Protecting With ARNI Against Cardiac Consequences of Coronavirus Disease 2019
Phase: PHASE1
Conditions: Covid19
Sponsor: Duke University

 
 
 
 
 
 
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Protecting with ARNI Against Cardiac Consequences of Coronavirus Disease 2019 
(PARACOR-19) 
 
 
 
NCT04883528 
 
 
 
 
 
 
 
 
Compiled by: 
Duke University Medical Center 
Version 2.0 Date: 2/26/2023 
 
 
 
 
 
 
 
Distributed by: 
 
 
G. Michael Felker, MD 
Stephen J. Greene, MD 
Duke Clinical Research Institute 
Duke Clinical Research Institute 
Duke University 
Duke University 
200 Morris Street 
200 Morris Street 
Durham, NC 27701 
Durham, NC 27701 
 

 
 
 
 
 
 
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Study Funding: 
 
 
 
Novartis Pharmaceuticals 
 
Principal Investigators:  
 
Stephen J. Greene, MD  
G. Michael Felker, MD MHS 
 
 
 
 
 
 
 
 
 
 
 
Protocol Development Team:  Stephen J. Greene, MD  
G. Michael Felker, MD MHS 
 
 
 
 
 
 
 
Javed Butler, MD MPH MBA 
 
 
 
 
 
 
 
Raymond J. Kim, MD 
 
 
 
 
 
  
 
  
 
 
 

 
 
 
 
 
 
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1 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACEI 
Angiotensin-Converting Enzyme Inhibitor 
AE 
Adverse Event 
ARB 
Angiotensin Receptor Blocker 
ARNI 
Angiotensin Receptor Neprilysin Inhibitor 
CRF 
Case Report Form 
DSMB 
Data Safety Monitoring Board 
EF 
Ejection Fraction 
eGFR 
Estimated Glomerular Filtration Rate 
GFR 
Glomerular Filtration Rate 
HF 
Heart Failure 
HFpEF 
Heart Failure with Preserved Ejection Fraction 
HFrEF 
Heart Failure with Reduced Ejection Fraction 
ITT 
Intention To Treat 
IRB 
Institutional Review Board 
LV 
Left Ventricular 
LVAD 
Left Ventricular Assist Device 
LVEF 
mmHG 
mmol/L 
MDRD 
NT-proBNP 
Left Ventricular Ejection Fraction 
Millimeters of mercury 
Millimole per liter 
Modification of Diet in Renal Disease 
N-terminal pro-B-type natriuretic peptide 
PO 
PPI 
SAE 
“Per os,” or by mouth 
Patient Package Insert 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
sST2 
Soluble ST2 
 
 
 
 

 
 
 
 
 
 
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2 
TABLE OF CONTENTS 
1 
LIST OF ABBREVIATIONS ..................................................................................................................... 3 
2 
TABLE OF CONTENTS........................................................................................................................... 4 
3 
EXECUTIVE SUMMARY ........................................................................................................................ 7 
4 
OBJECTIVES ......................................................................................................................................... 9 
4.1 
Primary Objectives ...................................................................................................................... 9 
4.2 
Exploratory Objectives ................................................................................................................ 9 
5 
BACKGROUND AND STUDY RATIONALE .............................................................................................. 9 
6 
STUDY DESIGN .................................................................................................................................. 10 
6.1 
Screening and Randomization (Study Visit 1) ............................................................................ 10 
6.2 
Dose Titration and Safety Visit .................................................................................................. 11 
6.3 
Final Study Visit ......................................................................................................................... 11 
7 
PATIENT POPULATION ...................................................................................................................... 11 
7.1 
Study Population ....................................................................................................................... 11 
7.2 
Inclusion Criteria ....................................................................................................................... 11 
7.3 
Exclusion Criteria ....................................................................................................................... 12 
8 
TREATMENT ...................................................................................................................................... 12 
8.1 
Intervention .............................................................................................................................. 12 
8.2 
Drug Dispensing ........................................................................................................................ 13 
8.3 
Drug Administration .................................................................................................................. 13 
8.4 
Drug Storage Requirements ...................................................................................................... 13 
8.5 
Drug accountability ................................................................................................................... 13 
8.6 
Destruction ............................................................................................................................... 13 
8.7 
Randomization, Stratification and Blinding ............................................................................... 13 
8.8 
Unblinding ................................................................................................................................. 14 
8.9 
Concomitant Medication .......................................................................................................... 14 
9 
RECRUITMENT AND SCREENING PROCEDURES ................................................................................. 14 
9.1 
Common Recruitment Procedures ............................................................................................ 14 

 
 
 
 
 
 
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9.2 
Estimated Enrollment Period .................................................................................................... 14 
9.3 
Informed Consent ..................................................................................................................... 14 
9.4 
Confidentiality and HIPAA Requirements.................................................................................. 15 
9.5 
Protections of Human Subjects ................................................................................................. 15 
9.6 
Summary of the Risks and Benefits ........................................................................................... 15 
10 VISIT SCHEDULE AND ASSESSMENTS ................................................................................................ 16 
10.1 
Baseline Evaluation, Enrollment and Randomization Visit ........................................................ 16 
10.2 
Follow-up Evaluations ............................................................................................................... 17 
11 OUTCOME DETERMINATIONS ........................................................................................................... 19 
11.1 
Primary Endpoints ..................................................................................................................... 19 
11.2 
Exploratory Endpoints ............................................................................................................... 19 
12 PARTICIPANT SAFETY MONITORING AND REPORTING...................................................................... 19 
12.1 
Institutional Review Boards ...................................................................................................... 19 
12.2 
Adverse Event Definition ........................................................................................................... 20 
12.3 
Suspected Adverse Reaction Definition .................................................................................... 20 
12.4 
Serious Adverse Events (SAE) .................................................................................................... 20 
12.5 
Laboratory Test Abnormalities .................................................................................................. 20 
12.6 
Assessment of Causal Relationship ........................................................................................... 20 
12.7 
Assessment of Adverse Event Severity ...................................................................................... 21 
12.8 
 Recording and Reporting of Adverse Events ............................................................................ 21 
12.9 
 Follow-up of Adverse Events .................................................................................................... 21 
12.10  Expectedness ........................................................................................................................... 22 
12.11  Suspected Unexpected Serious Adverse Reaction ................................................................... 22 
12.12  Pregnancy................................................................................................................................. 22 
13 STATISTICAL METHODS AND DATA ANALYSIS ................................................................................... 22 
13.1 
General Design Issues ............................................................................................................... 22 
13.2 
Sample Size Justification and Randomization ........................................................................... 23 
13.3 
Interim Analyses and Safety Reviews ........................................................................................ 23 
13.4 
Analysis of the Co-Primary Endpoints ....................................................................................... 23 
13.5 
Analysis of Exploratory Endpoints ............................................................................................. 24 

