Clinical trial NCT03988634
Conditions: Heart Failure With Preserved Ejection Fraction (HFpEF)
Keywords: Heart failure with preserved ejection fraction (HFpEF) Heart failure hospitalization NYHA NT-proBNP Acute decompensated heart failure Sacubitril/valsartan Global evaluation of treatment effectiveness (GETE) Worsening Heart Failure
Sponsor: Novartis Pharmaceuticals
Start date: 2019-06-29; Completion date: 2022-12-14
Enrollment: 467 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The effect of sacubitril/valsartan vs. valsartan on changes in NT-proBNP, safety, and tolerability in HFpEF patients with a WHF event (HFpEF decompensation) who had been stabilized and initiated at the time of or within 30 days post-decompensation.

Detailed description:
This study used a randomized, double-blind, double-dummy, active-controlled, parallel group design conducted across 100 centers in the US and Canada. The study duration was a maximum of 20 months (minimum follow up was 8 weeks).

Randomized patients were deemed hemodynamically stabilized and needed to meet all inclusion and none of the exclusion criteria. Patients were randomized 1:1 to LCZ696 or valsartan. Initial dose at randomization was determined based on the patient's previous dose of or lack of ACEi/angiotensin receptor blocker (ARB) immediately prior to current worsening heart failure (WHF) event (heart failure with preserved ejection fraction \[HFpEF\]) decompensation, or at the time of post-decompensation randomization.

LCZ696 dose or valsartan dose levels may have been increased to the targeted desired dose of 97/103 mg \[200 mg\] BID or valsartan 160 mg BID on an every 2-week basis or earlier based on clinical need and investigator judgment. Every effort was made to titrate to and maintain patients on the target dose level, as tolerated by the patient.

To maintain the blinding, patients were required to take their assigned active treatment tablet along with placebo matching the opposite treatment BID.

The protocol had 4 amendments. Protocol Version 00 (Original Protocol) included a double-blind phase through Week 8 followed by an open-label phase during Weeks 8 to 12. Protocol Amendment 01 omitted the open-label phase and followed patients for a maximum of 20 months in a double-blinded treatment phase. Throughout all protocol versions, the primary endpoint remained the time-averaged proportional change in N-terminal pro-brain natriuretic peptide (NT-proBNP) from Baseline to Weeks 4 and 8. The most recent protocol amendment (Amendment 04) reduced the sample size to approximately 450 patients (from 800) with 85% power for the primary endpoint, deemphasizing the statistical power for key secondary clinical endpoints; however, clinical events were still assessed as secondary endpoints.

No efficacy analyses include "OPEN LABEL' data. After Protocol Amendment 01, the open-label option was removed from the study, only the 233 patients randomized in the Double-blind Phase Sacubitril+ Valsartan (LCZ696) and the 233 patients randomized in the Double-blind Phase Valsartan arms were included in the efficacy analysis.

Arms: arm 1: Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg twice daily (Dose Level 3).

Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan , and one tablet of valsartan matching placebo) arm 2: Study treatment was titrated to the target dose of valsartan 160 mg twice daily (Dose Level 3).

Patients were required to take a total of two tablets twice daily (one tablet of active valsartan, and one tablet of sacubitril and valsartan matching placebo)
Interventions: intervention 1: sacubitril/valsartan intervention 2: valsartan intervention 3: sacubitril/valsartan matching placebo intervention 4: valsartan matching placebo
Intervention descriptions: intervention 1: Sacubitril/valsartan (LCZ696) was available as 24/26 mg, 49/51 mg, and 97/103 mg in tablet form to be taken orally, twice daily intervention 2: Valsartan was available as 40 mg, 80 mg, and 160 mg in tablet form to be taken orally, twice daily intervention 3: Sacubitril/valsartan (LCZ696) matching placebo was available as tablet form to be taken orally, twice daily intervention 4: Valsartan matching placebo was available as tablet form to be taken orally, twice daily

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development
LCZ696
Clinical Trial Protocol CLCZ696DUS01 / NCT03988634
A multicenter, randomized, double-blind, double-dummy, 
parallel group, active controlled study to evaluate the effect 
of sacubitril/valsartan (LCZ696) versus valsartan on 
changes in NT-proBNP, safety, and tolerability in HFpEF 
patients with a WHF event (HFpEF decompensation) who 
have been stabilized and initiated at the time of or within 30 
days post-decompensation (PARAGLIDE-HF)
Document type:
Amended Protocol Version (Clean)
EUDRACT number:
Not applicable
Version number:
V04
Clinical trial phase:
IIIB
Release date:
08-Dec-2021


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Amended Protocol Version No. 04 (clean)                                                 Protocol No. CLCZ696DUS01
Table of contents
Table of contents ........................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................9
Protocol summary..............................................................................................................11
1
Introduction .......................................................................................................................18
1.1
Background............................................................................................................18
1.2
Rationale for Protocol Amendments .....................................................................19
1.3
Changes to Protocol...............................................................................................20
1.4
Purpose ..................................................................................................................21
2
Objectives and endpoints...................................................................................................22
3
Study design ......................................................................................................................24
4
Rationale............................................................................................................................25
4.1
Rationale for study design .....................................................................................25
4.2
Rationale for dose/regimen and duration of treatment ..........................................26
4.3
Rationale for choice of comparator .......................................................................26
4.4
Purpose and timing of interim analyses/design adaptations..................................27
4.5
Risks and benefits..................................................................................................27
5
Population..........................................................................................................................27
5.1
Inclusion criteria ....................................................................................................28
5.2
Exclusion criteria...................................................................................................29
6
Treatment...........................................................................................................................31
6.1
Study treatment Investigational and control drugs ................................................31
6.1.1
Treatment arms/group ...........................................................................33
6.1.2
Treatment duration................................................................................33
6.1.3
Concomitant therapy.............................................................................33
6.1.4
Prohibited medication ...........................................................................34
6.1.5
Rescue medication ................................................................................35
6.2
Patient numbering, treatment assignment, randomization.....................................35
6.2.1
Patient numbering .................................................................................35
6.2.2
Treatment assignment, randomization ..................................................35
6.3
Treatment blinding.................................................................................................36
6.4
Dose modification..................................................................................................37


