EntrestoTM (LCZ696) In Advanced Heart Failure (LIFE Study) (HFN-LIFE)
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ClinicalTrials.gov Identifier: NCT02816736 |
Recruitment Status :
Completed
First Posted : June 29, 2016
Results First Posted : December 3, 2021
Last Update Posted : December 3, 2021
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Condition or disease | Intervention/treatment | Phase |
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Heart Failure | Drug: LCZ696 Drug: valsartan Drug: LCZ696 placebo Drug: valsartan placebo | Phase 4 |
Study Type : | Interventional (Clinical Trial) |
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 : | March 2, 2017 |
Actual Primary Completion Date : | September 15, 2020 |
Actual Study Completion Date : | September 29, 2020 |
Arm | Intervention/treatment |
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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
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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 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
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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 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.) |
- Change in NT-proBNP [ Time Frame: 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.
- 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, 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.
- Tolerability - Target Dose [ Time Frame: 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)
- Tolerability - Hypotension [ Time Frame: Randomization through 24 weeks ]Tolerability as measured by number of subjects developing hypotension (SBP ≤ 85 mmHg) with symptoms
- 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)
- Tolerability - Hyperkalemia [ Time Frame: 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
- Time to Death [ Time Frame: Randomization through 24 weeks ]Time to death through 24 weeks
- Time to First Heart Failure (HF) Hospitalization [ Time Frame: Randomization through 24 weeks ]Time to first HF hospitalization through 24 weeks
- Time to Death and First Heart Failure (HF) Hospitalization [ Time Frame: Randomization through 24 weeks ]Time to death and first HF hospitalization through 24 weeks
- Total Number of Heart Failure (HF) Hospitalizations [ Time Frame: Randomization through 24 weeks ]Total number of HF hospitalization admissions through 24 weeks
- Inotropic Therapy [ Time Frame: Randomization through 24 weeks ]Number of subjects on continuous inotropic therapy >/= 7 days after discharge from the index hospitalization through 24 weeks
- Number of Subjects Listed for Transplant (Status 1A, 1B or 1-4), Transplanted or Implanted With an LVAD [ Time Frame: 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.
- Change in eGFR and Cystatin C Levels [ Time Frame: 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
- Unanticipated IV Diuretic Use [ Time Frame: Randomization through 24 weeks ]Number of subjects with unanticipated use of IV diuretics (outpatient, ER or inpatient) through 24 weeks.
- Change in AUC in the Kansas City Cardiomyopathy Questionnaire (KCCQ) [ Time Frame: Randomization through 24 weeks ]Difference in AUC of the KCCQ at 4, 12 and 24 weeks
- Change in AUC for the Ratio of NT-proBNP/BNP [ Time Frame: 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
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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 |
Inclusion Criteria:
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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)
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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)
- 6 min walk test distance < 300 m (within the past 3 months)
- Age ≥18 years and ≤ 85 years
- Signed Informed Consent form
Exclusion Criteria:
- 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)
- Known pregnancy or anticipated pregnancy within the next 6 months or breastfeeding mothers
- Enrollment in any other investigational clinical trial within 30 days prior to screening
- Inability to comply with study procedures
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
Principal Investigator: | Kevin Anstrom | Duke Health | |
Study Chair: | Eugene Braunwald, MD | Harvard University |
Documents provided by Duke University:
Responsible Party: | Duke University |
ClinicalTrials.gov Identifier: | NCT02816736 |
Other Study ID Numbers: |
Pro00071722 5U01HL084904 ( U.S. NIH Grant/Contract ) |
First Posted: | June 29, 2016 Key Record Dates |
Results First Posted: | December 3, 2021 |
Last Update Posted: | December 3, 2021 |
Last Verified: | December 2021 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
Heart Failure Heart Diseases Cardiovascular Diseases Valsartan Entresto |
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