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

• ClinicalTrials.gov Identifier: NCT02816736
• Recruitment Status: Completed
• First Posted: June 29, 2016
• Results First Posted: December 3, 2021
• Last Update Posted: December 3, 2021
• Sponsor: Duke University
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Duke University

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Heart Failure
• Interventions: Drug: LCZ696; Drug: valsartan; Drug: LCZ696 placebo; Drug: valsartan placebo
• Enrollment: 365

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	LCZ696 (Entresto) + Placebo	Valsartan + Placebo
Arm/Group Description	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 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
Started [1]	179	186
Completed [2]	164	166
Not Completed	15	20
[1] Started is defined as randomized; [2] Completed is defined as all patients that died or completed follow-up.

Baseline Characteristics

Arm/Group Title		LCZ696 (Entresto) + Placebo	Valsartan + Placebo	Total
Arm/Group Description		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 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 Number of Baseline Participants		179	186	365
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	179 participants	186 participants	365 participants
		60.0 (13.7)	58.8 (13.0)	59.4 (13.3)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	179 participants	186 participants	365 participants
	Female	53 29.6%	50 26.9%	103 28.2%
	Male	126 70.4%	136 73.1%	262 71.8%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	179 participants	186 participants	365 participants
	Hispanic or Latino	7 3.9%	13 7.0%	20 5.5%
	Not Hispanic or Latino	172 96.1%	173 93.0%	345 94.5%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	179 participants	186 participants	365 participants
	American Indian or Alaska Native	0 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 0.0%	2 0.5%
	Black or African American	67 37.4%	68 36.6%	135 37.0%
	White	107 59.8%	115 61.8%	222 60.8%
	More than one race	1 0.6%	0 0.0%	1 0.3%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants
United States	Number Analyzed	179 participants	186 participants	365 participants
		179 100.0%	186 100.0%	365 100.0%

Outcome Measures

1. Primary Outcome

Title	Change in NT-proBNP
Description	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.
Time Frame	Baseline, 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 Title	LCZ696 (Entresto) + Placebo	Valsartan + Placebo
Arm/Group Description:	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 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.)
Overall Number of Participants Analyzed	155	158
Mean (Standard Deviation); Unit of Measure: 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	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.45
	Comments	[Not Specified]
	Method	Regression, Linear
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	ratio of the AUCs
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95%; 0.84 to 1.08
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Composite Endpoint of the Effects of LCZ696 (Number of Days)
Description	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.
Time Frame	Randomization 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 Title	LCZ696 (Entresto) + Placebo	Valsartan + Placebo
Arm/Group Description:	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 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.)
Overall Number of Participants Analyzed	167	168
Mean (95% Confidence Interval); Unit of Measure: days
	108.58; (95.22 to 121.95)	119.8; (107.64 to 131.96)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Entresto) + Placebo, Valsartan + Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.15
	Comments	[Not Specified]
	Method	general linear model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-11.22
	Confidence Interval	(2-Sided) 95%; -26.4 to 3.97
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Tolerability - Target Dose
Description	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)
Time Frame	Randomization 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 Title	LCZ696 (Entresto) + Placebo	Valsartan + Placebo
Arm/Group Description:	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 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.)
Overall Number of Participants Analyzed	167	168
Measure Type: Count of Participants; Unit of Measure: Participants
Not on study drug (0%)	49 29.3%	37 22.0%
Low dose (25%)	28 16.8%	41 24.4%
Mid dose (50%)	33 19.8%	30 17.9%
High dose (100%)	57 34.1%	60 35.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Entresto) + Placebo, Valsartan + Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.51
	Comments	[Not Specified]
	Method	ordinal logistic regression
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.78 to 1.68
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Tolerability - Hypotension
Description	Tolerability as measured by number of subjects developing hypotension (SBP ≤ 85 mmHg) with symptoms
Time Frame	Randomization 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 Title	LCZ696 (Entresto) + Placebo	Valsartan + Placebo
Arm/Group Description:	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 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.)
Overall Number of Participants Analyzed	167	168
Measure Type: Count of Participants; Unit of Measure: Participants
Yes	29 17.4%	20 11.9%
No	138 82.6%	148 88.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Entresto) + Placebo, Valsartan + Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.16
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.55
	Confidence Interval	(2-Sided) 95%; 0.84 to 2.87
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Tolerability - Renal Function
Description	Tolerability as measured by number of subjects developing worsening renal function (eGFR < 20 ml/min/1.73 m²)
Time Frame	Randomization 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 Title	LCZ696 (Entresto) + Placebo	Valsartan + Placebo
Arm/Group Description:	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 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.)
Overall Number of Participants Analyzed	167	168
Measure Type: Count of Participants; Unit of Measure: Participants
Yes	7 4.2%	7 4.2%
No	160 95.8%	161 95.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Entresto) + Placebo, Valsartan + Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.99
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.34 to 2.91
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Tolerability - Hyperkalemia
Description	Tolerability as measured by number of subjects developing moderate (>/= 5.5 mmol/L-5.9 mmol/L) or severe (>/= 6 mmol/L) hyperkalemia
Time Frame	Randomization 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 Title	LCZ696 (Entresto) + Placebo	Valsartan + Placebo
Arm/Group Description:	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 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.)
Overall Number of Participants Analyzed	167	168
Measure Type: Count of Participants; Unit of Measure: Participants
Yes	28 16.8%	15 8.9%
No	139 83.2%	153 91.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LCZ696 (Entresto) + Placebo, Valsartan + Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.035
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.05
	Confidence Interval	(2-Sided) 95%; 1.05 to 4.00
	Estimation Comments	[Not Specified]