 
 
 
 
 
 
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14 DATA MANAGEMENT PROCEDURES ................................................................................................. 24 
14.1 
Overview of Data Management ................................................................................................ 24 
14.2 
Data Security ............................................................................................................................. 24 
14.3 
Publication Policy ...................................................................................................................... 24 
15 STUDY ADMINISTRATION .................................................................................................................. 24 
15.1 
Data and Safety Monitoring Board ............................................................................................ 24 
15.2 
Biomarker Core Laboratory ....................................................................................................... 25 
16 REGULATORY ISSUES ......................................................................................................................... 25 
16.1 
Ethics and Good Clinical Practice .............................................................................................. 25 
16.2 
Institutional Review Board/Independent Ethics Committee ..................................................... 25 
16.3 
Informed Consent ..................................................................................................................... 25 
17 APPENDICES ...................................................................................................................................... 26 
17.1 
Appendix A - Schedule of Assessments ..................................................................................... 26 
18 REFERENCES ...................................................................................................................................... 27 
 

 
 
 
 
 
 
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3 
EXECUTIVE SUMMARY 
 
Title 
Protecting with ARNI Against Cardiac Consequences of Coronavirus 
Disease 2019 (PARACOR-19) 
Indication 
To decrease risk of cardiac injury and abnormalities in cardiac structure 
and function following COVID-19 infection 
Location 
Duke University Hospital  
Brief Rationale 
 
Although many patients presenting with Coronavirus Disease 2019 
(COVID-19) face high-risk of death, the vast majority of patients recover 
from the acute infection, either in the hospital or at home. Nonetheless, 
despite clinical improvement or resolution of symptoms, accumulating 
evidence supports significant potential for longer-term and insidious 
cardiac involvement. Moreover, within the heart, the virus appears to  
localize to interstitial cells and the extracellular matrix, with relative 
sparing of the myocytes themselves. These data, combined with others 
noting high levels of inflammation with COVID-19, suggest that the virus 
may increase propensity for downstream cardiac fibrosis and 
dysfunction. These collective data raise significant concerns that 
cardiomyopathy, heart failure, or other cardiovascular complications will 
evolve as the natural history of COVID-19 for many patients who recover 
from acute infection. 
 
Pre-clinical and clinical data across multiple cardiometabolic conditions 
suggest that sacubitril/valsartan may be particularly well-suited to prevent 
adverse cardiac remodeling and new-onset HF following COVID-19 
infection. Renin-angiotensin-aldosterone system (RAAS) inhibition has 
been postulated to have a cardio-protective role in COVID-19, but there 
is biologic plausibility that a dual compound with a neprilysin inhibitor 
would better prevent cardiac injury and dysfunction. In this context, the 
goal of the PARACOR-19 trial is to generate further evidence regarding 
the effects of sacubitril/valsartan on markers of cardiac injury, structure, 
and function among patients who have recovered from acute COVID-19 
infection. 
 
Hypothesis: Among patients with cardiovascular risk factors and 4-16 
weeks from prior COVID-19 infection, sacubitril/valsartan will reduce 
levels of high-sensitivity troponin T and/or soluble ST2 (sST2), compared 
with placebo. 
Study Design 
The PARACOR-19 trial will be an investigator-initiated, single center, 
double-blind trial of patients who have recovered from acute COVID-19 

 
 
 
 
 
 
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infection. There will be 1:1 randomization to sacubitril/valsartan or 
placebo. Approximately 50 participants will be randomized into the study. 
A subset of approximately 30 patients will be enrolled in the cardiac 
magnetic resonance (CMR) sub-study.   
Treatment 
Sacubitril/valsartan versus placebo 
Primary Objective 
and Endpoint 
1. Change from baseline in high-sensitivity troponin T 
2. Change from baseline in sST2 
Exploratory 
Objectives and 
Endpoints 
1. 
Change from baseline in high-sensitivity C-reactive peptide 
2. 
Change form baseline in PINP 
3. 
Change from baseline in Galectin-3 
4. 
Change from baseline in NT-proBNP 
5. 
Change from baseline in GDF-15 
6. 
Change from baseline in IL-6 
7. 
Change from baseline in CITP 
8.     Change from baseline in CMR measures (LVEF, LVEDVi, LVESVi, 
Native T1, Native T2) 
9. 
Change from baseline in focal fibrosis by delayed-enhancement 
10. Change from baseline in focal fibrosis as percentage of LV 
myocardial mass 
11. Change from baseline in health related quality of life, as measured 
by EQ-5D utility score and EQ-5D visual analog scale 
 
 

 
 
 
 
 
 
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4 
OBJECTIVES 
4.1 
Primary Objectives 
To determine the effect of sacubitril/valsartan versus placebo over 12 weeks on biomarkers of 
cardiac injury and fibrosis, as reflected in changes in high-sensitivity troponin T and sST2.  
 
