A Proof of Concept Study to Determine the Efficacy of Entresto™ in HFpEF Based on Circulating Neprilysin Levels: The Circulating NEP and NEP Inhibition (CNEPi) Study
Phase: PHASE4
Conditions: Heart Failure With Preserved Ejection Fraction
Sponsor: Mayo Clinic

 
 
A Proof of Concept Study to 
Determine the Efficacy of 
EntrestoTM in HFpEF Based on 
Circulating Neprilysin Levels: 
The Circulating NEP and NEPi 
(CNEPi) Study 
 
 NCT03506412 
 
29MAR2021 

(CNEPi Aim #2) 
 
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Dr. Naveen Pereira 
 
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A Proof of Concept Study to Determine the Efficacy of EntrestoTM in HFpEF Based on 
Circulating Neprilysin Levels: The Circulating NEP and NEPi (CNEPi) Study 
 
 
 
 
 
 
Principal Investigator: 
Dr. Naveen L. Pereira 
200 First Street SW 
Rochester, MN 55905 
 
mayoclinic.org 
 
Funding Sponsor: 
National Institute of Aging 
Building 31, Room 5A52 
31 Center Drive MSC 2486 
Bethesda, MD 20892 
 
Study Product: 
EntrestoTM 
Protocol Number: (IRBe): 
 
IRB # 18-000044 
 
 
 
 
 
 
 
 
 

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Table of Contents 
 
STUDY SUMMARY ................................................................................................................... 5 
1 
INTRODUCTION ................................................................................................................ 6 
1.1 BACKGROUND .................................................................................................................. 6 
1.2 PRELIMINARY DATA .........................................................ERROR! BOOKMARK NOT DEFINED. 
1.3 DOSE RATIONALE AND RISK/BENEFITS .............................................................................. 7 
2 
STUDY OBJECTIVES ....................................................................................................... 7 
3 
STUDY DESIGN ................................................................................................................ 7 
3.1 GENERAL DESIGN ............................................................................................................ 7 
3.2 PRIMARY STUDY ENDPOINTS ............................................................................................ 7 
3.3 SECONDARY STUDY ENDPOINTS ......................................ERROR! BOOKMARK NOT DEFINED. 
3.4 PRIMARY SAFETY ENDPOINTS ..........................................ERROR! BOOKMARK NOT DEFINED. 
4 
SUBJECT SELECTION ENROLLMENT AND WITHDRAWAL ......................................... 7 
4.1 INCLUSION CRITERIA ........................................................................................................ 7 
4.2 EXCLUSION CRITERIA ....................................................................................................... 8 
4.3 SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING .................................................... 9 
4.4 EARLY WITHDRAWAL OF SUBJECTS ................................................................................... 9 
4.4.1 When and How to Withdraw Subjects ..................................................................... 9 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects ........................................... 9 
5 
STUDY DRUG ................................................................................................................... 9 
5.1 DESCRIPTION ................................................................................................................... 9 
5.2 TREATMENT REGIMEN .....................................................................................................10 
5.3 METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ...........................................10 
5.4 PREPARATION AND ADMINISTRATION OF STUDY DRUG ......................................................10 
5.5 SUBJECT COMPLIANCE MONITORING ................................................................................10 
5.6 PRIOR AND CONCOMITANT THERAPY ................................................................................11 
5.7 PACKAGING ....................................................................ERROR! BOOKMARK NOT DEFINED. 
5.8 MASKING/BLINDING OF STUDY .........................................................................................11 
5.9 RECEIVING, STORAGE, DISPENSING AND RETURN .............................................................11 
5.9.1 Receipt of Drug Supplies .......................................................................................11 
5.9.2 Storage ..................................................................................................................11 
5.9.3 Dispensing of Study Drug ......................................................................................11 
5.9.4 Return or Destruction of Study Drug ......................................................................11 
6 
STUDY PROCEDURES ....................................................................................................11 
6.1 VISIT 1............................................................................ERROR! BOOKMARK NOT DEFINED. 
6.2 VISIT 2............................................................................................................................11 
6.3 VISIT 3............................................................................ERROR! BOOKMARK NOT DEFINED. 
7 
STATISTICAL PLAN ........................................................................................................14 
7.1 SAMPLE SIZE DETERMINATION .........................................................................................14 
7.2 STATISTICAL METHODS ...................................................................................................14 
8 
SAFETY AND ADVERSE EVENTS .........................ERROR! BOOKMARK NOT DEFINED. 

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8.1 DEFINITIONS ...................................................................ERROR! BOOKMARK NOT DEFINED. 
8.2 RECORDING OF ADVERSE EVENTS ...................................ERROR! BOOKMARK NOT DEFINED. 
8.3 REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ............ ERROR! 
BOOKMARK NOT DEFINED. 
8.3.1 Sponsor-Investigator reporting: notifying the Mayo IRBError! 
Bookmark 
not 
defined. 
8.3.2 Sponsor-Investigator reporting: Notifying the FDA ... Error! Bookmark not defined. 
8.4 UNMASKING/UNBLINDING PROCEDURES ...........................ERROR! BOOKMARK NOT DEFINED. 
8.5 STOPPING RULES ............................................................................................................17 
8.6 MEDICAL MONITORING ....................................................................................................17 
8.6.1 Internal Data and Safety Monitoring Board .............. Error! Bookmark not defined. 
9 
DATA HANDLING AND RECORD KEEPING ...................................................................17 
9.1 CONFIDENTIALITY ............................................................................................................17 
9.2 SOURCE DOCUMENTS .....................................................................................................18 
9.3 CASE REPORT FORMS .....................................................................................................18 
9.4 RECORDS RETENTION .....................................................ERROR! BOOKMARK NOT DEFINED. 
10 STUDY MONITORING, AUDITING, AND INSPECTING ...................................................19 
10.1 
STUDY MONITORING PLAN ...........................................................................................19 
10.2 
AUDITING AND INSPECTING ..........................................................................................19 
11 ETHICAL CONSIDERATIONS .................................ERROR! BOOKMARK NOT DEFINED. 
12 STUDY ADMINISTRATION ..............................................................................................20 
12.1 
COORDINATING CENTER ..............................................................................................20 
12.2 
CORE LABORATORIES  .................................................ERROR! BOOKMARK NOT DEFINED. 
13 STUDY FINANCES ...........................................................................................................20 
13.1 
FUNDING SOURCE .......................................................................................................20 
13.2 
SUBJECT STIPENDS OR PAYMENTS ...............................................................................20 
14 PUBLICATION PLAN .......................................................................................................21 
15 REFERENCES ..................................................................................................................21 
 