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Amended Protocol Version No. 04 (clean)                                                 Protocol No. CLCZ696DUS01
6.4.1
Dose modifications................................................................................37
6.4.2
Follow-up for angioedema....................................................................39
6.5
Additional treatment guidance...............................................................................39
6.5.1
Treatment compliance...........................................................................39
6.5.2
Emergency breaking of assigned treatment code..................................39
6.6
Preparation and dispensation.................................................................................40
6.6.1
Handling of study treatment and additional treatment..........................40
6.6.2
Instruction for prescribing and taking study treatment .........................41
7
Informed consent procedures ............................................................................................43
8
Visit schedule and assessments .........................................................................................44
8.1
Screening ...............................................................................................................50
8.1.1
Information to be collected on screening failures.................................50
8.2
Patient demographics/other baseline characteristics .............................................50
8.3
Efficacy..................................................................................................................50
8.3.1
Heart failure signs and symptoms.........................................................51
8.3.2
Estimated glomerular filtration rate (eGFR).........................................51
8.3.3
Biomarkers............................................................................................52
8.3.4
Appropriateness of efficacy assessments..............................................52
8.4
Safety.....................................................................................................................52
8.4.1
Laboratory evaluations..........................................................................54
8.4.2
Electrocardiogram (ECG) .....................................................................55
8.4.3
Pregnancy and assessments of fertility .................................................55
8.4.4
Appropriateness of safety measurements..............................................55
8.5
Additional assessments..........................................................................................56
56
56
9
Study discontinuation and completion ..............................................................................56
9.1
Discontinuation......................................................................................................56
9.1.1
Discontinuation of study treatment .......................................................56
9.1.2
Withdrawal of informed consent...........................................................57
9.1.3
Lost to follow-up...................................................................................58
9.1.4
Early study termination by the sponsor.................................................58
9.2
Study completion and post-study treatment ..........................................................59
10 Safety monitoring and reporting........................................................................................59
10.1
Definition of adverse events and reporting requirements......................................59
PP
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10.1.1
Adverse events ......................................................................................59
10.1.2
Serious adverse events ..........................................................................61
10.1.3
SAE reporting........................................................................................62
10.1.4
Pregnancy reporting ..............................................................................62
10.1.5
Reporting of study treatment errors including misuse/abuse................63
10.2
Additional Safety Monitoring................................................................................63
10.2.1
Reporting angioedema-like events........................................................63
10.2.2
Data Monitoring Committee .................................................................64
10.2.3
Steering Committee...............................................................................64
10.2.4
Adjudication committees ......................................................................64
11 Data collection and database management........................................................................65
11.1
Data collection.......................................................................................................65
11.2
Database management and quality control............................................................65
11.3
Site monitoring ......................................................................................................66
12 Data analysis and statistical methods ................................................................................66
12.1
Analysis sets ..........................................................................................................67
12.2
Patient demographics and other baseline characteristics.......................................67
12.3
Treatments .............................................................................................................67
12.4
Analysis of the primary endpoint ..........................................................................68
12.4.1
Analysis of the primary endpoint..........................................................68
12.4.2
Handling of missing values/censoring/discontinuations.......................68
12.4.3
Sensitivity and Supplementary Analyses..............................................68
12.5
Analysis of Secondary Endpoints..........................................................................69
12.5.1
Secondary endpoints .............................................................................69
12.5.2
Safety endpoints....................................................................................72
12.5.3
Biomarkers............................................................................................73
73
73
12.7
Interim analysis......................................................................................................75
12.8
Sample size and Power..........................................................................................75
13 Ethical considerations and administrative procedures ......................................................75
13.1
Regulatory and ethical compliance........................................................................75
13.2
Responsibilities of the investigator and IRB/IEC..................................................76
13.3
Publication of study protocol and results...............................................................76
13.4
Quality Control and Quality Assurance.................................................................76
PPD
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Amended Protocol Version No. 04 (clean)                                                 Protocol No. CLCZ696DUS01
14 Protocol adherence ............................................................................................................76
14.1
Protocol amendments.............................................................................................77
15 References .........................................................................................................................78
16 Appendices ........................................................................................................................80
16.1
Appendix 1: Clinically notable laboratory values and vital signs .........................80
16.2
Appendix 2: Treatment guidelines for hyperkalemia (serum potassium greater 
than or equal to 5.5 mEq/L)...................................................................................81
16.3
Appendix 3: Guidelines for the management of blood pressure ...........................83
16.4
Appendix 4: Guidelines for the management of renal dysfunction.......................83
16.5
Appendix 5: Expanded Assessment Schedule.......................................................85
List of tables
Table 2-1
Objectives and related endpoints ..........................................................22
Table 6-1
Investigational and control drug............................................................31
Table 6-2
Treatment Dose Levels .........................................................................32
Table 6-3
Prohibited medication ...........................................................................34
Table 6-4
Definition of low and high total daily doses for commonly used 
ACEIs and ARBs ..................................................................................42
Table 6-5
Starting dose of study medication.........................................................42
Table 8-1
Assessment Schedule ............................................................................46
Table 8-2
Assessments & Specifications...............................................................53
Table 8-3
Laboratory Assessments........................................................................55
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................63
List of figures
Figure 3-1
Study Design .........................................................................................24


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List of abbreviations
AC
Adjudication committee
ACE
angiotensin converting enzyme
ACEI
angiotensin converting enzyme inhibitor
ADHF
acute decompensated heart failure
AE
adverse event
AF
atrial fibrillation
AHF
acute heart failure
ALT
alanine aminotransferase
ANCOVA
analysis of covariance 
ANP
atrial natriuretic peptide
ARB
angiotensin receptor blocker
ARNI
angiotensin receptor neprilysin inhibitor
AST
aspartate aminotransferase
AT1
angiotensin type 1
ATC
Anatomical Therapeutic Chemical
BID
twice a day
BMI
Body mass index
BNP
B-type natriuretic peptide
BP
blood pressure
bpm
beats per minute
BUN
Blood urea nitrogen
CABG
Coronary artery bypass graft
CCB
Calcium channel blocker
cGMP
Cyclic guanosine monophosphate
CHF
chronic heart failure
CFR
US Code of Federal Regulations 
CMO&PS
Chief Medical Office and Patient Safety
COPD
Chronic obstructive pulmonary disease
COVID-19
COronaVIrus Disease 2019
COX-2
cyclo-oxygenase-2
CPK
creatine phosphokinase
CRA
clinical research associate (site monitor)
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CRT
Cardiac resynchronization therapy 
CTT
Clinical trial team
CV
cardiovascular
DBP
diastolic blood pressure
DM
diabetes mellitus
DMC
Data Monitoring Committee


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EAC
Endpoint Adjudication Committee
ECG
Electrocardiogram
Echo
echocardiogram
eCRF
electronic case report form
ED
Emergency Department
EDC
Electronic Data Capture
eGFR
estimated glomerular filtration rate
ESRD
end-stage renal disease
cGMP
cyclic guanosine monophosphate
EMA
European Medicines Agency
ER
emergency room
EU
European
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GCS
Global Clinical Supply
HF
heart failure
HFrEF
heart failure with reduced ejection fraction
HFpEF
Heart failure with preserved ejection fraction
Hgb
hemoglobin
hs-Troponin
high sensitivity troponin
HTN
hypertension
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use
IEC
Independent Ethics Committee
IN
investigator notification
IV
intravenous
IRB
Institutional Review Board
IRT
Interactive Response Technology
LS
least squared
LVAD
left ventricular assist device
LVEF
left ventricular ejection fraction
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical dictionary for regulatory activities 
MI
myocardial infarction
mm Hg
millimeters of mercury
NEP
neutral endopeptidase
PPD


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NSAID
non-steroidal anti-inflammatory drug
NT-proBNP
N-terminal pro-brain natriuretic peptide
NYHA
New York Heart Association
PCI
percutaneous coronary intervention
QMS
Quality Management System
RAN
Randomized Analysis Set
RAS
renin angiotensin system; randomize analysis set (statistics)
RASi
Renin angiotensin system inhibition
RBC
red blood cell
RR
relative risk
SAE
serious adverse event
SAF
safety set
SAP
Statistical Analysis Plan
SBP
systolic blood pressure
SD
Standard Deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SOP
standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
USPI
United States prescribing information/package insert
WBC
white blood cell(s)
WHF
Worsening heart failure
WHO
World Health Organization 


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Glossary of terms
Additional treatment
Medicinal products that may be used during the clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g. any background 
therapy)
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study patient
Cohort
A specific group of patients fulfilling certain criteria and generally treated at the same 
time
Control drug
A  study drug (active or placebo) used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug
Cycles
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days (e.g., q28 days)
Dosage
Dose of the study treatment given to the patient in a time unit (e.g. 100 mg once a 
day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study data 
using data collection systems, such as Web-based applications, interactive voice 
response systems and clinical laboratory interfaces. EDC includes the use of 
Electronic Case Report Forms (eCRFs) which are used to capture data transcribed 
from paper source forms used at the point of care
End of the clinical trial
The end of the clinical trial is defined as the last visit of the last patient or at a later 
point in time as defined by the protocol 
Enrollment
Point/time of patient entry into the study at which informed consent must be obtained 
Investigational drug/
treatment
The drug whose properties are being tested in the study
Medication number
A unique identifier on the label of medication bottles
Mis-randomized 
patients
Mis-randomized patients are those who were not qualified for randomization and 
who did not take study treatment, but have been inadvertently randomized into the 
study
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy)
Part 
A sub-division of a study used to evaluate specific objectives or contain different 
populations. For example, one study could contain a single dose part and a multiple 
dose part, or a part in patients with established disease and in those with newly-
diagnosed disease
Patient
An individual with the condition of interest for the study
Patient number
A unique number assigned to each patient upon signing the informed consent. This 
number is the definitive, unique identifier for the patient and should be used to 
identify the patient throughout the study for all data collected, sample labels, etc.
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) which are 
described in the Protocol. Periods define the study phases and will be used in 
clinical trial database setup and eventually in analysis
Perpetrator drug
A drug which affects the pharmacokinetics of the other drug
Personal data
Patient information collected by the Investigator that is transferred to Novartis for the 
purpose of the clinical trial. This data includes patient identifier information, study 
information and biological samples. 
Premature patient
withdrawal
Point/time when the patient exits from the study prior to the planned completion of all 
study drug administration and/or assessments; at this time all study drug 
administration is discontinued and no further assessments are planned
Randomization number
A unique identifier assigned to each randomized patient