Hypothesis: Among patients with cardiovascular risk factors and 4-16 weeks from prior COVID-
19 infection, sacubtril/valsartan will reduce levels of high-sensitivity troponin T and/or soluble 
ST2 (sST2), compared with placebo. 
4.2 
Exploratory Objectives 
To determine the effect of sacubitril/valsartan versus placebo over 12 weeks on cardiac 
biomarkers and measures of cardiac dysfunction and fibrosis on cardiac magnetic resonance 
imaging, as reflected by the following exploratory endpoints:. 
 
1. 
Change from baseline in high-sensitivity C-reactive peptide 
2. 
Change form baseline in PINP 
3. 
Change from baseline in Galectin-3 
4. 
Change from baseline in NT-proBNP 
5. 
Change from baseline in GDF-15 
6. 
Change from baseline in IL-6 
7.     Change from baseline in CITP 
8. 
Change from baseline in cardiac MRI (CMR) measures (LVEF, LVEDVi, LVESVi, Native 
T1, Native T2) 
9. 
Change from baseline in focal fibrosis by delayed-enhancement 
10. Change from baseline in focal fibrosis as percentage of LV myocardial mass 
11. Change from baseline in health related quality of life, as measured by EQ-5D utility score 
and EQ-5D visual analog scale 
5 
BACKGROUND AND STUDY RATIONALE 
Although many patients presenting with Coronavirus Disease 2019 (COVID-19) face high-risk of 
death, the vast majority of patients recover from the acute infection, either in the hospital or at 
home. Nonetheless, despite clinical improvement or resolution of symptoms, accumulating 
evidence supports significant potential for longer-term and insidious cardiac involvement. For 
example, in a recent study of patients seen a mean 71 days after COVID-19 diagnosis, 76% 
had detectable high-sensitivity troponin, 78% had demonstrable cardiac involvement on cardiac 
magnetic resonance (CMR) imaging, and 60% had evidence of cardiac inflammation by 
abnormal T1 and T2 imaging.1 Two-thirds of these patients recovered at home and there were 
no meaningful differences in troponin or CMR measures between patients who did and did not 
require hospitalization, suggesting that ongoing cardiac involvement may be common even 

 
 
 
 
 
 
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among those with a mild acute presentation.1 Likewise, in an autopsy study of patients with 
COVID-19 pneumonia as the clinical cause of death, 62% of patients had virus present in the 
heart, despite not meeting clinical or histologic criteria for acute myocarditis.2 Viral load was high 
and evidence of active viral replication was seen in most cases.2 Notably, the virus appeared to 
localize to interstitial cells and the extracellular matrix of the heart, with relative sparing of the 
myocytes themselves.3 These data, combined with others noting high levels of inflammation 
with COVID-19, suggest that the virus may increase propensity for downstream cardiac fibrosis 
and dysfunction. These collective data raise significant concerns that cardiomyopathy and heart 
failure will evolve as the natural history of COVID-19 for many patients who recover from acute 
infection.4  
Pre-clinical and clinical data across multiple cardiometabolic conditions suggest that 
sacubitril/valsartan may be particularly well-suited to prevent adverse cardiac remodeling and 
new-onset HF following COVID-19 infection. Renin-angiotensin-aldosterone system (RAAS) 
inhibition has been postulated to have a cardio-protective role in COVID-19, but there is strong 
biologic plausibility that a dual compound with a neprilysin inhibitor would better prevent cardiac 
injury and dysfunction.5 Across cardio-renal disease states, compared with ACEI/ARB therapy, 
sacubitril/valsartan offers superior cardio-protection for reducing clinical events and biomarkers 
of cardiac injury/ wall stress (e.g., troponin, natriuretic peptides), and these incremental benefits 
emerge quickly within a few weeks.6-11 Likewise, compared with ACEI/ARB, sacubitril/valsartan 
lowers levels of pro-inflammatory cytokines and other inflammatory biomarkers.12-14 Most 
recently, among patients with preserved ejection fraction, sacubitril/valsartan was shown to 
favorably alter biomarkers of cardiac extracellular matrix and collagen regulation compared with 
valsartan, adding further support for an anti-fibrotic mechanism well-suited to combat the 
propensity of COVID-19 for the cardiac interstitium.15  
In this context, the goal of the PARACOR-19 trial is to generate further evidence regarding the 
effects of sacubitril/valsartan on markers of cardiac injury, structure, and function among 
patients who have recovered from acute COVID-19 infection. 
 
6 
STUDY DESIGN 
6.1 
Screening and Randomization (Study Visit 1) 
Willing participants deemed likely to meet eligibility criteria will be consented. Participants will 
have an initial screening evaluation, including laboratory tests, at which time preliminary subject 
eligibility will be confirmed. Patients will also complete EuroQOL-5D (EQ-5D) surveys in order to 
be eligible. Participants consenting for and meeting entry criteria for the CMR substudy will 
undergo a CMR examination.  
 
Patients confirmed to meet study eligibility criteria will be randomized 1:1 in double-blind fashion 
to sacubitril/valsartan twice daily versus matching placebo twice daily. The starting dose of 
study drug will be dictated by systolic blood pressure. If systolic blood pressure is 100-120 
mmHg at randomization, participants will receive sacubitril/valsartan 24/26 mg twice daily or 

 
 
 
 
 
 
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matching placebo. If systolic blood pressure >120 mmHg at randomization, participants will 
receive sacubitril/valsartan 49/51 mg twice daily or matching placebo. At time of randomization, 
patients will also have serum biomarkers collected for central and local laboratory analysis. 
6.2 
Dose Titration and Safety Visit  
Patients will return between 7 and 21 days post-randomization for Study Visit 2. At this visit, 
tolerability and adherence to study medication will be assessed, renal function and potassium 
levels will be checked via local labs, and patients will have the dose of medication titrated based 
on systolic blood pressure and clinician assessment regarding presence of symptomatic 
hypotension. 
 