 
 
 
 
 

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List of Abbreviations 
 
ACEIs 
AE 
ANP 
ARB 
BNP 
Angiotensin converting enzyme inhibitors 
Adverse Event/Adverse Experience 
Atrial natriuretic peptide 
Angiotensin receptor blocker 
Brain natriuretic peptide 
CCaTS 
Center for Clinical and Translational Science 
CFR 
cGMP 
Code of Federal Regulations 
Cyclic guanosine monophosphate 
CHF 
CNP 
Congestive Heart Failure 
c-type natriuretic peptide 
CRF 
Case Report Form 
CRTU 
Clinical Research and Trials Unit 
DSMB 
Data and Safety Monitoring Board 
EF 
Ejection Fraction 
ES 
Executive Secretary 
FDA 
Food and Drug Administration 
GFR 
Glomerular Filtration Rate 
GCP 
Good Clinical Practice 
HF 
Heart Failure 
HFpEF 
HFrEF 
Heart Failure with Preserved Ejection Fraction 
Heart Failure with Reduced Ejection Fraction 
HIPAA 
HR 
Health Insurance Portability and Accountability Act 
Hazard ratio 
IB 
Investigator’s Brochure 
IRB 
Institutional Review Board 
IV 
LVEF 
NEP 
NEPi 
NP 
NPRC 
Intravenous 
Left ventricular ejection fraction 
Neprilysin 
Neprilysin inhibitor 
Natriuretic peptide 
Natriuretic peptide clearance receptor 
NYHA 
New York Heart Association 
 
 
 
 
 
 

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Study Summary 
Title 
A Proof of Concept Study to Determine the Efficacy of EntrestoTM in 
heart failure with preserved ejection fraction (HFpEF) Based on 
Circulating Neprilysin Levels: The Circulating NEP and NEPi (CNEPi) 
Study  
Running Title 
CNEPi  
Protocol Number 
IRB # 18-000044 
Phase 
Phase 4 
Methodology 
Proof of Concept Study 
Overall Study 
Duration 
21 months 
Subject Participation 
Duration 
5 weeks 
Single or Multi-Site  
Mayo Clinic Sites 
Objectives 
Determine biomarker (plasma NT-proANP, NT-proBNP, NT-proCNP, 
cGMP) responses to Entresto™ in patients with HFpEF who have high 
and low serum NEP levels 
Number of Subjects 
40 
Diagnosis and Main 
Inclusion Criteria 
Subjects with NYHA 2-4 HFpEF 
Study Product, 
Dose, Route, 
Regimen 
EntrestoTM 49/51 mg (sacubitril/valsartan) orally twice-daily  
Duration of 
Administration 
Up to 5 weeks 
Reference therapy 
NA 
Statistical 
Methodology 
Paired t-test comparing the change from baseline to up to 5 weeks 
after administration of EntrestoTM 
 
 

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1 
Introduction 
This document is a protocol for a human research study. This study will be carried out in 
accordance with the applicable United States government regulations and Mayo Clinic research 
policies and procedures.  
1.1 
Background 
Heart failure with preserved ejection fraction (HFpEF) can result from abnormalities in the 
process of active relaxation and passive stiffness of the heart1. The natriuretic peptides (NPs) 
play an important role in cyclic guanosine monophosphate (cGMP) mediated inhibition of 
cardiomyocyte growth, smooth muscle and fibroblast proliferation and collagen deposition that 
can affect passive stiffness2-4. Further, NPs can attenuate angiotensin-II, endothelin-1 and 
arginine-vasopressin induced increased proliferation of vascular smooth muscle cells5. HFpEF 
is characterized by elevated intra-cardiac pressures6 and the natriuretic and diuretic properties 
of NPs play a pivotal role in maintaining normal volume homeostasis7, 8. Natriuretic peptides 
also reduce peripheral vascular resistance and blood pressure9. The NPs additionally inhibit the 
effects of the renin-angiotensin-aldosterone and sympathetic nervous system10-13 the 
maladaptive activation of which results in the clinical syndrome of HF. Neprilysin (NEP) 
mediates the anti-fibrotic, anti-proliferative, myocardial relaxation, vasodilator and diuretic 
properties of NPs by maintaining NP homeostasis. NPs are degraded and cleared by NEP and 
the NP clearance receptor (NPRC) respectively. NEP inhibition (NEPi) therefore results in 
significant increases in plasma BNP, urinary BNP and urinary sodium, increases in cardiac 
output and reduction in intra-cardiac filling pressures14.  
1.2 
Preliminary Data 
Entresto™, a crystalline complex of a NEPi (sacubitril) and an angiotensin receptor blocker 
(ARB, valsartan), was recently approved to treat NYHA Class 2-4 patients with HFrEF after the 
PARADIGM-HF trial was stopped early due to an overwhelming benefit of the drug in reducing 
all-cause mortality (hazard ratio [HR]: 0.84; p<0.001), CV mortality (HR 0.80; p<0.001), 
hospitalization for HF (HR 0.79; p<0.001) and in addition reduced the symptoms and physical 
limitations of HF by 21% (p=0.001)15. Entresto™ due to its additional NEPi activity could be a 
promising new therapy for HFpEF. Entresto™ when administered to patients with HFpEF in a 
phase 2 study resulted in significantly reduced NT-proBNP levels, a surrogate marker of LV wall 
stress and NEP activity, as compared to being treated with valsartan alone16. Entresto™ 
therefore is being tested as treatment for HFpEF in a Phase 3 trial, PARAGON-HF, evaluating 
its efficacy in reducing CV death and HF hospitalizations as compared to valsartan. 
 
