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)
• Enrollment: 365
• Locations: 38
• Arms: 2
• Actual Duration (Months): 42.9
• Patients Per Site: 9.6
• Patients Per Site Per Month: 0.2

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 Disease	Intervention/Treatment	Phase
Heart Failure	Drug: LCZ696; Drug: valsartan; Drug: LCZ696 placebo; Drug: valsartan placebo	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

Arm	Intervention/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

	Site	City	State	Country	Postal Code
1	Cedars-Sinai Heart Institute	Beverly Hills	California	United States	90211
2	Sutter Health Mills-Peninsula Health Services	Sacramento	California	United States	95816
3	San Diego Cardiac Center	San Diego	California	United States	92123
4	MedStar Washington Hospital Center	Washington	District of Columbia	United States	20010
5	Piedmont Heart Institute	Atlanta	Georgia	United States	30309
6	Emory University School of Medicine	Atlanta	Georgia	United States	30322
7	Advocate Christ Medical Center	Oak Lawn	Illinois	United States	60453
8	St. Vincent Medical Group	Indianapolis	Indiana	United States	46260
9	Ochsner Clinic Foundation	New Orleans	Louisiana	United States	70121
10	Johns Hopkins Hospital	Baltimore	Maryland	United States	21287
11	Tufts Medical Center	Boston	Massachusetts	United States	02111
12	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
13	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
14	University of Michigan Health System	Ann Arbor	Michigan	United States	48109
15	Mayo Clinic	Rochester	Minnesota	United States	55905
16	Washington University	Saint Louis	Missouri	United States	63110
17	Saint Louis University Hospital	Saint Louis	Missouri	United States	63117
18	Mount Sinai Hospital	New York	New York	United States	10029
19	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
20	Charlotte-Mecklenburg Hospital Authority	Charlotte	North Carolina	United States	28203
21	Duke University Medical Center	Durham	North Carolina	United States	27705
22	The Christ Hospital	Cincinnati	Ohio	United States	45219
23	Case Western Medical Center	Cleveland	Ohio	United States	44106
24	Metro Health System	Cleveland	Ohio	United States	44109
25	Cleveland Clinic	Cleveland	Ohio	United States	44195
26	The Ohio State University Medical Center	Columbus	Ohio	United States	43210
27	Integris Baptist Medical Center	Oklahoma City	Oklahoma	United States	73112
28	Oregon Health and Science University	Portland	Oregon	United States	97239
29	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
30	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
31	Allegheny General Hospital	Pittsburgh	Pennsylvania	United States	15212
32	Geisinger Medical Center	Wilkes-Barre	Pennsylvania	United States	18711
33	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
34	Houston Methodist Research Institute	Houston	Texas	United States	77030
35	University of Utah School of Medicine	Salt Lake City	Utah	United States	84132
36	Inova Heart and Vascular Insititute	Falls Church	Virginia	United States	22042
37	Sentara Norfolk General Hospital	Norfolk	Virginia	United States	23507
38	University of Washington Medical Center	Seattle	Washington	United States	98195

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)

• Study Protocol - Feb 20, 2019
• Statistical Analysis Plan - Sep 11, 2020
• Informed Consent Form - Feb 20, 2019

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: Heart Failure; Heart Diseases; Cardiovascular Diseases; Valsartan; Entresto
• Additional relevant MeSH terms: Heart Failure; Valsartan; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

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	179	186
COMPLETED	164	166
NOT COMPLETED	15	20

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 Participants	179	186	365
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

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.)
Measure Participants	155	158
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 Hypothesis	p-Value	0.45
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	ratio of the AUCs
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95%; 0.84 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

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.)
Measure Participants	167	168
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 Hypothesis	p-Value	0.15
	Comments
	Method	general linear model
	Comments
Method of Estimation	Estimation Parameter	Mean 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

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.)
Measure Participants	167	168
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 Hypothesis	p-Value	0.51
	Comments
	Method	ordinal logistic regression
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.78 to 1.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

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.)
Measure Participants	167	168
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 Hypothesis	p-Value	0.16
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.55
	Confidence Interval	(2-Sided) 95%; 0.84 to 2.87
	Parameter Dispersion	Type: Value:
	Estimation Comments

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.)
Measure Participants	167	168
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 Hypothesis	p-Value	0.99
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.34 to 2.91
	Parameter Dispersion	Type: Value:
	Estimation Comments