If systolic blood pressure >100 mmHg and no symptomatic hypotension or deemed medication-
related adverse effects, dose of study medication will be increased to the next highest dose of 
sacubitril/valsartan or matching placebo (i.e., patients originally receiving sacubitril/valsartan 
24/26 mg twice daily will be increased to sacubitril/valsartan 49/51 mg twice daily; patients 
originally receiving sacubitril/valsartan 49/51 mg twice daily will be increased to 
sacubitril/valsartan 97/103 mg twice daily). Patients not meeting criteria for dose uptitration will 
remain on their original dose of study therapy, as tolerated. For patients who are reporting 
symptomatic hypotension or other possible medication related adverse effects from study drug, 
the investigator may use their discretion in decreasing the dose of study drug to the next lowest 
dosing level.    
6.3 
Final Study Visit  
Participants will return for a final study visit between 77 and 91 days (11-13 weeks) for the 12-
week visit (Study Visit 3). Tolerability and adherence to study medication will be assessed, and 
renal function and potassium levels will be checked via local labs. Participants will also have 
serum biomarkers collected for central and local laboratory analysis. Participants who 
consented for the CMR sub-study will undergo a CMR examination. 
7 
PATIENT POPULATION  
7.1 
Study Population  
It is anticipated that approximately 50 participants meeting eligibility criteria listed below will be 
randomized into the study. It is anticipated that 30 of these patients will be included within the 
CMR substudy. Individuals suitable for this protocol are patients with cardiovascular risk factors 
and 4-16 weeks from prior COVID-19 infection. 
7.2 
Inclusion Criteria 
1. 
Patient with a history of laboratory proven-diagnosis of COVID-19 who is 4-16 weeks 

 
 
 
 
 
 
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from their last positive COVID-19 test 
2. 
Systolic blood pressure ≥100 mmHg at screening 
3. 
≥18 years of age 
4. 
Successful collection of baseline serum biomarkers 
5. 
Successful completion of baseline EQ-5D questionnaire 
6. 
Successful completion of baseline CMR study (CMR sub-study only) 
7. 
High-sensitivity troponin at or above the level of detection on screening labs 
8. 
Presence of ≥1 of the following:  
a. 
Age ≥60 
b. 
History of atherosclerotic cardiovascular disease (ASCVD), including myocardial 
infarction, coronary artery disease, ischemic stroke/transient ischemic attack, or 
peripheral artery disease 
c. 
Diabetes mellitus (Type 1 or Type 2) 
d. 
Body mass index ≥35 kg/m2 
e. 
eGFR 30-60 ml/min/1.73m2 
f. 
History of atrial fibrillation/flutter 
7.3 
Exclusion Criteria 
1. 
Fever within the past 96 hours of >100.3 degrees Fahrenheit 
2. 
Actively receiving therapy with an angiotensin-converting enzyme inhibitor (ACEI), 
angiotensin II receptor blocker (ARB), aliskiren, or sacubitril/valsartan  
3. 
Last known left ventricular ejection fraction of ≤40% 
4. 
eGFR <30 ml/min/1.73m2 on screening labs, including patients on dialysis therapy 
5. 
Serum potassium >5.0 mEq/L on screening labs 
6. 
Prior intolerance, allergy or angioedema to ACEI, ARB, or sacubitril/valsartan 
7. 
Pregnant or breast-feeding 
8. 
In women of childbearing age, unwillingness to use birth control for the duration of the 
study 
9. 
History of heart transplant or durable left ventricular assist device 
10.   Currently implanted permanent pacemaker, defibrillator, or other device or condition 
that would preclude CMR testing (CMR sub-study only) 
11. Currently participating in another trial of an investigational medication or device for 
COVID-19.   
12. Any other condition that in the judgment of the investigator would jeopardize the 
patient’s compliance with the study protocol 
8 
TREATMENT  
8.1 
Intervention  
This will be a 2-arm randomized, double-blind, controlled trial. The therapeutic intervention will 
be treatment with either sacubitril/valsartan or placebo. Study drug will be given for 12 weeks 

 
 
 
 
 
 
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(+/- 1 week).   
8.2 
Drug Dispensing 
Sacubitril/valsartan and matching placebo will be provided to Duke University Hospital by 
Novartis Pharmaceuticals. Participants will receive a sufficient supply of study drug at each 
study visit to last until the next study visit by a blinded member of the study team. Drug storage, 
inventory, accountability, and dispensing will be managed at Duke University Hospital. 
Participants will be instructed to take the medication as required by the protocol and compliance 
will be assessed at each visit. 
8.3 
Drug Administration 
Subjects will take sacubitril/valsartan or placebo twice daily by mouth, with dosing determined 
as outlined in Section 6 above.  
8.4 
Drug Storage Requirements 
Study mediation must be received by designated personnel at Duke University Hospital, 
handled and stored safely and properly, and kept in a secured location to which only the 
investigator and designated site personnel have access. Upon receipt, doses of 
sacubitril/valsartan and matching placebos should be stored according to the instructions 
specified on the drug labels.  
8.5 
Drug accountability 
Participants are instructed to return all used, partly used and unused trial product at each study 
visit. Returned trial product(s) (used, partly used or unused including empty packaging material) 
must be stored separately from the non-allocated trial product(s) until drug accountability has 
been reconciled. The investigators will keep track of all received, used, partly used and unused 
trial products. 
8.6 
Destruction 
Used and unused study drug may be destroyed at the site according to accepted pharmacy 
practice, local and national guidelines, using the site’s destruction procedure.  
8.7 
Randomization, Stratification and Blinding 
Patients will be consented and enrolled at the first study visit.  Eligible patients will be 
randomized in a 1:1 allocation ratio to one of two treatment groups. Since this is a single center 
pilot study, randomization will not involve a permuted block design or any stratification.  
 