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Screen Failure
A patient who did not meet one or more criteria that were required for participation in 
the study
Source Data/Document
Source data refers to the initial record, document, or primary location from where 
data comes. The data source can be a database, a dataset, a spreadsheet or even 
hard-coded data, such as paper or eSource
Start of the clinical trial
The start of the clinical trial is defined as the signature of the informed consent by 
the first patient
Study treatment
Any single drug or combination of drugs or intervention administered to the patient
as part of the required study procedures
Study treatment 
discontinuation
When the patient permanently stops taking any of the study drug(s) prior to the 
defined study treatment completion date (if any) for any reason; may or may not also 
be the point/time of study discontinuation 
Subject
A trial participant (can be a healthy volunteer or a patient)
Treatment arm/group
A treatment arm/group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts.
Variable
A measured value or assessed response that is determined from specific 
assessments and used in data analysis to evaluate the drug being tested in the 
study
Withdrawal of study 
consent (WoC)
Withdrawal of consent from the study occurs only when a patient does not want to 
participate in the study any longer and does not allow any further collection of 
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Amended Protocol Version No. 04 (clean)                                                 Protocol No. CLCZ696DUS01
Protocol summary
Protocol number
CLCZ696DUS01
Full Title
A multicenter, randomized, double-blind, double-dummy, parallel group, 
active controlled study to evaluate the effect of sacubitril/valsartan 
(LCZ696) versus valsartan on changes in NT-proBNP, safety, and 
tolerability in HFpEF patients with a WHF event (HFpEF 
decompensation) who have been stabilized and initiated at the time of
or within 30 days post-decompensation (PARAGLIDE-HF)
Brief title
Prospective comparison of ARNI with ARB Given following 
stabiLization In DEcompensated HFpEF (PARAGLIDE-HF)
Sponsor and Clinical 
Phase
Novartis, Phase IIIB
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this study is to assess the effect of sacubitril/valsartan 
vs. valsartan on changes in NT-proBNP, safety, and tolerability in 
HFpEF patients with a WHF event (HFpEF decompensation) who have 
been stabilized and initiated at the time of or within 30 days post-
decompensation
Primary Objective(s) 
To demonstrate the effect of sacubitril/valsartan vs. valsartan on time-
averaged proportional change in NT-proBNP from baseline to Weeks 4 
and 8 in HFpEF patients with a WHF event (HFpEF decompensation)
who have been stabilized for and initiated at the time of or within 30 
days post-decompensation
Secondary Objectives

To determine the effect of sacubitril/valsartan vs. valsartan on the 
composite hierarchical outcome consisting of: a) time to CV death, 
b) total HF hospitalizations, c) total urgent HF visits, and d) time-
averaged proportional change in NT-proBNP (from baseline to 
Weeks 4 and 8) using win ratio methodology

To assess the effect of sacubitril/valsartan vs. valsartan on total 
composite events based on CV death, HF hospitalizations, and 
urgent HF visits

To assess the effect of sacubitril/valsartan vs. valsartan on the 
incidences of a composite endpoint of worsening renal function 
(renal death, reaching ESRD, or > 50% decline in eGFR relative to 
baseline

To assess the effect of sacubitril/valsartan vs. valsartan on change 
in NT-proBNP from baseline to Week 8 

To assess the effect of sacubitril/valsartan vs. valsartan on change 
from baseline in hs-Troponin (high sensitivity) at Weeks 4 and 8

To assess  the effect of sacubitril/valsartan vs. valsartan on 
tolerability and the incidence of adverse events of special interest 
during treatment
Study design
This study will use a randomized, double-blind, double-dummy, active-
controlled, parallel group design. Eligible patients will be randomized 
either during hospitalization for, or within 30 days of, a WHF event


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(HFpEF decompensation). A WHF event (HFpEF decompensation) is 
defined as a hospitalization, emergency department (ED) visit or out-of-
hospital urgent HF visit, all requiring IV diuretics.
Randomized patients will have been hemodynamically stabilized,
defined in this study as: 

SBP ≥100mmHg for the preceding 6 hours prior to 
randomization; no symptomatic hypotension 

No increase (intensification) in IV diuretic dose within last 6 
hours prior to randomization

No IV inotropic drugs for 24 hours prior to randomization

No IV vasodilators including nitrates within last 6 hours prior to 
randomization
All patients will need to meet all inclusion and none of the exclusion 
criteria.  
Patients will be randomized 1:1 to sacubitril/valsartan or valsartan. Initial 
dose at randomization will be determined based on the patient’s previous 
dose of or lack of ACEi/ARB immediately prior to current WHF event 
(HFpEF decompensation), or at the time of post-decompensation
randomization.
Patients currently or recently taking ACEi: In order to provide for a 
necessary 36-hour washout of prior ACEi treatment before receiving 
sacubitril/valsartan, eligible patients will be randomized no earlier than 
36 hours from their last ACEi dose).  Hospital medication administration 
and medication reconciliation records should be reviewed to confirm that 
eligible patients have not received ACEi for at least 36 hours prior to 
randomization and the first dose of study medication.  
The maximum duration of study for the first patient randomized after 
amendment 1 is approximately 20 months; the anticipated minimum 
follow-up would be for 8 weeks. 
Population
The study population will consist of male and female patients, ≥ 18 years 
of age, currently hospitalized for or within 30 days of a WHF event 
(HFpEF decompensation). A WHF event (HFpEF decompensation) is 
defined as a hospitalization, emergency department (ED) visit or out-of-
hospital urgent HF visit, all requiring IV diuretics. A total of approximately 
450 patients will be randomized to sacubitril/valsartan or valsartan in a 
1:1 ratio at approximately 130 centers in the United States and Canada. 
Randomized patients will have been hemodynamically stabilized defined 
in this study as: 

SBP ≥100mmHg for the preceding 6 hours prior to 
randomization; no symptomatic hypotension 

No increase (intensification) in IV diuretic dose within last 6 
hours prior to randomization

No IV inotropic drugs for 24 hours prior to randomization

No IV vasodilators including nitrates within last 6 hours prior to 
randomization


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All patients will need to meet all other inclusion and none of the exclusion 
criteria.
Key Inclusion criteria
1.
Signed informed consent must be obtained prior to participation in 
the study
2.
Patients ≥18 years of age, male or female
3.
Current hospitalization for WHF (HFpEF decompensation), or within 
30 days of discharge following a WHF event (defined as 
hospitalization, emergency department (ED) visit or out-of-hospital 
urgent HF visit, all requiring IV diuretics). Patients with a diagnosis 
of acute heart failure had to have symptoms and signs of fluid 
overload (i.e. jugular venous distention, edema or rales on 
auscultation or pulmonary congestion on chest x-ray). Eligible 
patients will be randomized after IV diuresis for HFpEF is given (and 
no earlier than 36 hours from their last ACEi dose if applicable) and 
within 30 days post-decompensation after presentation with acute 
HFpEF decompensation and meeting the following definitions of 
hemodynamic stability:
Randomized patients will have been hemodynamically stable defined in 
this study as: 
a.
SBP ≥100mmHg for the preceding 6 hours prior to 
randomization; no symptomatic hypotension 
b.
No increase (intensification) in IV diuretic dose within 
last 6 hours prior to randomization
c.
No IV inotropic drugs for 24 hours prior to randomization
d.
No IV vasodilators including nitrates within last 6 hours 
prior to randomization
4.
HFpEF with most recent LVEF >40% (within past 3 months)
5.
Elevated NT-proBNP or BNP at the time of acute HFpEF 
decompensation or post-decompensation screening (and within 72 
hours for out-of-hospital randomization, if applicable): 
a.
Patients not in AF at the time of biomarker 
assessment: NT-proBNP ≥ 500pg/mL or BNP ≥ 150 
pg/mL; patients in AF at the time of biomarker 
assessment: NT-proBNP ≥ 1000pg/mL or BNP ≥ 300 
pg/mL
b.
Patients recruited in-hospital will be randomized based 
on the qualifying local lab value in-hospital NT-proBNP 
or BNP value.
c.
Patients enrolled post-decompensation can be 
randomized based on their NT-proBNP or BNP value 
in the following way:
i.
if enrolling in post-decompensation setting 
then need eligible screening/local NT-
proBNP/BNP within 72 hours of randomization. 
The test value could be from recent 
hospitalization if within 72 hours or 
ii.
would require (re)drawing NT-proBNP or BNP 
labs in post-decompensation setting if the lab
value is not already available within the last 72 
hours).


