DescriptionDifference in AUC of the KCCQ at 4, 12 and 24 weeks
    Time FrameRandomization through 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    16. Other Pre-specified Outcome
    TitleChange in AUC for the Ratio of NT-proBNP/BNP
    DescriptionThe change in AUC for the ratio of NT-proBNP/BNP from baseline to weeks 2, 4, 8, 12 and 24 weeks
    Time FrameRandomization through 24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description

    Adverse Events

    Time FrameRandomization to week 24
    Adverse Event Reporting Description Adverse event collection was limited to those meeting serious criteria; SAEs were assessed at each study visit/phone call conducted. Population was reduced due to impact of COVID-19 by removing patients with inadequate follow-up after Feb 29th, 2020.
    Arm/Group TitleLCZ696 (Entresto) + PlaceboValsartan + Placebo
    Arm/Group DescriptionLCZ696 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 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. 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.)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 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). 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.)
    All Cause Mortality
    LCZ696 (Entresto) + PlaceboValsartan + Placebo
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total13/167 (7.8%) 8/168 (4.8%)
    Serious Adverse Events
    LCZ696 (Entresto) + PlaceboValsartan + Placebo
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total43/167 (25.7%) 27/168 (16.1%)
    Blood and lymphatic system disorders
    Anaemia0/167 (0%) 01/168 (0.6%) 1
    Coagulopathy0/167 (0%) 02/168 (1.2%) 2
    Haemorrhagic Anaemia1/167 (0.6%) 10/168 (0%) 0
    Leukocytosis1/167 (0.6%) 11/168 (0.6%) 1
    Thrombocytopenia0/167 (0%) 01/168 (0.6%) 1
    Cardiac disorders
    Cardiac Failure1/167 (0.6%) 10/168 (0%) 0
    Coronary Artery Disease1/167 (0.6%) 10/168 (0%) 0
    Gastrointestinal disorders
    Abdominal Pain1/167 (0.6%) 10/168 (0%) 0
    Gastrointestinal Haemorrhage1/167 (0.6%) 12/168 (1.2%) 2
    Gastrooesophageal Reflux Disease0/167 (0%) 01/168 (0.6%) 1
    Haematochezia1/167 (0.6%) 10/168 (0%) 0
    Heal Ulcer1/167 (0.6%) 10/168 (0%) 0
    Ileus0/167 (0%) 01/168 (0.6%) 2
    Impaired Gastric Emptying1/167 (0.6%) 10/168 (0%) 0
    Large Intestinal Obstruction0/167 (0%) 01/168 (0.6%) 1
    Pancreatitis Acute1/167 (0.6%) 10/168 (0%) 0
    Rectal haemorrhage1/167 (0.6%) 10/168 (0%) 0
    Retroperitoneal haematoma1/167 (0.6%) 10/168 (0%) 0
    General disorders
    Complication Associated With Device0/167 (0%) 01/168 (0.6%) 1
    Multiple Organ Dysfunction Syndrome4/167 (2.4%) 40/168 (0%) 0
    Non-Cardiac Chest Pain1/167 (0.6%) 10/168 (0%) 0
    Pyrexia2/167 (1.2%) 20/168 (0%) 0
    Hepatobiliary disorders
    Cholecystitis Acute0/167 (0%) 01/168 (0.6%) 1
    Hepatic Failure0/167 (0%) 01/168 (0.6%) 1
    Immune system disorders
    Heart Transplant Rejection0/167 (0%) 01/168 (0.6%) 1
    Infections and infestations
    Abdominal Abscess0/167 (0%) 01/168 (0.6%) 2
    Appendicitis0/167 (0%) 01/168 (0.6%) 1
    Arthritis Infective1/167 (0.6%) 10/168 (0%) 0
    Bacteraemia1/167 (0.6%) 11/168 (0.6%) 1
    Bacterial Infection1/167 (0.6%) 10/168 (0%) 0
    Bronchitis Bacterial1/167 (0.6%) 10/168 (0%) 0
    Cellulitis1/167 (0.6%) 11/168 (0.6%) 1
    Device Related Infection1/167 (0.6%) 10/168 (0%) 0
    Endocarditis1/167 (0.6%) 10/168 (0%) 0
    Epididymitis0/167 (0%) 01/168 (0.6%) 1
    Gangrene1/167 (0.6%) 10/168 (0%) 0
    Gastroenteritis Bacterial0/167 (0%) 01/168 (0.6%) 1
    Hepatitis C0/167 (0%) 01/168 (0.6%) 1
    Infuenza1/167 (0.6%) 10/168 (0%) 0