7. Other Pre-specified Outcome

Title	Time to Death
Description	Time to death through 24 weeks
Time Frame	Randomization through 24 weeks

Outcome Measure Data Not Reported

8. Other Pre-specified Outcome

Title	Time to First Heart Failure (HF) Hospitalization
Description	Time to first HF hospitalization through 24 weeks
Time Frame	Randomization through 24 weeks

Outcome Measure Data Not Reported

9. Other Pre-specified Outcome

Title	Time to Death and First Heart Failure (HF) Hospitalization
Description	Time to death and first HF hospitalization through 24 weeks
Time Frame	Randomization through 24 weeks

Outcome Measure Data Not Reported

10. Other Pre-specified Outcome

Title	Total Number of Heart Failure (HF) Hospitalizations
Description	Total number of HF hospitalization admissions through 24 weeks
Time Frame	Randomization through 24 weeks

Outcome Measure Data Not Reported

11. Other Pre-specified Outcome

Title	Inotropic Therapy
Description	Number of subjects on continuous inotropic therapy >/= 7 days after discharge from the index hospitalization through 24 weeks
Time Frame	Randomization through 24 weeks

Outcome Measure Data Not Reported

12. Other Pre-specified Outcome

Title	Number of Subjects Listed for Transplant (Status 1A, 1B or 1-4), Transplanted or Implanted With an LVAD
Description	Number of subjects listed for transplant (status 1A, 1B or 1-4), transplanted or implanted with an LVAD through 24 weeks.
Time Frame	Randomization through 24 weeks

Outcome Measure Data Not Reported

13. Other Pre-specified Outcome

Title	Change in eGFR and Cystatin C Levels
Description	Change in eGFR and cystatin C levels compared to baseline. Renal function will be assessed at baseline, 4, 8, 12, and 24 weeks
Time Frame	Randomization through 24 weeks

Outcome Measure Data Not Reported

14. Other Pre-specified Outcome

Title	Unanticipated IV Diuretic Use
Description	Number of subjects with unanticipated use of IV diuretics (outpatient, ER or inpatient) through 24 weeks.
Time Frame	Randomization through 24 weeks

Outcome Measure Data Not Reported

15. Other Pre-specified Outcome

Title	Change in AUC in the Kansas City Cardiomyopathy Questionnaire (KCCQ)
Description	Difference in AUC of the KCCQ at 4, 12 and 24 weeks
Time Frame	Randomization through 24 weeks