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.)
Measure Participants	167	168
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 Hypothesis	p-Value	0.035
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.05
	Confidence Interval	(2-Sided) 95%; 1.05 to 4.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

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

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

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

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

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

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

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

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

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

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

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

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

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

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

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

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

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

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

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

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

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 (%)	# Events	Affected / at Risk (%)	# Events
Total	13/167 (7.8%)		8/168 (4.8%)
Serious Adverse Events
	LCZ696 (Entresto) + Placebo		Valsartan + Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/167 (25.7%)		27/168 (16.1%)
Blood and lymphatic system disorders
Anaemia	0/167 (0%)	0	1/168 (0.6%)	1
Coagulopathy	0/167 (0%)	0	2/168 (1.2%)	2
Haemorrhagic Anaemia	1/167 (0.6%)	1	0/168 (0%)	0
Leukocytosis	1/167 (0.6%)	1	1/168 (0.6%)	1
Thrombocytopenia	0/167 (0%)	0	1/168 (0.6%)	1
Cardiac disorders
Cardiac Failure	1/167 (0.6%)	1	0/168 (0%)	0
Coronary Artery Disease	1/167 (0.6%)	1	0/168 (0%)	0
Gastrointestinal disorders
Abdominal Pain	1/167 (0.6%)	1	0/168 (0%)	0
Gastrointestinal Haemorrhage	1/167 (0.6%)	1	2/168 (1.2%)	2
Gastrooesophageal Reflux Disease	0/167 (0%)	0	1/168 (0.6%)	1
Haematochezia	1/167 (0.6%)	1	0/168 (0%)	0
Heal Ulcer	1/167 (0.6%)	1	0/168 (0%)	0
Ileus	0/167 (0%)	0	1/168 (0.6%)	2
Impaired Gastric Emptying	1/167 (0.6%)	1	0/168 (0%)	0
Large Intestinal Obstruction	0/167 (0%)	0	1/168 (0.6%)	1
Pancreatitis Acute	1/167 (0.6%)	1	0/168 (0%)	0
Rectal haemorrhage	1/167 (0.6%)	1	0/168 (0%)	0
Retroperitoneal haematoma	1/167 (0.6%)	1	0/168 (0%)	0
General disorders
Complication Associated With Device	0/167 (0%)	0	1/168 (0.6%)	1
Multiple Organ Dysfunction Syndrome	4/167 (2.4%)	4	0/168 (0%)	0
Non-Cardiac Chest Pain	1/167 (0.6%)	1	0/168 (0%)	0
Pyrexia	2/167 (1.2%)	2	0/168 (0%)	0
Hepatobiliary disorders
Cholecystitis Acute	0/167 (0%)	0	1/168 (0.6%)	1
Hepatic Failure	0/167 (0%)	0	1/168 (0.6%)	1
Immune system disorders
Heart Transplant Rejection	0/167 (0%)	0	1/168 (0.6%)	1
Infections and infestations
Abdominal Abscess	0/167 (0%)	0	1/168 (0.6%)	2
Appendicitis	0/167 (0%)	0	1/168 (0.6%)	1
Arthritis Infective	1/167 (0.6%)	1	0/168 (0%)	0
Bacteraemia	1/167 (0.6%)	1	1/168 (0.6%)	1
Bacterial Infection	1/167 (0.6%)	1	0/168 (0%)	0
Bronchitis Bacterial	1/167 (0.6%)	1	0/168 (0%)	0