NEP is a cell membrane bound metalloendopeptidase and can be released from the cell 
surface, resulting in the formation of a circulating peptide that maintains its catalytic activity17, 18. 
In recent clinical studies, circulating NEP levels were significantly associated with the composite 
endpoint of cardiovascular death or HF hospitalization (HR 1.17; p=0.001) and cardiovascular 
death (HR: 1.19; p=0.002) in patients with HF19. The PARAGON-HF trial includes all-comers 
with HFpEF; the final data collection will be completed May 2019. It is being increasingly 
recognized that HFpEF is a disease entity that has considerable phenotypic heterogeneity20, 21. 
Therefore, targeting all-comers who suffer from a heterogeneous disease process using a single 
treatment intervention may not result in desirable outcomes as has been evident with multiple 
prior negative HFpEF trials22, 23. The importance of biomarker based clinical trials that deliver the 
right drug to the right patient is being increasingly recognized as a useful strategy to limit 
sample size and decrease costs by enriching such trials with potential responders24, 25. Whether 
the beneficial effects of Entresto™ therapy are dependent on baseline NEP levels is unknown 
and is being explored in this study. The hypothesis in this proof of concept study is that 

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subjects with lower NEP levels will not have an equivalent response to Entresto™, a NEPi, as 
compared to those with higher NEP levels. The primary endpoint measured is change in 
biomarkers with Entresto™ administration that reflect NEP activity and myocardial stress (NT 
pro-ANP, -BNP, -CNP) and drug action (cGMP). This endpoint has been well validated as a 
measure of Entresto™ drug response26. 
 
To establish a median value which will be used to categorize subjects recruited for this pilot 
study into a low and high NEP group we have measured circulating NEP levels in 242 samples 
from the RELAX and NEAT-HFpEF studies. The RELAX study was a multicenter, double-blind, 
placebo-controlled, randomized clinical trial of 216 stable outpatients with HFpEF27. NEAT-
HFpEF was a multicenter, randomized study of 110 outpatients with HFpEF28. The median 
circulating NEP level in these populations was 1.55 ng/ml (Q1=0.49, Q3=24.99). Therefore 
subjects with circulating NEP levels of ≤1.55 ng/ml will be considered as having low NEP levels 
and those with values >1.55 ng/ml will fall into the high NEP level group. 
 
1.3 Dose Rationale and Risk/Benefits 
The effect of administering Entresto™ to subjects with “high” or “low” NEP levels will be studied. 
Favorable response to Entresto™ therapy in these subjects will be assessed by evaluating a 
change in biomarkers that reflect NEP activity, myocardial wall stress and clinical outcomes 
(NT-proANP, NT-proBNP, NT-proCNP)29 and reflect efficacy of drug action (cGMP)26. Entresto 
is FDA approved for use in HFrEF and will be administered as recommended in the drug 
labeling information as an off label use in HFpEF as 49/51 mg twice-daily.  
 
2 
Study Objectives 
Primary Objective: To determine biomarker (plasma NT-proANP, NT-proBNP, NT-proCNP and 
cGMP) responses to Entresto™ in patients with HFpEF who have high and low serum NEP levels.  
 
3 
Study Design 
3.1 
General Design 
 
Study design: This is a proof of concept single arm study that will be performed in the Clinical 
Research and Trials Unit (CRTU) at the Center for Clinical and Translational Science (CCaTS), 
Mayo Clinic. 40 subjects with HFpEF will be assigned to Entresto 49/51 mg (sacubitril/valsartan) 
twice-daily for a total duration of up to 5 weeks of treatment. 
3.2 
Primary Study Endpoints 
The primary endpoint measured is change in biomarkers with Entresto™ administration that 
reflect NEP activity and myocardial stress (NT pro-ANP, -BNP, -CNP) and drug action (cGMP). 
This endpoint has been well validated as a measure of Entresto™ drug response. 
 
4 
Subject Selection Enrollment and Withdrawal 
4.1 
Inclusion Criteria 
1. Age ≥ 50 years  
2. LVEF ≥ 45% assessed by echocardiography, nuclear scan, MRI or left ventriculogram 
within the past 24 months   