Blinding of the study, with respect to treatment groups, will be preserved by the use of matching 
placebo. The investigator may be asked at the end of the trial if they had obtained any 

 
 
 
 
 
 
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information which may have led to the unblinding of treatment.   
8.8 
Unblinding 
The investigator will be given access to the treatment code for their participants for emergency 
unblinding only.  Any suspected study drug-related events should be treated as though the 
subject received sacubitril/valsartan.  Randomization data are kept strictly confidential, 
accessible only to authorized persons, until the time of unblinding. Randomization codes will be 
provided to Novartis Pharmaceuticals at the time of study initiation. Upon completion of the 
double blind period, Novartis Pharmaceuticals will unblind data in the Argus safety database 
once database lock is completed and confirmed by Duke University Medical Center. This time 
frame is in accordance with Novartis standard operating procedures and unblinding will take 
place in coordination with the Duke study. 
8.9 
Concomitant Medication 
Participants should be treated per standard care with their regular clinicians. However, the 
following medications should not be taken during the treatment period of this study: ACEI, ARB, 
aliskiren, or sacubitril/valsartan (other than blinded study drug), bile acid sequestering agents 
(e.g., cholestyramine), and nesiritide or intravenous nitrates (interrupt or discontinue study drug, 
as concomitant administration of sacubitril/valsartan with nesiritide or intravenous nitrates has 
not been studied).  
 
The following medications should be used with caution during the study period: agents that raise 
potassium (e.g., potassium sparking diuretics, potassium supplements, mineralocorticoid 
receptor antagonists), and phosphodiesterase-5 inhibitors (may increase risk of hypotension).  
9 
RECRUITMENT AND SCREENING PROCEDURES 
9.1 
Common Recruitment Procedures 
Individual meeting eligibility criteria will be approached regarding participation in this study.  
9.2 
Estimated Enrollment Period 
This study will randomize approximately 50 subjects in the Duke University Health System in the 
U.S. The anticipated enrollment period is approximately 12 months. 
9.3 
Informed Consent 
Study personnel will explain to eligible individuals the purpose of the study, study interventions 
and evaluations, and the potential risks and benefits of participation, and will answer any 
questions. If a subject agrees to participate in the study, they will review and sign the Duke 
University institutional review board (IRB) approved informed consent form (ICF).  

 
 
 
 
 
 
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9.4 
Confidentiality and HIPAA Requirements 
All information collected on study subjects will be stored in a confidential manner using the 
procedures in place at Duke University Hospital. Only approved study personnel will have 
access to data collected as part of the study. Consented study subjects will be identified by a 
subject ID number on all study documents.  
9.5 
Protections of Human Subjects 
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. 
9.6 
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.  
 
Cardiac Magnetic Resonance Imaging (sub-study patients only): Serious reactions to the 
contrast agent used during some MRI tests are very rare. However, side effects are possible 
and include headache, nausea, dizziness, changes in taste, and allergic reactions.  Rarely, the 
contrast agent can harm people who have severe kidney or liver disease. The substance may 
cause nephrogenic systemic fibrosis. 
 
Sacubitril/valsartan: Sacubitril/valsartan is indicated to reduce the risk of cardiovascular death 
and hospitalization for heart failure in adult patients with chronic heart failure.7, 8, 16 Moreover, 
sacubitril/valsartan has been shown to reduce mortality in patients with heart failure and 
reduced ejection fraction (HFrEF).7 This agent is recommended in all patients with HFrEF (Class 
I, Level of Evidence B-R), unless contraindicated.17  
 
Sacubitril/valsartan is teratogenic and contraindicated in pregnancy. Use of drugs that act on the 
renin-angiotensin system (of which sacubitril/valsartan is included) during the second and third 
trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity 
and death. When pregnancy is detected, discontinue study drug as soon as possible. These 
adverse outcomes are usually associated with use of these drugs in the second and third 
trimesters of pregnancy.  There is no information regarding the presence of sacubitril/valsartan 
in human milk, the effects on the breastfed infant, or the effects on milk production. Sexually 
active subjects must agree to use appropriate contraception as long as they are taking study 
drug.  Medically acceptable contraceptives include:  
 

 
 
 
 
 
 
     16
 
 
 
 
 
 
• 
surgical sterilization (such as a tubal ligation or hysterectomy) 
• 
approved hormonal contraceptives (such as birth control pills, patches, implants or 
injections) 
• 
barrier methods (such as a condom or diaphragm) used with a spermicide, or 
• 
Intrauterine device (IUD) 
 
Sacubitril/valsartan should be used with caution in the setting of concomitant non-steroidal anti-
inflammatory drugs, lithium, other potassium-sparing diuretics. Sacubitril/valsartan is 
contraindicated with use an ACEI, ARB, and should not be used with aliskiren in patients with 
diabetes.  
 
In the PARADIGM-HF trial of patients with chronic heart failure with reduced ejection fraction, 
sacubitril/valsartan reduced the risk of cardiovascular mortality or heart failure hospitalization by 
20%, as compared with guideline-indicated ACEI therapy (i.e., enalapril). In the PARADIGM-HF 
trial, use of sacubitril/valsartan was associated with a greater incidence of angioedema than the 
comparator drug enalapril (0.5% vs. 0.2%).7 The risk of angioedema with sacubitril/valsartan 
compared with 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 PARADIGM-HF was more common among patients taking 
sacubitril/valsartan than enalapril (18% vs. 12%).7 In the PARAGON-HF trial, which tested the 
efficacy and safety of sacubitril/valsartan versus valsartan among patients with heart failure with 
preserved ejection fraction, no new adverse reactions were identified.8  
10 VISIT SCHEDULE AND ASSESSMENTS 
10.1 
Baseline Evaluation, Enrollment and Randomization Visit  
A schedule of assessments throughout the study is also provided in Appendix A. 
 