Cellulitis	1/167 (0.6%)	1	1/168 (0.6%)	1
Device Related Infection	1/167 (0.6%)	1	0/168 (0%)	0
Endocarditis	1/167 (0.6%)	1	0/168 (0%)	0
Epididymitis	0/167 (0%)	0	1/168 (0.6%)	1
Gangrene	1/167 (0.6%)	1	0/168 (0%)	0
Gastroenteritis Bacterial	0/167 (0%)	0	1/168 (0.6%)	1
Hepatitis C	0/167 (0%)	0	1/168 (0.6%)	1
Infuenza	1/167 (0.6%)	1	0/168 (0%)	0
Ophthalmic herpes Zoster	0/167 (0%)	0	1/168 (0.6%)	1
Osteomyelitis	0/167 (0%)	0	1/168 (0.6%)	1
Pneumonia	4/167 (2.4%)	4	3/168 (1.8%)	3
Pneumonia Klebsiella	1/167 (0.6%)	1	0/168 (0%)	0
Respiratory syncytial Virus Infection	1/167 (0.6%)	1	0/168 (0%)	0
Sepsis	2/167 (1.2%)	3	0/168 (0%)	0
Septic Shock	0/167 (0%)	0	2/168 (1.2%)	2
Upper Respiratory Tract Infection	1/167 (0.6%)	2	0/168 (0%)	0
Urinary Tract Infection	0/167 (0%)	0	1/168 (0.6%)	1
Viral Upper Respirator Tract Infection	1/167 (0.6%)	1	0/168 (0%)	0
Injury, poisoning and procedural complications
Accidental Overdose	0/167 (0%)	0	1/168 (0.6%)	1
Facial bones Fracture	0/167 (0%)	0	1/168 (0.6%)	1
Fall	1/167 (0.6%)	1	0/168 (0%)	0
Foreign body In Gastrointestinal Tract	1/167 (0.6%)	1	0/168 (0%)	0
Overdose	0/167 (0%)	0	1/168 (0.6%)	1
Post Procedural Haemorrhage	1/167 (0.6%)	1	0/168 (0%)	0
Subdural Haematoma	1/167 (0.6%)	1	1/168 (0.6%)	1
Investigations
Anticoagulation Drug Level Below Therapeutic	1/167 (0.6%)	1	0/168 (0%)	0
Metabolism and nutrition disorders
Dehydration	2/167 (1.2%)	2	0/168 (0%)	0
Diabetes Mellitus	0/167 (0%)	0	1/168 (0.6%)	1
Diabetic Ketoacidosis	0/167 (0%)	0	1/168 (0.6%)	1
Hyperglycaemia	2/167 (1.2%)	2	1/168 (0.6%)	1
Hyperglycaemic Hyperosmolar Nonketotic Syndrome	0/167 (0%)	0	1/168 (0.6%)	1
Hypoglycaemia	0/167 (0%)	0	1/168 (0.6%)	1
Hypokalaemia	0/167 (0%)	0	2/168 (1.2%)	2
Musculoskeletal and connective tissue disorders
Costochondritis	0/167 (0%)	0	1/168 (0.6%)	1
Musculoskeletal Chest Pain	0/167 (0%)	0	1/168 (0.6%)	1
Musculoskeletal Pain	0/167 (0%)	0	1/168 (0.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of Colon	2/167 (1.2%)	2	0/168 (0%)	0
Plasma Cell Myeloma	1/167 (0.6%)	1	0/168 (0%)	0
Rectal Adenocarcinoma	0/167 (0%)	0	1/168 (0.6%)	1
Nervous system disorders
Encephalopathy	1/167 (0.6%)	1	1/168 (0.6%)	1
Seizure	1/167 (0.6%)	1	0/168 (0%)	0
Product Issues
Device Dislocation	1/167 (0.6%)	1	0/168 (0%)	0
Lead Dislodgement	1/167 (0.6%)	1	0/168 (0%)	0
Psychiatric disorders
Major Depression	1/167 (0.6%)	1	0/168 (0%)	0
Mania	0/167 (0%)	0	1/168 (0.6%)	1
Substance Abuse	1/167 (0.6%)	1	0/168 (0%)	0
Substance-Induced Psychotic Disorder	0/167 (0%)	0	1/168 (0.6%)	1
Renal and urinary disorders
Urinary Tract Obstruction	2/167 (1.2%)	2	0/168 (0%)	0
Reproductive system and breast disorders
Vaginal Haemorrhage	1/167 (0.6%)	1	0/168 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic Obstructive Pulmonary Disease	1/167 (0.6%)	1	0/168 (0%)	0
Epistaxis	0/167 (0%)	0	1/168 (0.6%)	1
Mediastinal Haematoma	1/167 (0.6%)	1	0/168 (0%)	0
Respiratory Failure	2/167 (1.2%)	2	0/168 (0%)	0
Skin and subcutaneous tissue disorders
Diabetic ulcer	1/167 (0.6%)	1	0/168 (0%)	0
Vascular disorders
Haematoma	1/167 (0.6%)	1	0/168 (0%)	0
Hypotension	0/167 (0%)	0	1/168 (0.6%)	1
Peripheral Ischaemia	0/167 (0%)	0	1/168 (0.6%)	1
Shock Haemorrhagic	1/167 (0.6%)	1	0/168 (0%)	0
Other (Not Including Serious) Adverse Events
	LCZ696 (Entresto) + Placebo		Valsartan + Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (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.