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3. Current New York Heart Association (NYHA) class 2-4 symptoms of heart failure (HF) 
4. Stable medical therapy for 30 days as defined by: 
a. No addition or removal of ACE, ARB, beta-blockers, calcium channel blockers  
(CCBs) or aldosterone antagonists 
b. No change in dosage of ACE, ARBs, beta-blockers, CCBs or aldosterone 
antagonists of more than 100% 
5. Elevated NT-proBNP (>300 pg/ml) or BNP (>200 pg/ml) 
6. One of the following within the last 24 months 
a. Previous hospitalization for HF with radiographic evidence of pulmonary 
congestion (pulmonary venous hypertension, vascular congestion, interstitial 
edema, pleural effusion) or 
b. Catheterization documented elevated filling pressures at rest (LVEDP≥15 or 
PCWP≥20) or with exercise (PCWP≥25) or 
c. Echo evidence of diastolic dysfunction / elevated filling pressures (at least two) 
i. E/A > 1.5  + decrease in E/A of > 0.5 with valsalva 
ii. Deceleration time ≤ 140 ms 
iii. Pulmonary vein velocity in systole < diastole (PVs<PVd) (sinus rhythm) 
iv. E/e’≥15 
v. Left atrial enlargement (≥ moderate) 
vi. Pulmonary artery systolic pressure > 40 mmHg 
vii. Evidence of left ventricular hypertrophy 
1. LV mass/BSA ≥ 96 (♀) or ≥ 116 (♂) g/m2 
2. Relative wall thickness ≥ 0.43 (♂ or ♀) [(IVS+PW)/LVEDD] 
3. Posterior wall thickness ≥ 0.9 (♀) or 1.0 (♂) cm 
4.2 
Exclusion Criteria 
1. History of hypersensitivity or allergy to ACE inhibitors (ACEIs), ARBs, or NEP inhibitors 
2. Known history of angioedema to ACE inhibitors (ACEIs) or ARBs 
3. Previous LVEF < 40% at any time 
4. Systolic blood pressure < 100 mmHg or > 180 mmHg 
5. Current acute decompensated HF (exacerbation of chronic HF manifested by signs and 
symptoms that may require intravenous therapy) 
6. Unstable angina, myocardial infarction, stroke, transient ischemic attack, or 
cardiovascular surgery or urgent percutaneous coronary intervention (PCI) within 3 
months of screening or elective PCI within 30 days of entry 
7. Significant valvular stenosis or regurgitation (greater than moderate in severity), 
hypertrophic, restrictive or obstructive cardiomyopathy including amyloidosis, constrictive 
pericarditis, primary pulmonary hypertension, or biopsy proven active myocarditis 
8. Severe congenital heart disease 
9. History of heart transplant or with LV assist device  
10. Evidence of severe hepatic disease as determined by any one of the following: history of 
hepatic encephalopathy, history of esophageal varices, or history of porto-caval shunt. 
11. Glomerular filtration rate < 20 ml/min/1.73 m2 on most recent clinical laboratories* 
12. Serum potassium of > 5.5 mEq/dL on most recent clinical laboratories* 
13. Concomitant use of aliskiren in patients with diabetes 
14. Currently receiving an investigational drug  
15. Inability to comply with planned study procedures 

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16. Female subject who is pregnant or breastfeeding 
* Performed within 90 days of enrollment 
4.3 
Subject Recruitment, Enrollment and Screening 
Subjects meeting the inclusion criteria of the study will be recruited at the Mayo Clinic from the 
Cardiovascular Diseases Clinic, Community Internal Medicine, General Internal Medicine, Mayo 
Clinic Cardiovascular Disease database, and past participants of HFpEF studies. The Mayo Clinic 
Life Science System (MCLSS) will aid recruitment for all the protocols. The MCLSS 
 
 
 
 
 
 allows identification of patients in real time 
during an episode of care no matter where (inpatient or outpatient) at Mayo the patients are being 
seen. 
 
 The study coordinator will query the system daily for potential candidates, review the 
integrated electronic medical records and if appropriate, contact the patient’s physician to discuss 
the study and the patient’s participation. Patients will then be contacted for personal interview in 
person, by phone or letter. Informed consent will be obtained at the screening visit during which 
blood will be drawn for safety laboratories and NEP levels. Subjects will be assigned to a low or 
high NEP level group based on the levels and it is anticipated that up to 100 subjects will undergo 
a screening visit to ultimately enroll 40 subjects for the study which will be carried out during Visits 
1 and 2. Subjects will receive a reimbursement of $100 for participation in each visit (Visits 1 and 
2) of the study. 
4.4 
Early Withdrawal of Subjects 
If a subject should stop taking study medication for any reason before completing the 5 weeks of 
study drug dosing, an attempt should be made to restart the study drug at the lowest starting dose 
when the subject is stable, per physician discretion. If the treating physician decides to stop study 
medication and start the patient on an ACEI, then a 36 hour wash-out period is required after the 
last dose of study drug before starting the ACEI.  
4.5 
When and How to Withdraw Subjects 
If subjects experience an adverse reaction to EntrestoTM or if disease progression occurs after 
consent, the Principal Investigator may consider discontinuing study drug treatment.  
4.6 
Data Collection and Follow-up for Withdrawn Subjects 
Subjects will complete all study assessments of Study Visit 2 if they have received study drug 
for at least 2 weeks or more, regardless of whether they have received the full 5 weeks of study 
drug treatment. The blood collection component of the study assessment will need to occur 
within 24 hours of drug discontinuation. 
 
5 
Study Intervention  
5.1 
Description 
Please see accompanying Figure. Study Intervention comprises of eligible HFpEF subjects who 
have provided informed consent and in whom blood will be collected (screening visit) to 
measure serum NEP levels and based on these levels will be assigned to a low or high NEP 
group. These subjects after having blood drawn at Visit 1 for baseline NEP, NT pro-ANP, -BNP, 

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-CNP and cGMP levels will then receive Entresto™ for up to 5 weeks. They will return in the 5th 
week for another blood draw to measure NEP, NT pro-ANP, -BNP, -CNP and cGMP levels. At 
visits 1 and 2 subjects will also provide urine samples for cGMP levels at baseline and post 
intervention analysis. Blood will also be collected and stored for future transcriptomic, 
metabolomic and genomic studies.  
 
5.2 
Treatment Regimen 
40 subjects with HFpEF will be administered their first dose of Entresto™ at Visit 1. Sitting systolic 
and diastolic BP will be monitored in the subject’s dominant arm 3 times with an automatic blood-
pressure monitor (Omron, Bannockburn, IL) and an average reading of these 3 measurements 
will be used. BPs will be checked 60 minutes after first dose is administered at Visit 1 to ensure 
tolerance of the medication. If tolerated, subjects will receive Entresto™ at a recommended dose 
of 49/51 mg on an empty stomach twice daily for up to 5 weeks. Patients will be reassessed at 
Visit 2 in the 5th week. 
5.3 
Method for Assigning Subjects to Treatment Groups 
This single arm study will be performed at in the Clinical Research and Trials Unit (CRTU) at the 
Center for Clinical and Translational Science (CCaTS), Mayo Clinic. Subjects with circulating 
NEP levels of ≤1.55 ng/ml will be considered as having low NEP levels and those with values 
>1.55 ng/ml will fall into the high NEP level group 
5.4 
Preparation and Administration of Entresto™ 
▪ 
Dispensed by the Research Pharmacy  
▪ 
Entresto will be taken by mouth by the patient twice daily for up to 5 weeks 
5.5 
Subject Compliance Monitoring 
For this protocol, first dose of Entresto™ is administered in the CRTU by CRTU staff. 
Subsequent compliance will be monitored by a 2 week phone call made by the study 
coordinator. 