Study Visit 1 (Enrollment and Randomization) 
This visit will include the screening and informed consent process followed by a baseline 
assessment including:  
• 
Demographics and medical history  
• 
Review of medications patient is actively taking, and the doses 
• 
Vital signs, including systolic and diastolic blood pressure, heart rate, height, weight 
• 
EQ-5D quality of life questionnaire 
• 
Residual COVID-19 symptoms 
• 
Local laboratory testing, including the following: 
 
Basic metabolic/renal function panel, including sodium, potassium, chloride, 
CO2/bicarbonate, blood Urea Nitrogen (BUN), creatinine 
 
High-sensitivity troponin  

 
 
 
 
 
 
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• 
Central laboratory testing, including the following 
 
High-sensitivity troponin T  
 
sST2 
 
hs-CRP 
 
PINP 
 
Galectin-3 
 
NT-proBNP 
 
GDF-15 
 
IL-6  
 
CITP 
• 
CMR examination, with intravenous gadolinium contrast (CMR sub-study patients only) 
• 
Urine pregnancy test on women of childbearing potential 
 
Patients will be initiated on blinded study medication, as dictated by systolic blood pressure. If 
systolic blood pressure is 100-120 mmHg at randomization, participants will receive 
sacubitril/valsartan 24/26 mg twice daily or matching placebo. If systolic blood pressure >120 
mmHg at randomization, participants will receive sacubitril/valsartan 49/51 mg twice daily or 
matching placebo. 
 
10.2 
Follow-up Evaluations 
 
Study Visit 2 (Titration Visit) 
Visit 2 should take place within 7-21 days after the randomization visit.  
Assessments at this visit include:  
• 
Review of medications patient is actively taking, and the doses 
• 
Vital signs, including systolic and diastolic blood pressure, and heart rate 
• 
Local laboratory testing, including the following: 
 
Basic metabolic/renal function panel, including sodium, potassium, chloride, 
CO2/bicarbonate, BUN, creatinine 
• 
Urine pregnancy test on women of childbearing potential 
• 
Adverse event monitoring, including hospitalizations 
• 
Study medication adherence 
 
If systolic blood pressure >100 mmHg and no symptomatic hypotension or deemed medication-
related adverse effects, dose of study medication will be increased to the next highest dose of 
sacubitril/valsartan or matching placebo (i.e., patients originally receiving sacubitril/valsartan 
24/26 mg twice daily will be increased to sacubitril/valsartan 49/51 mg twice daily; patients 
originally receiving sacubitril/valsartan 49/51 mg twice daily will be increased to 
sacubitril/valsartan 97/103 mg twice daily). Patients not meeting criteria for dose uptitration will 
remain on their original dose of study therapy, as tolerated.  For patients who are reporting 

 
 
 
 
 
 
     18
 
 
 
 
 
 
symptomatic hypotension or other possible medication related adverse effects from study drug, 
the investigator may use their discretion in decreasing the dose of study drug to the next lowest 
dosing level.    
 
 
Study Visit 3 (Final Study Visit) 
Participants will return for a final study visit between 77 and 91 days (11-13 weeks) for the 12-
week visit.  
Assessments at this visit include:  
• 
Review of medications patient is actively taking, and the doses 
• 
Vital signs, including systolic and diastolic blood pressure, heart rate, weight 
• 
EQ-5D quality of life questionnaire 
• 
Residual COVID-19 symptoms 
• 
Local laboratory testing, including the following: 
 
Basic metabolic/renal function panel, including sodium, potassium, chloride, 
CO2/bicarbonate, BUN, creatinine 
• 
Central laboratory testing, including the following 
 
High-sensitivity troponin T  
 
sST2 
 
hs-CRP 
 
PINP 
 
Galectin-3 
 
NT-proBNP 
 
GDF-15 
 
IL-6  
 
CITP 
• 
CMR examination, with intravenous gadolinium contrast (CMR sub-study patients only) 
• 
Urine pregnancy test on women of childbearing potential 
• 
Adverse event monitoring, including hospitalizations  
• 
Study medication adherence 
 
Study Drug Interruption: 
If a subject should stop taking study medication for any reason before completing the 12 weeks 
of study drug dosing, an attempt should be made to restart the study drug at the last tolerated 
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. All subjects will complete all 
study assessments through study visit 3, regardless of whether they continue to receive the 
study drug for the full 12 weeks. 
 
Unscheduled Visits: 
If the Investigator determines that a participant should be brought to the clinic to be evaluated 

 
 
 
 
 
 
     19
 
 
 
 
 
 
for a potential change in study drug dose between scheduled study visits, an “unscheduled visit” 
should be done. Study drug dose changes will be recorded in the eCRF. 
Assessments at this visit include:  
• 
Interim history 
• 
Review of medications patient is actively taking, and the doses 
• 
Vital signs, including systolic and diastolic blood pressure, and heart rate 
• 
Local laboratory testing, including the following: 
 
Basic metabolic/renal function panel, including sodium, potassium, chloride, 
CO2/bicarbonate, BUN, creatinine 
• 
Adverse event monitoring  
• 
Study medication adherence 
11 OUTCOME DETERMINATIONS 
11.1 
Primary Endpoints 
1. Relative change from baseline in high-sensitivity troponin T levels from randomization to 
12 weeks.  
2. Relative change from baseline in sST2 from randomization to 12 weeks.  
11.2 
Exploratory Endpoints 
1. Change from baseline in high-sensitivity C-reactive peptide 
2. Change form baseline in PINP 
3. Change from baseline in Galectin-3 
4. Change from baseline in NT-proBNP 
5. Change from baseline in GDF-15 
6. Change from baseline in IL-6 
7. Change from baseline in CITP 
8. Change from baseline in CMR measures (LVEF, LVEDVi, LVESVi, Native T1, Native T2) 
9. Change from baseline in focal fibrosis by delayed-enhancement 
10. Change from baseline in focal fibrosis as percentage of LV myocardial mass 
11. Change from baseline in health related quality of life, as measured by EQ-5D utility score 
and EQ-5D visual analog scale 
12 PARTICIPANT SAFETY MONITORING AND REPORTING 
12.1 
Institutional Review Boards 
The study protocol, consent form, and other study documents will be submitted to Duke 
University IRB for approval. Any amendments to the protocol, other than minor administrative 
changes, must be approved by each Duke University IRB before they are implemented. 