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6.
Has not taken an ACEi for 36 hours prior to randomization
Key Exclusion criteria
1)
Any clinical event within the 90 days prior to randomization that could 
have reduced the LVEF (i.e., MI, CABG), unless an echo 
measurement was performed after the event confirming the LVEF to 
be >40%
2)
Entresto™ (sacubitril/valsartan) usage within the past 60 days
3)
eGFR < 20ml/min/1.73 m2 as measured by the simplified 
Modification of Diet in Renal Disease (MDRD) formula at most recent 
assessment prior to randomization and within 24 hours prior to
inpatient randomization or 72 hours prior to outpatient randomization
4)
Serum potassium > 5.2 mEq/L at most recent assessment prior to 
randomization and within 24 hours prior to inpatient randomization
or 72 hours prior to outpatient randomization
5)
Acute coronary syndrome, stroke, transient ischemic attack; cardiac, 
carotid or other major CV surgery; percutaneous coronary 
intervention (PCI) or carotid angioplasty, within 30 days prior to
randomization
6)
Probable alternative diagnoses that in the opinion of the investigator 
could account for the patient’s HF symptoms (i.e. dyspnea, fatigue) 
such as significant pulmonary disease (including primary pulmonary 
HTN), anemia or obesity. 
7)
Isolated right HF in the absence of left-sided structural heart disease
8)
History of hypersensitivity (i.e. including angioedema), known or 
suspected contraindications, or intolerance to any of the study drugs 
including ARNIs (i.e. sacubitril/valsartan), and/or ARBs
9)
Patients with a known history of angioedema due to any etiology
10) Patients with a history of heart transplant or LVAD, currently on the 
transplant list, or with planned intent to implant LVAD or CRT device 
within the initial three months of enrollment during the trial 
11) A cardiac or non-cardiac medical condition other than HF with an 
estimated life expectancy of < 6 months
12) Known pericardial constriction, genetic hypertrophic 
cardiomyopathy, or infiltrative cardiomyopathy including suspected 
or confirmed amyloid heart disease (amyloidosis)
13) Life-threatening or uncontrolled dysrhythmia, including 
symptomatic or sustained ventricular tachycardia and atrial 
fibrillation or flutter with a resting ventricular rate >110 bpm
14) Clinically significant congenital heart disease felt to be the cause of 
the patient’s symptoms and signs of HF
15) Coronary or carotid artery disease or valvular heart disease likely 
to require surgical or percutaneous intervention within the duration 
of the trial 
16) Any surgical or medical condition, which in the opinion of the 
investigator, may place the patient at higher risk from his/her 
participation in the study, or is likely to prevent the patient from 
complying with the requirements of the study or completing the 
study
17) Known hepatic impairment (as evidenced by total bilirubin > 3 
mg/dL, or increased ammonia levels, if performed), or history of 
cirrhosis with evidence of portal hypertension such as varices


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18) Participation in any other clinical trial involving investigational 
agents or devices within the past 30 days
19) Current confirmed COVID19 infection
20) Past COVID19 infection with persistent symptom burden suspected 
due to COVID19 (further defined in Section 5.2).
21) Pregnant or nursing (lactating) women, where pregnancy is defined 
as the state of a female after conception and until the termination of 
gestation, confirmed by a positive hCG laboratory test.
22) Women of child-bearing potential, defined as all women 
physiologically capable of becoming pregnant, unless they are 
using highly effective methods of contraception during dosing of 
investigational drug and for 7 days off of study drug. Highly 
effective contraception methods are defined in Section 5.2.
Study treatment
All 
eligible 
patients 
will 
be 
randomized 
to 
receive 
either 
sacubitril/valsartan or valsartan.  The following treatment will be provided 
(double-blind, double dummy) until the last patient randomized is 
followed for 8 weeks: 
Dose 
Level
Sacubitril/valsartan
Valsartan
1
24/26 mg [50mg] BID
40 mg BID
2
49/51 mg [100mg] BID
80 mg BID
3
97/103 mg [200 mg] BID
160 mg BID
Sacubitril/valsartan with matching placebo and valsartan with matching 
placebo will be provided for the double-blind treatment period.
Initial dose at randomization will be determined based on the patient’s 
previous dose of or lack of ACEi/ARB immediately prior to current WHF 
event (HFpEF decompensation), or at the time of post-decompensation
randomization..  Every attempt should be made to titrate to and maintain 
patients on target study drug Dose Level 3 for as long as possible 
throughout the study.
Key safety 
assessments

Incidence of worsening renal function, defined as an increase in 
serum creatinine of ≥0.5mg/dl and worsening of the eGFR by at 
least 25% 

Incidence of symptomatic hypotension 

Incidence of hyperkalemia (potassium >5.5 mEq/l)

Incidence of angioedema 
Safety assessments will consist of monitoring and recording of all 
adverse events and serious adverse events, evaluation of hematology, 
blood chemistry and urine values, regular measurement of vital signs 
and the performance of physical examinations.
Sample Size and power 
The target sample size for this study is approximately 450 total 
patients, randomized in the two treatment groups in 1:1 ratio. The 
maximum planned duration of follow-up after randomization (for 
patients enrolled under Amendment 1 or later) is approximately 20 
months; the anticipated minimum follow-up would be for 8 weeks.  The 


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power of the study is determined based on these 450 patients for the 
primary endpoint. 
Power for the primary endpoint
This sample size of 450 patients would have 85% power to detect a 
23% reduction in the geometric mean of the proportional change from 
baseline to an average of Weeks 4 and 8 in NT-proBNP for the 
sacubitril/valsartan treatment group. The power is estimated assuming 
a two-sided significance level of 0.05,  a common standard deviation of 
0.85 for change in log transformed NT-proBNP and a 15% rate of 
missingness of NT-proBNP at baseline or both Week 4 and Week 8.
nQuery Version 8.4.1.0 (2019) software package is used in calculating 
the power of the test.
Data analysis
The Full Analysis Set (FAS) comprises all participants to whom study 
treatment has been assigned by randomization. According to the intent-
to-treat principle, participants will be included for analysis according to 
the treatment they have been assigned to during the randomization 
procedure.
The patients in this trial are divided in two groups, (1) Those who are 
randomized under Protocol Version 00 (Original Protocol patients) and 
(2) Those who are randomized under Protocol Version 01 or later.  FAS 
includes patients from both groups. See Section 3 for details.
Analysis of the primary endpoint
The primary null hypothesis (H10) to be tested is that the ratio of the 
geometric means of NT-proBNP (average of Weeks 4 and 8) divided 
by baseline for the sacubitril/valsartan and valsartan groups are equal 
versus the alternative hypothesis (H1a) that the ratio of the geometric 
means of NT-proBNP are not equal.
First, the arithmetic mean of NT-proBNP at Weeks 4 and 8 will be 
calculated, then the change from baseline in natural log-transformed 
NT-proBNP will be calculated as follows: ln(mean post dose value) –
ln(baseline value). The natural logarithm will be used in all these 
calculations. This log-transformed value will be used as the dependent 
variable in the analysis of covariance (ANCOVA) model described 
below. This dependent variable is called, the time-averaged 
proportional change from baseline in logarithmic scale. The dependent 
variable will be analyzed using an ANCOVA model with treatment in-
/out-of-hospital randomization, gender, race, baseline LVEF (<=57%, 
>57%) as fixed effect factors, age and the logarithmic baseline NT-
proBNP as covariates.
The treatment effect in terms of ratios of geometric means is 
estimated based on the least-squared means (LS-means) from the 
ANCOVA model and the corresponding two-sided 95% confidence 
interval will be provided. Geometric means will be calculated by 
exponentially back transforming the LS-means based on the fitted 
ANCOVA model.