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5.6 
Prior and Concomitant Therapy 
Subjects should be treated with standard HF strategies (diuretics for congestion, blood pressure 
control and heart rate control if subject is in atrial fibrillation) as per recommended guidelines. 
Subjects may not take ARBs, ACE inhibitors and direct renin inhibitors during the study. If 
subjects are on ACEi or ARBs, these drugs will be withheld 36 hours before the initiation of 
treatment with Entresto™ at Visit 1. All other medications will be allowed.  
5.7 
Masking/Blinding of Study Drug 
There is no masking or blinding of study drug since this is an open label study. 
5.8 
Receiving, Storage, Dispensing and Return 
Will be managed by Research Pharmacy. 
5.9 
Receipt of Drug Supplies 
Will be managed by Research Pharmacy  
5.10 Storage 
Entresto™ will be kept in a secure, limited-access storage area by Research Pharmacy. 
5.11 Dispensing of Entresto™ 
Entresto™ reconciliation will be performed by the Research Pharmacy per their standard 
procedures. 
5.12 Return or Destruction of Entresto™ 
Patients will be asked to destroy any unused Entresto™ tablets. 
 
6 
Study Procedures 
6.1 
Screening Visit 
Possible study participants will meet with study coordinator to review consent form. Medical 
history and current medications will be reviewed. Blood will be drawn for baseline serum NEP 
levels, safety laboratory tests (potassium, creatinine) and pregnancy test if necessary at the 
CRTU. Dependent on the results of the NEP levels which will be available within 48 hours, 
subjects will be assigned to a high or low NEP group. If subjects are found to be eligible and are 
on ACEi or ARBs, subjects will be instructed to withhold these drugs 36 hours before the initiation 
of treatment with Entresto™ at Visit 1 and throughout the duration of the study while subjects are 
on Entresto™. 
6.2 
Visit 1 
Visit 1 will occur within 30 days of the Screening Visit. Qualified subjects will be evaluated as 
outpatients at the CRTU. Interim history, a review of medications, NYHA class assessment and 
a brief physical exam will be performed by a qualified study team member. Blood will be drawn 
for serum NEP levels, NT-proANP, NT-proBNP, NT-proCNP, cGMP and a pregnancy test will be 
performed, if necessary; urine sample will also be collected for cGMP levels. An additional 55 mL 
blood sample will be collected from subjects, for future transcriptomic, metabolomic and genomic 
analysis, who provide consent to allow their blood to be stored in the BAP laboratory for future 
studies. Subjects will be given the option to opt in or out of this component of the study. Following 
this, subjects will receive their first dose of Entresto™. BPs will be monitored at baseline prior to 

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administration of Entresto™ and 60 minutes after this first dose to ensure tolerance of the 
medication. Sitting systolic and diastolic BP will be monitored in the subject’s dominant arm 3 
times with an automatic blood-pressure monitor (Omron, Bannockburn, IL) and an average 
reading of these 3 measurements will be used. Before dismissal, subjects will be provided with 
Entresto™ tablets for the duration of the study. Study coordinator will follow-up with the subject 
by telephone on day 14 ± 5 post-visit 1 to monitor compliance and to assess tolerance.  
6.3 
Visit 2 
Upon completion of 4 weeks of drug intervention, during the 5th week of therapy subjects will be 
admitted as outpatients to the CRTU. Subjects will be asked to take their last dose of Entresto™ 
prior to their clinical visit. Interim history, a review of medications, NYHA class assessment and a 
brief physical exam will be performed by a qualified study team member. Baseline sitting systolic 
and diastolic BP will be monitored in the subject’s dominant arm 3 times with an automatic blood-
pressure monitor (Omron, Bannockburn, IL) and an average reading of these 3 measurements 
will be used. Blood will be drawn for serum NEP levels, NT-proANP, NT-proBNP, NT-proCNP 
and cGMP; urine sample will also be collected for cGMP levels. An additional 55 mL blood sample 
will also be collected from subjects, for future transcriptomic, metabolomic and genomic analysis, 
who provide consent to allow their blood to be stored in the BAP laboratory for future studies as 
in Visit 1. 
 
 
7 
Potential Risks and Adequacy of Protection against Risks 
Protections for human subjects of research are required under Department of Health and 
Human Services (HHS) regulations at 21 CFR parts 50, 56, and 312. 
 
7.1 Summary of the Risks and Benefits 
 
Blood draws: The risks of drawing blood include bleeding at the puncture site, bruising and 
pain. These occur in a very small portion of the population. 
 
Entresto™ (sacubitril/valsartan): The use of Entresto™ compared to the guideline-indicated 
ACE inhibitor enalapril reduced mortality was shown in the PARADIGM trial to reduce the 
hazard ratio for cardiovascular death and mortality by 20%. The known risks of Entresto™ 
overlap with those of valsartan, a drug that has been used in patients with HFpEF. In the 
PARADIGM trial, use of Entresto™ was associated with a greater incidence of angioedema 
than the comparator drug enalapril (0.5% vs. 0.2%). The risk of angioedema with Entresto™ 
compared to enalapril was relatively greater among Black patients (2.4% vs. 0.5%). Patients 
with a history of angioedema are contraindicated from taking this drug. Trial data indicate 
adverse reactions occurring ≥5% are hypotension, hyperkalemia, cough, dizziness, and renal 
failure. Symptomatic hypotension in PARAGON was more common among patients taking 
Entresto™ than enalapril (18% vs. 12%). 
 
Subjects will be given appropriate instructions to monitor for any untoward effects and to report 
immediately and seek medical attention if required. Also, a study team member will be following-
up with the subjects on a timely basis as described above to monitor compliance and to assess 
tolerance, Hence, the study has extremely little risk of causing irreversible consequence on the 
patients.  
 