 
 
 
 
 
 
     20
 
 
 
 
 
 
12.2 
Adverse Event Definition 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
a participant, whether or not considered drug or biologic related. An AE can therefore be any 
undesirable sign, symptom or medical condition occurring after starting study drug, even if the 
event is not considered to be related to the pharmaceutical product.  
12.3 
Suspected Adverse Reaction Definition 
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.  
12.4 
Serious Adverse Events (SAE) 
An adverse event or suspected adverse reaction is considered serious if the investigator or 
sponsor believes any of the following outcomes occurred: 
• 
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 participant 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 the investigator. 
12.5 
Laboratory Test Abnormalities 
For laboratory test abnormalities that meet the definition of an SAE, that required the participant 
to have the investigational product discontinued or interrupted or require the participant to 
receive 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). 
12.6 
Assessment of Causal Relationship 
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:  

 
 
 
 
 
 
     21
 
 
 
 
 
 
• 
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. 
12.7 
Assessment of Adverse Event Severity 
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.  
12.8 
 Recording and Reporting of Adverse Events 
The site Investigator is responsible for monitoring the safety of subjects enrolled into the study.  
  
All AEs occurring from signed informed consent through study visit 3 will be captured on the AE 
eCRF. For patients who die during the course of the study, the cause of death will be reported 
by the investigator in the eCRF. The Duke Heart Center Clinical Research Unit will share all 
SAEs with Novartis Pharmaceuticals within 24 hours after the investigators are made aware. AE 
reports will be shared with Novartis Pharmaceuticals, as requested.  
 
Any misuse or abuse of the study drug, other medication errors and uses outside of what is 
foreseen in the protocol (irrespective of whether a clinical event has occurred) will also be 
documented in the eCRF. 
12.9  
Follow-up of Adverse Events 
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 Duke University IRB in 
accordance with local requirements. The Data Safety Monitoring Board (DSMB) will review 
detailed safety data approximately every 6 months throughout the study. 

 
 
 
 
 
 
     22
 
 
 
 
 
 
12.10  Expectedness 
The expectedness of an AE or Suspected Adverse Reaction (SAR) shall be determined 
according to the most current patient package insert (PPI). Any AE that is not identified in 
nature, severity, or specificity in the current PPI is considered unexpected. Events that are 
mentioned in the PPI as occurring with a class 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. 
12.11  Suspected Unexpected Serious Adverse Reaction 
AEs that meet the criteria of serious, related to study drug, and unexpected per PPI, qualify for 
expedited reporting to the regulatory authorities. The site Investigator will assess all SAE’s 
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 events 
viewed as serious, study drug related and unexpected at: 
https://www.accessdata.fda.gov/scripts/medwatch/. 
12.12  Pregnancy 
Pregnancy occurring during a clinical investigation, although not considered a serious adverse 
event, will be recorded in the eCRF. Study drug will be discontinued among patients confirmed 
to be become pregnant during the study. The pregnancy will be followed until final outcome. Any 
associated AEs or SAEs that occur to the mother or fetus will be recorded in the AE/SAE 
eCRF,. The pregnancy outcome of a female partner to a male study participant will not be 
followed.   
13 STATISTICAL METHODS AND DATA ANALYSIS 
13.1 
General Design Issues 
Planned analyses will be prospectively defined for this study prior to unblinding of data.  
 
Primary analysis of the PARACOR-19 trial will be based on the intention to treat (ITT) principle. 
That is, subjects will be analyzed (and endpoints attributed) according to the treatment strategy 
to which subjects are randomized, regardless of subsequent additional post-randomization 
treatment and medical care. The ITT population will correspond to all randomized subjects. 
Secondary analysis will include per-protocol analysis, which will include randomized patients 
who remain on assigned study drug and complete the entirety of the study protocol.  
 
Statistical comparisons will be performed using two-sided significance tests. Baseline 
demographic and clinical variables will be summarized for each randomized arm of the study. 
Descriptive summaries of the distribution of continuous variables will be presented in terms of 
percentiles (e.g., median, 25th and 75th percentiles) along with means and standard deviations.  

 
 
 
 
 
 
     23
 
 
 
 
 
 
Categorical variables will be summarized in terms of frequencies and percentages. 
 
In addition, exploratory analyses will be performed to help explain and understand findings 
observed from the planned analyses. Statistical tests with a 2-sided p-value <0.05 will be 
considered statistically significant, unless otherwise stated. Analyses will be performed using 
SAS software (SAS Institute, Inc, Cary, NC).  
13.2 
Sample Size Justification and Randomization 
Subjects will be randomized in a 1:1 allocation ratio. We plan to randomize approximately 50 
participants with planned follow-up of 12 weeks. Given the exploratory nature of this early phase 
study, the co-primary endpoints (relative change in hs-troponin T, relative change in sST2) will 
be assessed separately using a type 1 error of 0.05.   
 