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Interim analysis:
There is no planned interim analysis for efficacy in the study. 
An independent Data Monitoring Committee (DMC) will be responsible 
for performing interim safety assessment using independent statistician 
and programmer who will not be involved in the trial conduct. The DMC 
charter will contain the committee’s responsibilities regarding the interim 
safety assessment. Details of this safety assessment will be included in 
the Statistical Analysis Plan.
Interim safety assessments are planned to be performed during the 
study and results will be provided to DMC for their review and 
recommendation.  The number and/or
timing of these safety 
assessments will be mentioned in the Data Monitoring Committee 
Charter. No adjustment of the level of significance will be made for these 
interim safety assessments.
See Section 12 for additional information on planned data analyses.
Key words
Heart failure with preserved ejection fraction, HFpEF, heart failure 
hospitalization, NYHA, NT-proBNP, win ratio, acute decompensated 
heart failure, sacubitril/valsartan, 
 
 Worsening heart failure (WHF), heart failure 
decompensation
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1
Introduction
1.1
Background
Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI). The 
PARAMOUNT and PARAGON-HF trials provided information regarding the effect of
sacubitril/valsartan compared with valsartan on clinical outcomes in patients with chronic heart 
failure with preserved ejection fraction (HFpEF), initiating treatment in the outpatient setting 
(Solomon et al 2012; Solomon et al 2019). Further data are needed regarding the use of 
sacubitril/valsartan in patients hospitalized due to acute decompensated HFpEF and in key 
populations not broadly represented in PARAGON-HF, including newly diagnosed, morbidly 
obese, recently hospitalized, and Black patients. PARAGLIDE-HF will provide important 
information regarding the efficacy, safety, and tolerability of initiating sacubitril/valsartan 
therapy in patients with a WHF event (HFpEF decompensation) who have been 
hemodynamically stabilized during a hospitalization or WHF event requiring IV diuretics.
Sacubitril/valsartan has been evaluated for efficacy and safety in ambulatory patients with 
chronic HFpEF. The PARAMOUNT study was a randomized, double-blind, active-controlled 
phase 2 trial of 308 patients with HFpEF (Left ventricular ejection fraction (LVEF) ≥45%) 
(Solomon et al 2012). Patients enrolled in the study received sacubitril/valsartan titrated to 
97/103 mg twice daily or valsartan titrated to 160 mg twice daily. The primary end point, change 
in NT-proBNP levels from baseline to 12 weeks, was significantly reduced in the
sacubitril/valsartan group compared with the valsartan group (sacubitril/valsartan: baseline, 783
pg/mL [95% CI 670-914], 12 weeks 605 pg/mL [95% CI512-714]; valsartan: baseline, 862 
pg/mL [95% CI 733-1012], 12 weeks 835 pg/mL [95% CI 710-981]; ratio of change from 
baseline: sacubitril/valsartan / valsartan, 0.77, 95% CI 0.64-0.92, p=0.005. Sacubitril/valsartan 
was well tolerated and had a similar adverse effect profile compared to valsartan.  
In PARAGON-HF, a randomized, double-blind, active-controlled phase 3 trial with 4822 
ambulatory chronic HFpEF patients, the primary endpoint was a composite of total 
hospitalizations for heart failure and death from cardiovascular causes.  After a single blind run-
in period, patients were randomized to either sacubitril/valsartan or valsartan at target doses of 
97/103mg or 160mg twice daily, respectively, and were followed for a median duration of 35 
months.  There were 894 (12.8 per 100 patient-years) primary composite events (CEC-
confirmed total heart failure hospitalizations and CV deaths) in the sacubitril/valsartan group 
compared to 1009 (14.6 per 100 patient-years) in the valsartan group, indicating a 13% relative 
rate reduction in the primary composite endpoint, a treatment effect that narrowly missed 
statistical significance (RR=0.87; 95% CI: 0.75-1.01; p=0.0587) (Solomon et al 2019).  No new 
safety signals were seen in PARAGON-HF, and safety assessments were consistent with 
PARADIGM-HF, a HF with reduced ejection fraction study comparing sacubitril/valsartan to 
enalapril (McMurray et al 2014).  
It has been reported that the period subsequent to a worsening heart failure event is when the 
patients are most vulnerable for hospitalization, re-hospitalizations, and increased mortality. In 
a post-hoc analysis of PARAGON-HF, those HFpEF patients who were recently hospitalized 
had a 2-3 fold higher risk of rehospitalization and cardiovascular death. Of the 4796 patients


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randomized and included in the full analysis set (FAS), 48% had a hospitalization prior to the 
index hospitalization in PARAGON-HF.   Moreover, 622 (13% of the total randomized) 
patients had had at least one hospitalization within 30 days of trial screening. The event rate 
was 26.7 (≤30 days) vs. 7.9 (not previously hospitalized) per 100 patient-years in the valsartan 
group.  In comparison, the absolute risk reduction for patients enrolled at ≤ 30 days after 
hospitalization was 6.4% in the group receiving sacubitril/valsartan compared to valsartan and 
this effect decreased as time from hospitalization increased (Vaduganathan et al 2019).  
HFpEF patients with ADHF are known to have markedly elevated levels of BNP and NT-
proBNP, which are reduced following adequate treatment and normalization of their cardiac 
decompensation. In the I-PRESERVE trial, patients with both a recent hospitalization and 
elevated NT-ProBNP (> 360 pg/mL) had a greater risk of cardiovascular death and subsequent 
heart failure hospitalization (Kristensen et al 2015). Therefore, it is important to evaluate 
therapeutic strategies that can lead to superior reductions in NT-proBNP in patients hospitalized 
due to acute decompensation.
The PIONEER-HF trial evaluated the effect of in-hospital initiation of sacubitril/valsartan vs. 
enalapril in patients with heart failure with reduced ejection fraction (HFrEF) who had been 
stabilized during hospitalization for acute decompensated heart failure. PIONEER-HF 
demonstrated greater reduction with sacubitril/valsartan vs. enalapril in time-averaged 
proportional change in NT-ProBNP from baseline to weeks 4 and 8 (percent change, -46.7% vs.
-25.3%; ratio of change with sacubitril/valsartan vs. enalapril 0.71 [0.63 – 0.81], p<0.001) and 
a decrease in the exploratory clinical composite outcome of death, re-hospitalization for heart 
failure, LVAD implantation, or listing for cardiac transplant (Velazquez et al 2018).
Based on the above, PARAGLIDE-HF is designed to assess the efficacy, safety and tolerability 
of sacubitril/valsartan in HFpEF patients with a WHF event (HFpEF decompensation) who 
have been stabilized and initiated at the time of or within 30 days post-decompensation.
These data from PARAGLIDE-HF will complement TRANSITION and PIONEER-HF, where 
both examined the safety and efficacy of sacubitril/valsartan in hospitalized patients 
hemodynamically stabilized after an acute decompensated HFrEF event (Wachter R et al 2018, 
Velazquez et al 2018).
1.2
Rationale for Protocol Amendments
Amendment 1 (January 2020)
PARAGLIDE-HF amendment 1 reflects learnings from the PARAGON-HF trial, which was 
completed 3 months into PARAGLIDE-HF trial enrollment. From PARAGON-HF, learnings 
about hospitalized HF with preserved ejection fraction (HFpEF) patients helped guide 
additional key endpoints as well as sample size, timeline, and duration of treatment changes.
Amendment 2 (September 2020)
Based on technology advancements, site-level changes, and regulatory adjustments during the 
COVID-19 pandemic, Amendment 2 reflects allowances for virtual visits, per patient stability 
and Investigator discretion, at time points defined in Section 8.


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Amendment 3 (October 2020)
Amendment 3 corrects an administrative error identified within Amendment 2.  As described
in Amendment 2, Visit 14, based on patient stability and Investigator discretion, can be 
conducted virtually.  
 