Plan of intervention in the event of adverse effects to the subjects During the course of the 
treatment, if the patient does develop angioedema, or signs or symptoms of hypotension, or any 

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other untoward symptoms the study drug may be discontinued and the clinical care team will 
manage the subject according to standard policies and procedures. 
 
Other potential risks include: 
This protocol may be hazardous to an unborn child. When pregnancy is detected, EntrestoTM 
will be discontinued as soon as possible. Drugs that act directly on the renin-angiotensin system 
such as EntrestoTM can cause injury and death to the developing fetus. Therefore, female 
participants must be postmenopausal or have been surgically sterilized or have a negative 
pregnancy test and must agree to use a reliable method of contraception until study completion. 
Methods of contraception include: birth control pill/implants/injections, intrauterine devices, 
spermicide, diaphragm or condoms.    
 
Schedule of Events Table 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a: Plasma NEP, serum potassium, creatinine if required 
 
 
Study Activity 
Screen 
 
Visit 1 
Day 1 
 
Interim Call 
Day 14±5 
 
Visit 2 
Week 5 
Study Agent 
 
X 
 
X 
Informed consent 
X 
 
 
 
History (NYHA Class) 
X 
X 
X 
X 
Concurrent meds 
X 
X 
X 
X 
Physical Exam (Ht, 
Wt, BSA, VS, 
 
X 
 
X 
Blood draw  
 
Xa 
Xb 
 
Xb 
B-hCG 
Xc 
Xc 
 
 
Urine collection 
 
Xd 
 
Xd 

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b: Plasma NEP, NT pro-ANP, -BNP, -CNP, and cGMP; Blood for future studies 
c: Serum pregnancy test (women of childbearing potential) 
d. cGMP levels in urine sample 
 
7 
Statistical Plan 
7.1 
Sample Size Determination 
The sample size calculation and statistical analysis have been designed in collaboration with the 
Division of Biostatistics. This is a proof of concept study; 40 subjects will be recruited, with 20 in 
each group (Group 1: subjects with HFpEF - low NEP levels and, Group 2: subjects with HFpEF 
- high NEP levels). It is anticipated that 100 subjects will be screened. 
  
7.2 
Statistical Methods 
The primary analysis for this study will be a comparison of the changes in values of parameters 
of interest between the study groups low NEP vs. high NEP following up to 5 weeks of study drug 
intervention. This analysis will be completed using a paired t-test comparing the change from 
baseline to 5 weeks after study drug intervention. A secondary analysis will also be performed to 
evaluate the effects of the varying doses (in case, if the dose of the drug is changed during the 
course of the study). Analysis of variance methods will be used to compare changes from baseline 
to 6 hours, and pairwise group comparisons will be made via two-sample t-test if the overall 
ANOVA F-test is found to be significant. Distributions of changes will be examined and 
appropriate transformations applied prior to analyses, if necessary. Values will be expressed as 
the mean + SEM. A statistically significant difference will be considered to be present when 
p<0.05.  
 
8 
Participant Safety and Adverse Events 
8.1 
Institutional Review Boards 
All sites will submit the study protocol, informed consent form, and other study documents to 
their IRB for approval—the approval letter for each clinical center will be stored. Any 
amendments to the protocol, other than minor administrative changes, must be approved by 
each IRB before they are implemented.  
8.2 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
a subject whether or not considered drug or biologic related. An AE can therefore be any 
unfavorable and unintended sign, symptom or disease temporally associated with the use of a 
pharmaceutical product or biologic. 
8.3 
Suspected Adverse Reaction  
A suspected adverse reaction (SAR) is any adverse event for which there is a reasonable 
possibility that the drug caused the event. “Reasonable possibility” suggests there is a causal 
relationship between the drug and the adverse event. “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse 
event caused by a drug.  

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8.4 
Serious Adverse Events  
An AE or SAR is considered serious if the Investigator or sponsor believes any of the following 
outcomes may occur: 
• 
Death 
• 
Life-threatening AE: Places the subject at immediate risk of death at the time of the 
event as it occurred. It does not include an AE that, had it occurred in a more severe 
form, might have caused death. 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• 
Inpatient hospitalization or prolongation of hospitalization.  
• 
Congenital anomaly or birth defect.  
• 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered a serious adverse event when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition above. 
This determination is based on the opinion of either the investigator or sponsor (e.g., if either 
believes it is serious, it must be considered serious). 
8.5 
Laboratory Test Abnormalities 
For laboratory test abnormalities that meet the definition of a serious adverse event (SAE), 
which required the subject to have the study drug discontinued or interrupted, or required the 
subject to received specific corrective therapy, the clinical diagnosis rather than the laboratory 
term will be used by the reporting investigator (e.g., anemia versus low hemoglobin value). 
8.6 
Assessment of Causal Relationship and Severity 
A medically-qualified investigator must assess the relationship of any AE to the use of study 
drug, based on available information, using the following guidelines:  
• 
Not related: There is not a reasonable causal relationship to the investigational product 
and the adverse event.  
• 
Unlikely related: No temporal association or the cause of the event has been identified, 
or the drug or biologic cannot be implicated. 
• 
Possibly related: There is reasonable evidence to suggest a causal relationship 
between the drug and adverse event. 
• 
Related: There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. 
 