We assume a 25% relative reduction in hs-troponin T compared with placebo at 12 weeks, and 
a 25% relative reduction in sST2 compared with placebo at 12 weeks. A two-sided, two-sample 
t-test with group sample sizes of 25 and 25 achieves at least 80% power to detect a ratio of 0.75 
when the ratio under the null hypothesis is 1.00. The coefficient of variation (CV) on the original 
scale is assumed to be ≤ 0.36 which is reasonable based on historical data.18 The significance 
level (alpha) is 0.05.  As the CV decreases, the statistical power increases; however, it the CV 
increases we would need to find a larger ratio to have at least 80% power.  For example, if the 
CV were actually 0.57, then we would have 80.3% power to find a significant ratio of 35%. For 
all primary and exploratory biomarker endpoints, values below the lower limit of the assay will 
be imputed with values just below the level of detection, consistent with approaches in prior 
cardiovascular biomarker trials.18  
13.3 
Interim Analyses and Safety Reviews 
It is anticipated that the DSMB will review the accumulating data and schedule ad hoc meetings 
if SAEs accrue. During such meetings, the DSMB may be provided the following information: 
subject enrollment reports, rates of adherence with the assigned treatment, and description of 
SAEs. The DSMB will review data masked by study group (such as X vs. Y). Due to the size of 
the trial, no formal interim analysis of efficacy is planned. There will be no futility analysis.  
13.4 
Analysis of the Co-Primary Endpoints 
For each serum biomarker, we will calculate the ratio of geometric means at baseline and 12 
weeks for the sacubitril/valsartan treatment arm compared with the placebo arm, with 95% 
confidence intervals.  A two-sample t-test will be used to test for a significant difference using a 
p-value <0.05 for each co-primary endpoint.  A sensitivity analysis will be done using 
generalized linear regression to assess the ratio after adjusting for possible baseline 
differences. 

 
 
 
 
 
 
     24
 
 
 
 
 
 
13.5 
Analysis of Exploratory Endpoints 
Serum biomarker exploratory endpoints will be assessed in an identical manner to the co-
primary endpoints.  
 
CMR exploratory endpoints will be analyzed as change from baseline using 
linear regression (with treatment, randomization group assignment, and the baseline value as 
covariates) to determine estimated mean, the differences compared with placebo, and 95% 
confidence intervals (CI). Sensitivity analyses will be considered adjusting for possible baseline 
differences. 
14 DATA MANAGEMENT PROCEDURES 
14.1 
Overview of Data Management  
The Duke Heart Center Clinical Research Unit will have primary responsibility for data 
management, including the development of data collection systems, data monitoring processes, 
and data storage and back-up.   
14.2 
Data Security  
Access to databases will be controlled centrally by Duke Heart Center Clinical Research Unit 
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 Duke University firewall and through controlled physical access. All disk drives that 
provide network services, and all user computers, will be protected using virus-scanning 
software. 
14.3 
Publication Policy 
Dissemination of preliminary information can adversely affect the objectivity of study data. For 
this reason, investigators will not be allowed to perform subset analyses at any point before 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 or discontinued by the DSMB.  
15 STUDY ADMINISTRATION 
15.1 
Data and Safety Monitoring Board 
An independent DSMB will be for this trial. This committee will consist of a group of highly 
experienced individuals with extensive pertinent expertise in HF and clinical trials. The DSMB 
will advise the investigators regarding the continuing safety of current subjects and those yet to 
be recruited, as well as the continuing validity and scientific merit of the trial. Safety data, 
summarized at the treatment level, will be assessed approximately every 6 months by the 

 
 
 
 
 
 
     25
 
 
 
 
 
 
DSMB. The safety analyses will be based on the entire ITT population. Safety will be evaluated 
by comparing the occurrence of AEs and changes in laboratory values of the active treatment 
arm compared to the active control arm. 
15.2 
Biomarker Core Laboratory  
Plasma specimens collected for central laboratory analysis will be sent to the core laboratory for 
measurement of serum biomarkers. These specimens will be collected at Study Visits 1 and 3, 
processed at the Duke Heart Center Clinical Research Unit according to the appropriate 
procedures, and shipped to the core laboratory on ice. 
16 REGULATORY ISSUES 
16.1 
Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol. 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). 
The investigators agree to adhere to the instructions and procedures described in the protocol 
and thereby to adhere to the principles of Good Clinical Practice that it conforms to. 
16.2 
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 the Duke University IRB. Documentation that the 
protocol and informed consent have been approved by the IRB must be in place before study 
initiation.  Any amendments to the protocol, other than administrative ones, must be approved 
by the IRB. 
16.3 
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.  The informed consent form(s) must be submitted by 
the investigator for IRB approval.  

 
 
 
 
 
 
     26
 
 
 
 
 
 
17 APPENDICES 
17.1 
Appendix A - Schedule of Assessments 
 
 
 
 
 
 
Visit number 
1 
2 
3 
Time of Visit 
Enrollment/ 
Randomization 
Titration Visit  
(Week 1-2) 
12 weeks  
Inclusion/Exclusion criteria 
X 
Informed consent 
X 
 
 
Dispense study medication 
X  
X 
 
Demographics, past medical
history 
X  
 
 
Vital signs 
X 
X 
X 
Concurrent medications and 
doses 
X 
X 
X 
EQ-5D questionnaire 
X 
 
X 
Residual COVID Symptoms 
X 
 
X 
Urine pregnancy test1 
X 
X 
X 
Local laboratories  
X2 
X3 
X3 
Serum biomarkers  
X4 
 
X4 
Cardiac MRI (30 patients, 
sub-study patients only) 
X 
 
X 
Vital status 
 
X 
Adverse events, including 
hospitalizations 
 
X 
X 
Study medication 
adherence 
 
X 
X 
1 For women of childbearing potential 
2 hs-TnT, basic metabolic panel (including serum creatinine and serum potassium) 
3 Basic metabolic panel (including renal function and serum potassium)  
4 hs-TnT, sST2, hs-CRP, PINP, Galectin-3, NT-proBNP, GDF-15, IL-6, CITP 

 
 
 
 
 
 
     27
 
 
 
 
 
 
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