 
Amendment 4 (December 2021)
Amendment 4 adjusts the protocol to adapt to recruitment challenges experienced during the 
COVID19 pandemic which have affected patients and research sites and negatively impacted 
study timelines. This amendment decreases the sample size (from 800 to 450 patients) to focus 
on the primary endpoint of changes from baseline in NT-proBNP and moves the key (clinical) 
secondary endpoints to traditional secondary endpoints due to the key secondary endpoints 
having reduced statistical power. Inclusion and exclusion criteria were adjusted based on a 
thorough examination of screening logs and discussions with investigators who noted that many 
patients with bona fide HFpEF were being excluded due to the stringent exclusion language 
(example, prior exclusion #6a, b, and c). These changes aim to increase the generalizability of 
the trial population to real world patients. In addition, a HFpEF patient with a WHF event 
(including a HF hospitalization, ED visit, or urgent HF visit, all requiring IV diuretics) within 
30 days would now qualify for enrollment, versus the prior criteria requiring hospitalization 
within 30 days. Patients with WHF events have a similar risk of future cardiovascular events to 
those hospitalized for HF and remain understudied.
1.3
Changes to Protocol
Changes to specific sections in the protocol are shown in the track changes version of the 
protocol using the strike through font for deletions and red underlined for insertions.
Amendment 1: Significant changes from Protocol Version 00 include:
!
Addition of two key secondary endpoints that will assess clinical outcomes
!
Increased sample size from 616 to approximately 800 patients (with increased study sites 
from 100 to approximately 130)
!
Extended duration of treatment from 12 weeks (Original Protocol) to maximum of 
approximately 20 months and an average duration of study for all patients is anticipated to 
be approximately 11 months.
!
Extended trial recruitment period extending to within 30 days post-discharge
!
Some of the inclusion and exclusion criteria were changed/modified based on additional 
data from other analyses/publications or input from the Steering Committee/external 
experts.
!
Based on safety data from a randomized trial including 414 subjects with estimated GFR 
of 20-60 mL/min/1.73 m2 comparing sacubitril/valsartan to irbesartan, the exclusion 
criteria was lowered to allow subjects with an estimated GFR of 20 mL/min/1.73 m2 and 
higher (Haynes R et al 2018)
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Amendment 2: Significant changes from Protocol Version 01 include:
!
Covid-19 exclusion criteria language was added
!
Allowance for virtual visits at visits 10, 12, 14, and 16, based on patient stability and 
Investigator discretion
!
Updated dosing table 6-5 and Section 6.6.2 to initiate study drug at Dose Level 1 if the 
patient’s estimated GFR is <30mL/min/1.73 m2
A copy of this amended protocol will be sent to the Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs) and Health Authorities.
The changes described in this amendment require IRB/IEC approval prior to implementation. 
In addition, since the changes herein do affect the informed consent, sites will be required to 
update and submit for approval a revised informed consent that takes into account the changes.
Amendment 3: Significant changes from Protocol Version 02 include:
 
 
Amendment 4: Significant changes from Protocol Version 03 include: 
!
Inclusion of patients with a WHF event (HFpEF decompensation), defined as a 
hospitalization, emergency department (ED) visit or out-of-hospital urgent HF visit, all 
requiring IV diuretics
!
Qualifying age changed from >=40 to >=18 years old
!
Sample size reduced to 450 patients (from 800 patients)
!
Key secondary endpoints (the win ratio endpoint and the triple composite endpoint) were 
moved to a secondary position, with the trial power shifting to the NTproBNP primary 
endpoint
!
Exclusion 2 modified to allow prior Entresto usage if >60 days
!
Exclusion 6 modified to allow PI discretion on other reasons for HF-like symptoms 
(COPD, Hgb, Obesity) 
!
Altered the visit schedule (see Section 8) reducing total visits from 15 to 10 visits
!
Updated language for contraception (exclusion 22) 
1.4
Purpose
The purpose of this study is to assess the effect of sacubitril/valsartan vs. valsartan on changes 
in NT-proBNP, safety, and tolerability in HFpEF patients with a WHF event (HFpEF 
decompensation) who have been stabilized and initiated at the time of or within 30 days post 
decompensation.
P
P
D


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2
Objectives and endpoints
Table 2-1
Objectives and related endpoints 
Objective(s)
Endpoint(s)
Primary Objective(s)
Endpoint(s) for primary objective(s) 

To demonstrate the effect of 
sacubitril/valsartan vs. valsartan on 
time-averaged proportional change 
in NT-proBNP from baseline to 
weeks 4 and 8  in HFpEF patients 
with a WHF event (HFpEF 
decompensation) who have been 
stabilized for and initiated at the 
time of or within 30 days post-
decompensation

The time averaged proportional change in NT-
proBNP from Baseline to Weeks 4 and 8.
Secondary Objective(s)
Endpoint(s) for secondary objective(s)

To determine the effect of 
sacubitril/valsartan vs. valsartan on 
the composite hierarchical 
outcome consisting of: a) time to 
CV death, b) total HF 
hospitalizations, c) total urgent HF 
visits, and d) time-averaged 
proportional change in NT-
proBNP (from baseline to weeks 4 
and 8) using win ratio 
methodology

The composite hierarchical outcome consisting 
of: a) time to CV death, b) number and times 
of HF hospitalizations during follow-up, c) 
number and times of urgent HF visits during 
follow-up, and d) time averaged proportional 
change in NT-proBNP (from baseline to 
Weeks 4 and 8)

To assess the effect of 
sacubitril/valsartan vs. valsartan on 
total composite events based on 
CV death, HF hospitalizations, and 
urgent HF visits

The cumulative number of recurrent composite 
events overtime, i.e., the total number of 
composite events of HF hospitalizations, 
urgent HF visits, and CV death. 

To assess the effect of 
sacubitril/valsartan vs. valsartan on 
the incidences of a composite 
endpoint of worsening renal 
function (renal death, reaching 
ESRD, or decline in eGFR >/= 
50%)

The incidences of a composite endpoint of 
worsening renal function, defined as:
o
renal death
o
reaching 
end-stage 
renal 
disease 
(ESRD)
o
≥ 50% decline in estimated glomerular 
filtration rate (eGFR) relative to 
baseline

To assess the effect of 
sacubitril/valsartan vs. valsartan on 

Proportional change in NT-proBNP from 
baseline to Week 8


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Objective(s)
Endpoint(s)
change in NT-proBNP from 
baseline to Week 8 
!
To assess the effect of 
sacubitril/valsartan vs. valsartan on 
change from baseline in hs-
Troponin (high sensitivity) at 
Weeks 4 and 8
!
Proportional change from baseline in hs-
Troponin (high sensitivity) at Weeks 4 and 8
!
To assess the effect of 
sacubitril/valsartan vs. valsartan on 
tolerability and the incidence of 
adverse events of special interest 
during treatment
!
Dosing levels and discontinuations
!
Incidence of symptomatic hypotension during
treatment 
!
!
Incidence of hyperkalemia (potassium >5.5 
mEq/L)  
!
Incidence of angioedema 
!
Incidence of worsening renal function, defined 
as an increase in serum creatinine of 
≥0.5mg/dl and worsening of the eGFR by at 
least 25% 
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3
Study design
Figure 3-1
Study Design
This study will use a randomized, double-blind, double-dummy, active-controlled, 
parallelgroup design. Eligible patients will be randomized either during hospitalization for, or
within 30 days of, a WHF event (HFpEF decompensation). A WHF event (HFpEF 
decompensation) is defined as a hospitalization, emergency department (ED) visit or out-of-
hospital urgent HF visit, all requiring IV diuretics.
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Randomized patients will have been hemodynamically stabilized defined in this study as: 

SBP ≥100mmHg for the preceding 6 hours prior to randomization; no symptomatic 
hypotension 

No increase (intensification) in IV diuretic dose within last 6 hours prior to randomization