The determination of adverse event severity rests on medical judgment of a medically-qualified 
Investigator. The severity of AEs will be graded using the following definitions:  
• 
Mild: Awareness of sign, symptom, or event, but easily tolerated;  
• 
Moderate: Discomfort enough to cause interference with usual activity and may warrant 
intervention;  
• 
Severe: Incapacitating with inability to do usual activities or significantly affects clinical 
status, and warrants intervention. 
8.7 
Expectedness 
The expectedness of an AE or SAR shall be determined according to the specified reference 
document containing safety information (e.g., most current product label). Any AE that is not 
identified in nature, severity, or specificity in the current study drug reference document(s) is 
considered unexpected. Events that are mentioned in the product label as occurring with a class 

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of drugs or as anticipated from the pharmacological properties of the drug, but not specifically 
mentioned as occurring with the particular drug under investigation are considered unexpected. 
Anticipated Adverse Events and Procedure Effects 
The following are anticipated, disease-related events in patients with HF or anticipated events of 
interest in patients with HFpEF taking EntrestoTM: 
• 
Arrhythmias: This refers to both atrial and ventricular arrhythmias. 
• 
Acute coronary syndrome: This refers to unstable angina, non ST segment elevation 
myocardial infarction (NSTEMI), and ST segment elevation myocardial (STEMI). 
• 
Unplanned hospitalization, ER visit or clinic visit for worsening HF: This refers to 
treatment for acute heart failure such as receiving intravenous diuretics. 
• 
Cerebrovascular event: This refers to cerebrovascular accidents (stroke) of any cause 
(hemorrhagic, ischemic, or embolic) and transient ischemic attack (TIA). 
• 
Venous thromboembolism: This includes both deep venous thrombosis and 
pulmonary embolus. 
• 
Worsening renal function: This refers to acute kidney injury, typically defined as an 
increase in eGFR ≥ 20% over 48 hours, or progressive loss of renal function over time. 
• 
LVAD implantation: This refers to implantation of a temporary or durable LVAD. 
• 
Cardiac Transplantation 
• 
Hyperkalemia > 6 mEq/L 
• 
Acute renal failure with serum creatinine > 2.5 mg/dL 
• 
Angioedema 
• 
Symptomatic hypotension 
Anticipated disease related events will not be captured as AEs/SAEs during the study, but will 
be entered on the appropriate case report form (“Events of Interest” page). 
8.8 
   Recording and Reporting of Adverse Events 
The site Investigator is responsible for monitoring the safety of participants enrolled into the 
study at the study sites. For this study, non-serious AEs will not be collected on the safety 
reporting page of the CRF, but should be documented in the source documents and followed 
according to local standard of care. 
 
SAEs, except for those anticipated AEs listed above, occurring from signed informed consent to 
Week 5 visit will be captured on the SAE CRF. Unless exempted as described above, all SAEs, 
whether or not deemed drug-related or expected, must be reported by the investigator or 
qualified designee within 1 working day of first becoming aware of the event. The investigator or 
qualified designee will enter the required information regarding the SAE into the appropriate 
CRF, which will be distributed to the appropriate sponsor contact. 
 
Information collected on the adverse event worksheet (and entered in the research database):  
• 
Subject’s name:  
• 
Medical record number:  
• 
Disease/histology (if applicable):  
• 
The date the adverse event occurred:  
• 
Description of the adverse event:  
• 
Relationship of the adverse event to the research (drug, procedure, or intervention):  
• 
If the adverse event was expected:  
• 
The severity of the adverse event: (use a table to define severity scale 1-5) 
• 
If any intervention was necessary:  

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• 
Resolution: (was the incident resolved spontaneously, or after discontinuing treatment) 
• 
Date of Resolution 
 
8.2.7 Follow-up 
When additional relevant information becomes available, the Investigator will record follow-up 
information according to the same process used for reporting the initial event as described 
above. The Investigator will follow all reportable events until resolution, stabilization or the event 
is otherwise explained. Investigators are also responsible for promptly reporting AEs to their 
reviewing IRB/EC in accordance with local requirements.  
 
8.2.8 Suspected Unexpected Serious Adverse Reaction 
AEs that meet the criteria of serious, related to study drug, and unexpected for that drug, qualify 
for expedited reporting to the regulatory authorities. The Site Investigator will assess all SAEs 
occurring at his/her site and evaluate for “unexpectedness” and relationship to study drug. The 
Site Investigator is required to complete and submit a voluntary MedWatch Report for the 
events identified as serious, study drug related and unexpected at:  
https://www.accessdata.fda.gov/scripts/medwatch/. A copy of this report should be kept at the 
site and also forwarded to the overall study PI within the same timeline used for reporting to 
regulatory authorities.  
 
8.2.9 Pregnancy 
Pregnancy occurring during the study period, although not considered a serious adverse event, 
must be reported within the same timelines as a serious adverse event. The pregnancy will be 
recorded on the appropriate pregnancy form. The pregnancy will be followed until final outcome. 
Any associated AEs or SAEs that occur to the mother or fetus/child will be recorded in the AE or 
SAE CRF. 
8.9 
Stopping Rules  
The study would be stopped only if advised because of unanticipated adverse events. 
8.10 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of 
adverse events as noted above, as well as the construction and implementation of a site data 
and safety-monitoring plan.  Medical monitoring will include a regular assessment of the number 
and type of serious adverse events.  After informal discussions with IRB staff in the midst of the study, 
given that 1. This was not a Phase 1,2,,3 study or clinical trial providing definitive information about 
effectiveness or safety of the drug 2. Prior data suggesting that the drug was safe to use leading to FDA 
approval for its use in heart failure 3. No major clinical endpoints were being evaluated to assess safety 
and effectiveness 4. No ethical issues were being raised in this proof of concept study regarding efficacy 
or safety that would lead to premature stopping of the study - a decision was made not to engage a 
DSMB. 
 