Outcome Measure Data Not Reported

16. Other Pre-specified Outcome

Title	Change in AUC for the Ratio of NT-proBNP/BNP
Description	The change in AUC for the ratio of NT-proBNP/BNP from baseline to weeks 2, 4, 8, 12 and 24 weeks
Time Frame	Randomization through 24 weeks

Outcome Measure Data Not Reported

Adverse Events

Time Frame	Randomization 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 Title	LCZ696 (Entresto) + Placebo		Valsartan + Placebo
Arm/Group Description	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 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) + Placebo		Valsartan + Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	13/167 (7.78%)		8/168 (4.76%)
Serious Adverse Events
	LCZ696 (Entresto) + Placebo		Valsartan + Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/167 (25.75%)		27/168 (16.07%)
Blood and lymphatic system disorders
Anaemia † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Coagulopathy † 1	0/167 (0.00%)	0	2/168 (1.19%)	2
Haemorrhagic Anaemia † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Leukocytosis † 1	1/167 (0.60%)	1	1/168 (0.60%)	1
Thrombocytopenia † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Cardiac disorders
Cardiac Failure † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Coronary Artery Disease † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Gastrointestinal disorders
Abdominal Pain † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Gastrointestinal Haemorrhage † 1	1/167 (0.60%)	1	2/168 (1.19%)	2
Gastrooesophageal Reflux Disease † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Haematochezia † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Heal Ulcer † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Ileus † 1	0/167 (0.00%)	0	1/168 (0.60%)	2
Impaired Gastric Emptying † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Large Intestinal Obstruction † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Pancreatitis Acute † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Rectal haemorrhage † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Retroperitoneal haematoma † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
General disorders
Complication Associated With Device † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Multiple Organ Dysfunction Syndrome † 1	4/167 (2.40%)	4	0/168 (0.00%)	0
Non-Cardiac Chest Pain † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Pyrexia † 1	2/167 (1.20%)	2	0/168 (0.00%)	0
Hepatobiliary disorders
Cholecystitis Acute † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Hepatic Failure † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Immune system disorders
Heart Transplant Rejection † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Infections and infestations
Abdominal Abscess † 1	0/167 (0.00%)	0	1/168 (0.60%)	2
Appendicitis † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Arthritis Infective † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Bacteraemia † 1	1/167 (0.60%)	1	1/168 (0.60%)	1
Bacterial Infection † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Bronchitis Bacterial † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Cellulitis † 1	1/167 (0.60%)	1	1/168 (0.60%)	1
Device Related Infection † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Endocarditis † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Epididymitis † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Gangrene † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Gastroenteritis Bacterial † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Hepatitis C † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Infuenza † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Ophthalmic herpes Zoster † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Osteomyelitis † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Pneumonia † 1	4/167 (2.40%)	4	3/168 (1.79%)	3
Pneumonia Klebsiella † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Respiratory syncytial Virus Infection † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Sepsis † 1	2/167 (1.20%)	3	0/168 (0.00%)	0
Septic Shock † 1	0/167 (0.00%)	0	2/168 (1.19%)	2
Upper Respiratory Tract Infection † 1	1/167 (0.60%)	2	0/168 (0.00%)	0
Urinary Tract Infection † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Viral Upper Respirator Tract Infection † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Injury, poisoning and procedural complications
Accidental Overdose † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Facial bones Fracture † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Fall † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Foreign body In Gastrointestinal Tract † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Overdose † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Post Procedural Haemorrhage † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Subdural Haematoma † 1	1/167 (0.60%)	1	1/168 (0.60%)	1
Investigations
Anticoagulation Drug Level Below Therapeutic † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Metabolism and nutrition disorders
Dehydration † 1	2/167 (1.20%)	2	0/168 (0.00%)	0
Diabetes Mellitus † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Diabetic Ketoacidosis † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Hyperglycaemia † 1	2/167 (1.20%)	2	1/168 (0.60%)	1
Hyperglycaemic Hyperosmolar Nonketotic Syndrome † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Hypoglycaemia † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Hypokalaemia † 1	0/167 (0.00%)	0	2/168 (1.19%)	2
Musculoskeletal and connective tissue disorders
Costochondritis † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Musculoskeletal Chest Pain † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Musculoskeletal Pain † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of Colon † 1	2/167 (1.20%)	2	0/168 (0.00%)	0
Plasma Cell Myeloma † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Rectal Adenocarcinoma † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Nervous system disorders
Encephalopathy † 1	1/167 (0.60%)	1	1/168 (0.60%)	1
Seizure † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Product Issues
Device Dislocation † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Lead Dislodgement † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Psychiatric disorders
Major Depression † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Mania † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Substance Abuse † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Substance-Induced Psychotic Disorder † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Renal and urinary disorders
Urinary Tract Obstruction † 1	2/167 (1.20%)	2	0/168 (0.00%)	0
Reproductive system and breast disorders
Vaginal Haemorrhage † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Chronic Obstructive Pulmonary Disease † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Epistaxis † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Mediastinal Haematoma † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Respiratory Failure † 1	2/167 (1.20%)	2	0/168 (0.00%)	0
Skin and subcutaneous tissue disorders
Diabetic ulcer † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Vascular disorders
Haematoma † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
Hypotension † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Peripheral Ischaemia † 1	0/167 (0.00%)	0	1/168 (0.60%)	1
Shock Haemorrhagic † 1	1/167 (0.60%)	1	0/168 (0.00%)	0
1 Term from vocabulary, MedDRA (19.0); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	LCZ696 (Entresto) + Placebo		Valsartan + Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0		0/0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Kevin J. Anstrom, Ph.D., Director of Biostatistics
• Organization: Duke Clinical Research Institute
• Phone: 919-668-8902
• EMail: kevin.anstrom@duke.edu