    Ophthalmic herpes Zoster0/167 (0%) 01/168 (0.6%) 1
    Osteomyelitis0/167 (0%) 01/168 (0.6%) 1
    Pneumonia4/167 (2.4%) 43/168 (1.8%) 3
    Pneumonia Klebsiella1/167 (0.6%) 10/168 (0%) 0
    Respiratory syncytial Virus Infection1/167 (0.6%) 10/168 (0%) 0
    Sepsis2/167 (1.2%) 30/168 (0%) 0
    Septic Shock0/167 (0%) 02/168 (1.2%) 2
    Upper Respiratory Tract Infection1/167 (0.6%) 20/168 (0%) 0
    Urinary Tract Infection0/167 (0%) 01/168 (0.6%) 1
    Viral Upper Respirator Tract Infection1/167 (0.6%) 10/168 (0%) 0
    Injury, poisoning and procedural complications
    Accidental Overdose0/167 (0%) 01/168 (0.6%) 1
    Facial bones Fracture0/167 (0%) 01/168 (0.6%) 1
    Fall1/167 (0.6%) 10/168 (0%) 0
    Foreign body In Gastrointestinal Tract1/167 (0.6%) 10/168 (0%) 0
    Overdose0/167 (0%) 01/168 (0.6%) 1
    Post Procedural Haemorrhage1/167 (0.6%) 10/168 (0%) 0
    Subdural Haematoma1/167 (0.6%) 11/168 (0.6%) 1
    Investigations
    Anticoagulation Drug Level Below Therapeutic1/167 (0.6%) 10/168 (0%) 0
    Metabolism and nutrition disorders
    Dehydration2/167 (1.2%) 20/168 (0%) 0
    Diabetes Mellitus0/167 (0%) 01/168 (0.6%) 1
    Diabetic Ketoacidosis0/167 (0%) 01/168 (0.6%) 1
    Hyperglycaemia2/167 (1.2%) 21/168 (0.6%) 1
    Hyperglycaemic Hyperosmolar Nonketotic Syndrome0/167 (0%) 01/168 (0.6%) 1
    Hypoglycaemia0/167 (0%) 01/168 (0.6%) 1
    Hypokalaemia0/167 (0%) 02/168 (1.2%) 2
    Musculoskeletal and connective tissue disorders
    Costochondritis0/167 (0%) 01/168 (0.6%) 1
    Musculoskeletal Chest Pain0/167 (0%) 01/168 (0.6%) 1
    Musculoskeletal Pain0/167 (0%) 01/168 (0.6%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of Colon2/167 (1.2%) 20/168 (0%) 0
    Plasma Cell Myeloma1/167 (0.6%) 10/168 (0%) 0
    Rectal Adenocarcinoma0/167 (0%) 01/168 (0.6%) 1
    Nervous system disorders
    Encephalopathy1/167 (0.6%) 11/168 (0.6%) 1
    Seizure1/167 (0.6%) 10/168 (0%) 0
    Product Issues
    Device Dislocation1/167 (0.6%) 10/168 (0%) 0
    Lead Dislodgement1/167 (0.6%) 10/168 (0%) 0
    Psychiatric disorders
    Major Depression1/167 (0.6%) 10/168 (0%) 0
    Mania0/167 (0%) 01/168 (0.6%) 1
    Substance Abuse1/167 (0.6%) 10/168 (0%) 0
    Substance-Induced Psychotic Disorder0/167 (0%) 01/168 (0.6%) 1
    Renal and urinary disorders
    Urinary Tract Obstruction2/167 (1.2%) 20/168 (0%) 0
    Reproductive system and breast disorders
    Vaginal Haemorrhage1/167 (0.6%) 10/168 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Chronic Obstructive Pulmonary Disease1/167 (0.6%) 10/168 (0%) 0
    Epistaxis0/167 (0%) 01/168 (0.6%) 1
    Mediastinal Haematoma1/167 (0.6%) 10/168 (0%) 0
    Respiratory Failure2/167 (1.2%) 20/168 (0%) 0
    Skin and subcutaneous tissue disorders
    Diabetic ulcer1/167 (0.6%) 10/168 (0%) 0
    Vascular disorders
    Haematoma1/167 (0.6%) 10/168 (0%) 0
    Hypotension0/167 (0%) 01/168 (0.6%) 1
    Peripheral Ischaemia0/167 (0%) 01/168 (0.6%) 1
    Shock Haemorrhagic1/167 (0.6%) 10/168 (0%) 0
    Other (Not Including Serious) Adverse Events
    LCZ696 (Entresto) + PlaceboValsartan + Placebo
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total0/0 (NaN) 0/0 (NaN)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/TitleKevin J. Anstrom, Ph.D., Director of Biostatistics
    OrganizationDuke Clinical Research Institute
    Phone919-668-8902
    Emailkevin.anstrom@duke.edu
    Responsible Party:
    Duke University
    ClinicalTrials.gov Identifier:
    NCT02816736
    Other Study ID Numbers:
    • Pro00071722
    • 5U01HL084904
    First Posted:
    Jun 29, 2016
    Last Update Posted:
    Dec 3, 2021
    Last Verified:
    Dec 1, 2021