No IV inotropic drugs for 24 hours prior to randomization

No IV vasodilators including nitrates within last 6 hours prior to randomization
All patients will need to meet all other inclusion and none of the exclusion criteria.  
Patients will be randomized 1:1 to sacubitril/valsartan or valsartan. Initial dose at randomization 
will be determined based on the patient’s previous dose of or lack of ACEi/ARB immediately 
prior to current WHF event (HFpEF decompensation), or at the time of post-decompensation
randomization.
Patients currently or recently taking ACEi: In order to provide for a necessary 36-hour washout 
of prior ACEi treatment before receiving sacubitril/valsartan, eligible patients will be 
randomized no earlier than 36 hours from their last  ACEi dose.  Hospital medication 
administration and medication reconciliation records should be reviewed to confirm that 
eligible patients have not received ACEi for at least 36 hours prior to randomization and the 
first dose of study medication.  
The maximum duration of study for the first patient randomized after the amendment is 
approximately 20 months; the anticipated minimum follow-up would be for 8 weeks.  
4
Rationale
4.1
Rationale for study design
Hospitalization for ADHF identifies patients at increased risk of death and re-hospitalization 
following discharge. This increased risk justifies intervention with novel treatment strategies 
initiated prior to hospital discharge to improve patient outcomes.
The PARADIGM-HF and PARAMOUNT trials demonstrated reductions in NT-proBNP 
compared to the comparator enalapril and valsartan, respectively, in patients with chronic 
reduced ejection fraction and preserved ejection fraction heart failure (McMurray et al 2014; 
Packer et al 2015; Solomon et al 2012).
PARAGON-HF demonstrated increased risk of events in HFpEF patients who were recently 
hospitalized and the benefit from sacubitril/valsartan appeared greater in those patients 
hospitalized within 30 days of screening, compared to those hospitalized greater than 30 days 
or never previously hospitalized (Vaduganathan et al 2019). 
The PIONEER-HF trial evaluated the effect of in-hospital initiation of sacubitril/valsartan vs. 
enalapril in patients with HFrEF who had been stabilized during hospitalization for ADHF. 
PIONEER-HF demonstrated greater reduction in NT-proBNP with sacubitril/valsartan vs. 
enalapril in time-averaged proportional change in NT-proBNP from baseline to weeks 4 and 8 


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(percent change, -46.7% vs. -25.3%; ratio of change with sacubitril/valsartan vs. enalapril 0.71 
[0.63 – 0.81], p<0.001) and a decrease in the pre-specified, exploratory, serious clinical 
composite outcome of death, re-hospitalization for heart failure, LVAD implantation, or listing 
for cardiac transplant (Velazquez et al 2018).  This current trial (PARAGLIDE-HF) will build
upon the data generated through the PIONEER-HF trial by specifically studying patients with 
HFpEF and ADHF.  PARAGLIDE-HF will have a similar primary end-point of NT-proBNP to 
PIONEER-HF, but will also include patients randomization during a WHF event (requiring IV 
diuretics) and within thirty days post-decompensation.  The duration of PARAGLIDE-HF will 
be up to 20 months to account for accrual of the secondary outcome events.
The need for a 36-hour wash-out period is required per the FDA approved USPI label because 
there is a potential for increased risk for angioedema in patients who receive both an ACE 
inhibitor and the combination of sacubitril/valsartan. The requirement to stop the ARB is 
because there is an ARB contained within sacubitril/valsartan combination.
4.2
Rationale for dose/regimen and duration of treatment
Sacubitril/valsartan 97/103 mg BID was selected as the target dose. This is the USPI approved 
target dose of sacubitril/valsartan in patients with HFrEF and is the target dose studied in the 
phase III PARAGON-HF trial in patients with HFpEF (Solomon et al 2019). This dose of 
sacubitril/valsartan delivers similar exposures of valsartan as Diovan 160 mg BID, the maximal 
approved Diovan dose for heart failure and the dose recommended in international guidelines 
for the treatment of heart failure. In addition, biomarker analysis (increase in ANP and cGMP) 
indicates  that  this  sacubitril  dose  delivers   approximately  90%  of  its  maximal neutral 
endopeptidase (NEP) inhibition Dosing with 97/103 mg twice daily is to ensure sustained NEP 
inhibition over 24 hours, which is thought to be critical for patients with heart failure. Boththe 
PIONEER-HF and TRANSITION studies demonstrated that patients with heart failure with 
reduced ejection fraction could be safely initiated on sacubitril/valsartan in the hospital after 
stabilization of an ADHF episode (Velazquez et al 2018, Wachter et al 2018). 
In PARAGON-HF, HFpEF patients were followed for a median time of 35 months 
(interquartile range, 30 to 41) with no new safety signal seen, and consistent safety to 
PARADIGM-HF.  In this study, the duration of treatment will be from 8 weeks (minimum) to 
approximately 20 months (maximum). The longer duration of follow-up allows for more events 
to occur, facilitating more accurate assessment of the clinical outcome secondary endpoints..
4.3
Rationale for choice of comparator
To date, there is no evidence-based, guideline-recommended, pharmacologic therapy for 
HFpEF patients that has been proven to reduce morbidity and mortality (Yancy et al 2013). 
Valsartan is being given to treat the comorbidities that are prevalent in HFpEF, such as HTN, 
DM, and coronary artery disease where there is an indication for RAS blocking therapy 
(McMurray et al 2012). For the same reason, background ACEIs or ARBs were permitted in 
other outcomes studies in HFpEF for treating comorbidities, including TOPCAT, where a RAS 
blocker was used in 85% of patients at baseline (Desai et al 2011).


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Valsartan was chosen as the RAS blocker comparator because it is a commonly prescribed ARB 
and the target dose of sacubitril/valsartan (LCZ696) delivers systemic exposure similar to the 
target dose of valsartan for heart failure. It was also the comparator used in both the 
PARAMOUNT study as well as in the PARAGON-HF study in patients with HFpEF.
A placebo comparator is not considered appropriate in this trial, as the comorbidities commonly 
present in HFpEF patients require RAS inhibition (i.e., ACEI or ARB). RAS inhibition should 
not be used concomitantly with LCZ696 due to the potential increased risk of angioedema 
(ACEI), and because LCZ696 already provides AT1 blockade (ARB).
4.4
Purpose and timing of interim analyses/design adaptations
There is no planned interim analysis for efficacy in the study. See Section 12.8 for sample size 
calculation for the primary endpoint.  See Section 10.2.2 and Section 12.7 for descriptions of 
the Data Monitoring Committee and interim safety assessments.
4.5
Risks and benefits
In order to minimize the interaction between an ACEi and sacubitril in potentiating the 
development of angioedema, patients cannot receive ACEi for 36 hours prior to the first dose 
of study medication.  To help ensure this documented washout, patients currently or recently 
taking ACEi will not be eligible for randomization until at least 36 hours from their last ACEi 
dose.  Medication administration records should be reviewed to insure no ACEi was 
administered for at least 36 hours prior to the first dose of study medication.
All patients will be allowed to continue receiving the rest of their background cardiovascular 
(CV) medications. The risk to patients in this trial will be minimized by compliance with the 
eligibility criteria and close clinical monitoring.  A Data Monitoring Committee (DMC) will 
also monitor the study for all safety considerations, since this population represents a patient 
population who are being initiated on study drug during the same hospitalization for admission 
for acute decompensated heart failure. 
Women of child bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study, and agree that in order to participate in the study they must adhere to the highly effective 
contraception requirements outlined in the exclusion criteria. If there is any question that the 
patient will not reliably comply, they should not be entered or continue in the study.
Participating patients will benefit from careful monitoring and follow-up during the entire study 
duration regardless of whether they are receiving study medication.
5
Population
The study population will consist of male and female patients, ≥ 18 years of age, currently 
hospitalized for or within 30 days of a WHF event (HFpEF decompensation).  A WHF event 
(HFpEF decompensation) is defined as a hospitalization, emergency department (ED) visit or 
out-of-hospital urgent HF visit, all requiring IV diuretics. A total of approximately 450 patients 