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Vader JM, Givertz MM, Starling RC, McNulty SE, Anstrom KJ, Desvigne-Nickens P, Hernandez AF, Braunwald E, Mann DL; LIFE Investigators. Tolerability of Sacubitril/Valsartan in Patients With Advanced Heart Failure: Analysis of the LIFE Trial Run-In. JACC Heart Fail. 2022 Jul;10(7):449-456. doi: 10.1016/j.jchf.2022.04.013.

Mann DL, Givertz MM, Vader JM, Starling RC, Shah P, McNulty SE, Anstrom KJ, Margulies KB, Kiernan MS, Mahr C, Gupta D, Redfield MM, Lala A, Lewis GD, DeVore AD, Desvigne-Nickens P, Hernandez AF, Braunwald E; LIFE Investigators. Effect of Treatment With Sacubitril/Valsartan in Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. JAMA Cardiol. 2022 Jan 1;7(1):17-25. doi: 10.1001/jamacardio.2021.4567.

Mann DL, Greene SJ, Givertz MM, Vader JM, Starling RC, Ambrosy AP, Shah P, McNulty SE, Mahr C, Gupta D, Redfield MM, Lala A, Lewis GD, Mohammed SF, Gilotra NA, DeVore AD, Gorodeski EZ, Desvigne-Nickens P, Hernandez AF, Braunwald E; LIFE Investigators. Sacubitril/Valsartan in Advanced Heart Failure With Reduced Ejection Fraction: Rationale and Design of the LIFE Trial. JACC Heart Fail. 2020 Oct;8(10):789-799. doi: 10.1016/j.jchf.2020.05.005. Epub 2020 Jun 10. Erratum In: JACC Heart Fail. 2020 Dec;8(12):1059.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT02816736
• Other Study ID Numbers: Pro00071722; 5U01HL084904 ( U.S. NIH Grant/Contract )
• First Submitted: June 13, 2016
• First Posted: June 29, 2016
• Results First Submitted: September 15, 2021
• Results First Posted: December 3, 2021
• Last Update Posted: December 3, 2021