9 
Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 

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• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (long term survival status that 
the subject is alive) at the end of their scheduled study period. 
9.2 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Examples of these original documents, and data 
records include: hospital records, clinical and office charts, laboratory notes, memoranda, 
subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject 
files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial. 
9.3 
Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded.  All missing data must be explained.  If a space 
on the CRF is left blank because the procedure was not done or the question was not asked, 
write “N/D”.  If the item is not applicable to the individual case, write “N/A”.  All entries should be 
printed legibly in black ink.  If any entry error has been made, to correct such an error, draw a 
single straight line through the incorrect entry and enter the correct data above it.  All such 
changes must be initialed and dated.  Do not erase or use “white-out” for errors.  For 
clarification of illegible or uncertain entries, print the clarification above the item, then initial and 
date it.  If the reason for the correction is not clear or needs additional explanation, neatly 
include the details to justify the correction. Study CRF components will include an enrollment 
and demographics form; forms for recording relevant history, HF symptoms, physical exam 
results, laboratory results, and other baseline presenting characteristics; follow-up forms for use 
during regular follow-up visits; forms to track the participant’s clinical course over time; and 
event forms for recording the circumstances and details surrounding the occurrence of a death 
or hospitalization.  
9.4 
Data Quality Control 
Prior to the start of enrollment, the Investigators and Study Coordinators will be trained on the 
clinical protocol and data collection procedures. Personnel at the clinical sites will enter the data 
mandated by the protocol into the CRFs. The data will be extracted from the participant’s 
medical charts and other source documents. All CRFs will be completed according to the 
current Good Clinical Practice (GCP) guidelines. Follow-up training and training for new study 
personnel will be conducted as needed. 
 
9.5 
Data Security  
Access to databases will be controlled centrally through user passwords linked to appropriate 
privileges. This protects the data from unauthorized changes and inadvertent loss or damage. 
Database and web servers will be secured by a firewall and through controlled physical access. 

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Database back-up will be performed daily using standard procedures. All disk drives that 
provide network services, and all user computers, will be protected using virus-scanning 
software. 
 
9.6 
Publication Policy 
Dissemination of preliminary information can adversely affect the objectivity of study data. For 
this reason, Investigators will be prohibited from performing subset analyses at any point prior to 
the conclusion of the study, and any data, other than safety data, cannot be used for publication 
or reporting outside of this study until the study is completed.  
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
The investigator will allocate adequate time for such monitoring activities. The investigator will 
also ensure that the monitor or other compliance or quality assurance reviewer is given access 
to all the study-related documents and study related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.), and has adequate space to conduct the monitoring visit. 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, and 
government regulatory agencies, of all study related documents (e.g. source documents, 
regulatory documents, data collection instruments, study data etc.). The investigator will ensure 
the capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.).Participation as an investigator in this study implies acceptance of potential 
inspection by government regulatory authorities and applicable compliance offices. 
11 Regulatory Issues 
11.1 Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and in accordance with DCRI 
standard operating procedures. These procedures are designed to ensure adherence to Good 
Clinical Practice, as described in the following documents: 
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 
56 concerning informed consent and IRB regulations). 
3. Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, 
amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 
By signing the protocol, the investigator agrees to adhere to the instructions and procedures 
described in it and thereby to adhere to the principles of Good Clinical Practice to which it 
conforms. 
11.2 Institutional Review Board/Independent Ethics Committee 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee (IRB/IEC). A signed and dated statement that the protocol 
and informed consent have been approved by the IRB/IEC must be provided to the CC before 
study initiation. The name and occupation of the chairman and the members of the IRB/IEC 

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must be supplied to the CC if this information is released by IRB/IEC. Any amendments to the 
protocol, other than administrative ones, must be approved by this committee. 
11.3 Informed Consent 
The Investigator or designee must explain to each subject (or legally authorized representative) 
the nature of the study, its purpose, the procedures involved, the expected duration, the 
potential risks and benefits involved and any discomfort it may entail. Each subject must be 
informed that participation in the study is voluntary and that he/she may withdraw from the study 
at any time and that withdrawal of consent will not affect his/her subsequent medical treatment 
or relationship with the treating physician. 
 
This informed consent should be given by means of a standard written statement, written in 
non-technical language. The subject should read and consider the statement before signing and 
dating it, and should be given a copy of the signed document. If written consent is not possible, 
oral consent can be obtained if witnessed by a signed statement from one or more persons not 
involved in the study, mentioning why the patient was unable to sign the form. No patient can 
enter the study before his/her informed consent has been obtained. The informed consent forms 
are part of the protocol, and must be submitted by the investigator with it for IRB/IEC approval. 
The CC will supply proposed informed consent forms, which comply with regulatory 
requirements, and are considered appropriate for the study. Any changes to the proposed 
consent form suggested by the Investigator must be agreed to by the CC before submission to 
the IRB/IEC, and a copy of the approved version must be provided to the CC after IRB/IEC 
approval. 
 
12 Study Administration 
 
12.1 
Coordinating Center 
Mayo Clinic will function as the CC for this trial. 
 
12.2 
Core Laboratories  
Mayo Clinic will serve as the core laboratory for measurement of serum NEP and other 
biomarkers. Plasma specimens will be collected at Study Visits (weeks 0, and 5), processed at 
the clinical centers according to the procedures provided by the core laboratory, and shipped to 
the core laboratory on dry ice (Refer to Biomarker Core Laboratory Manual of Procedures). Any 
subjects who agree to participate in the biorepository will have samples collected at the clinical 
sites stored at the Mayo Clinic BAP.  
 
13 Study Finances 
13.1 Funding Source 
This study is financed through a grant from the US National Institute of Aging, National Institutes 
of Health.   
13.2 Subject Stipends or Payments 
Participants completing the study will receive $100.00 each for Study Visit 1 and 2 for a total 
remuneration of $200. 

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14 Publication Plan 
The primary responsibility for publication of the results lies with the principal investigator. The 
trial will be registered on ClinicalTrials.gov. 
 
15 References 
 
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Rouleau JL, Bull DA, Mann DL, Deswal A, Stevenson LW, Givertz MM, Ofili EO, O'Connor 
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24. 
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Felker GM, et al. Charting a roadmap for heart failure biomarker studies. JACC Heart Fail. 
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25. 
Pereira NL, Sargent DJ, Farkouh ME, Rihal CS. Genotype-based clinical trials in 
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Packer M, McMurray JJ, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi 
VC, Solomon SD, Swedberg K, Zile M, Andersen K, Arango JL, Arnold JM, Belohlavek J, 
et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of 
clinical progression in surviving patients with heart failure. Circulation. 2015;131(1):54-61. 
 
27. 
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