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will be randomized to sacubitril/valsartan or valsartan in a 1:1 ratio at approximately 130 centers
in the United States and Canada
Patients are defined as, (1) those randomized and completing the trial according to the Original 
Protocol Version 00, and (2) those randomized (or eligible and re-consented Original protocol 
patients) based on Amendment 1, which will be pooled for the final analysis (including a 
sensitivity analysis to ensure consistency (see Section 12.4.3).
A total of approximately 450 patients will be randomized to sacubitril/valsartan or valsartan in 
a 1:1 ratio at approximately 130 centers. 
Randomized patients will have been hemodynamically stabilized defined in this study as: 

SBP ≥100mmHg for the preceding 6 hours prior to randomization; no symptomatic 
hypotension 

No increase (intensification) in IV diuretic dose within last 6 hours prior to randomization

No IV inotropic drugs for 24 hours prior to randomization

No IV vasodilators including nitrates within last 6 hours prior to randomization
All patients will need to meet all other inclusion criteria and none of the exclusion criteria.
5.1
Inclusion criteria
Patients eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent must be obtained prior to participation in the study
2. Patients ≥18 years of age, male or female
3. Current hospitalization for WHF (HFpEF decompensation), or within 30 days of 
discharge following a WHF event (defined as hospitalization, emergency department 
(ED) visit or out-of-hospital urgent HF visit, all requiring IV diuretics). Patients with a 
diagnosis of acute heart failure had to have symptoms and signs of fluid overload (i.e. 
jugular venous distention, edema or rales on auscultation or pulmonary congestion on 
chest x-ray). Eligible patients will be randomized after IV diuresis for HFpEF is given 
(and no earlier than 36 hours from their last ACEi dose if applicable) and within 30 days 
post-decompensation after presentation with acute HFpEF decompensation and meeting 
the following definitions of hemodynamic stability:
Randomized patients will have been hemodynamically stable defined in this study as: 
a. SBP≥100mmHg for the preceding 6 hours prior to randomization; no symptomatic 
hypotension 
b. No increase (intensification) in IV diuretic dose within last 6 hours prior to 
randomization
c. No IV inotropic drugs for 24 hours prior to randomization
d. No IV vasodilators including nitrates within last 6 hours prior to randomization
4. HFpEF with most recent LVEF >40% (within past 3 months)


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5. Elevated NT-proBNP or BNP at the time of acute HFpEF decompensation or post-
decompensation screening (and within 72 hours for post-decompensation randomization, 
if applicable):Patients not in AF at the time of biomarker assessment: NT-proBNP ≥ 
500pg/mL or BNP ≥ 150 pg/mL; patients in AF at the time of biomarker assessment: NT-
proBNP ≥ 1000pg/mL or BNP ≥ 300 pg/mL
a. Patients recruited in-hospital will be randomized based on the qualifying local lab 
value in-hospital NT-proBNP or BNP value.
b. Patients enrolled post-decompensation can be randomized based on their NT-proBNP 
or BNP value in the following way:

if enrolling in post-decompensation setting then need eligible screening/local NT-
proBNP/BNP within 72 hours of randomization. The test value could be from 
recent hospitalization if within 72 hours or 

would require (re)drawing NT-proBNP or BNP labs in post-decompensation
setting if the lab value is not already available within the last 72 hours
6. Has not taken an ACEi for 36 hours prior to randomization
5.2
Exclusion criteria
Patients meeting any of the following criteria are not eligible for inclusion in this study.  No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1. Any clinical event within the 90 days prior to randomization that could have reduced the 
LVEF (i.e., MI, CABG), unless an echo measurement was performed after the event 
confirming the LVEF to be >40%
2. Entresto™ (sacubitril/valsartan) usage within the past 60 days
3. eGFR < 20ml/min/1.73 m2 as measured by the simplified Modification of Diet in Renal 
Disease (MDRD) formula at most recent assessment prior to randomization and within 24 
hours prior to inpatient randomization or 72 hours prior to outpatient randomization
4. Serum potassium > 5.2 mEq/L at most recent assessment prior to randomization and 
within 24 hours prior to inpatient randomization or 72 hours prior to outpatient 
randomization
5. Acute coronary syndrome, stroke, transient ischemic attack; cardiac, carotid or other 
major CV surgery; percutaneous coronary intervention (PCI) or carotid angioplasty, 
within 30 days prior to randomization
6. Probable alternative diagnoses that in the opinion of the investigator could account for the 
patient’s HF symptoms (i.e. dyspnea, fatigue) such as significant pulmonary disease 
(including primary pulmonary HTN), anemia or obesity. 
7. Isolated right HF in the absence of left-sided structural heart disease
8. History of hypersensitivity (i.e. including angioedema), known or suspected
contraindications, or intolerance to any of the study drugs including ARNIs (i.e. 
sacubitril/valsartan), and/or ARBs


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9. Patients with a known history of angioedema due to any etiology
10. Patients with a history of heart transplant or LVAD, currently on the transplant list, or 
with planned intent to implant LVAD or CRT device within the initial three months of 
enrollment during the trial 
11. A cardiac or non-cardiac medical condition other than HF with an estimated life 
expectancy of < 6 months
12. Known pericardial constriction, genetic hypertrophic cardiomyopathy, or infiltrative 
cardiomyopathy including suspected or confirmed amyloid heart disease (amyloidosis)
13. Life-threatening or uncontrolled dysrhythmia, including symptomatic or sustained 
ventricular tachycardia and atrial fibrillation or flutter with a resting ventricular rate >110 
bpm
14. Clinically significant congenital heart disease felt to be the cause of the patient’s 
symptoms and signs of HF
15. Coronary or carotid artery disease or valvular heart disease likely to require surgical or 
percutaneous intervention within the duration of the trial 
16. Any surgical or medical condition, which in the opinion of the investigator, may place the 
patient at higher risk from his/her participation in the study, or is likely to prevent the 
patient from complying with the requirements of the study or completing the study
17. Known hepatic impairment (as evidenced by total bilirubin > 3 mg/dL, or increased 
ammonia levels, if performed), or history of cirrhosis with evidence of portal hypertension 
such as varices
18. Participation in any other clinical trial involving investigational agents or devices within 
the past 30 days
19. Current confirmed COVID19 infection
20. Past COVID19 infection with persistent symptom burden suspected due to COVID19

Persistent symptoms may include, but are not limited to, continued cough, breathing 
difficulty, muscle/joint aches, and gastrointestinal symptoms from the time of 
COVID19 infection onward.  
21. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
hCG laboratory test.
22. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing of investigational drug and for 7 days off of study drug. Highly effective 
contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow-up hormone level assessment


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
Male sterilization (at least 6 months prior to Visit 1). For female patients on the study, 
the vasectomized male partner should be the sole partner for that patient

Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system
(IUS) or other forms of hormonal contraception that have comparable efficacy (failure 
rate <1%), for example hormone vaginal ring or transdermal hormone contraception
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy 
alone, only when the reproductive status of the woman has been confirmed by follow-up 
hormone level assessment is she considered not of child bearing potential. 
In case local regulations deviate from the contraception methods listed above, local regulations 
apply and will be described in the ICF.
6
Treatment
6.1
Study treatment Investigational and control drugs
The study treatment in Table 6-1 will be provided until the last patient appropriately randomized 
has had the opportunity of at least eight (8) weeks of follow-up in accordance to the protocol.
Novartis will supply the investigators with all study medications required for the course of the 
study. Patients will be provided with study drug corresponding to their assigned treatment arm 
and dose level, sufficient to last until the next scheduled visit.
This study is designed as a double-blind, double-dummy trial to ensure the blinding during the 
entire course of the study.  To maintain the blinding, patients will be required to take their 
assigned active treatment tablet along with placebo matching the opposite treatment twice daily.
Both sacubitril/valsartan and valsartan and their matching placebos will be packaged and 
labeled by the sponsor in accordance with the US Code of Federal Regulations governing 
handling of investigational treatments, and will be dispensed by the study physician.
Table 6-1
Investigational and control drug
Investigational/ 
Control Drug
(Name and Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply 
Type
Sponsor 
(global or 
local)
Sacubitril/valsartan 
24/26mg BID
Tablet 
Oral use
Double Blind 
supply; 
bottles
Sponsor 
(global) 


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Sacubitril/valsartan 
49/51mg BID
Tablet 
Oral use
Double Blind 
supply; 
bottles
Sponsor 
(global) 
Sacubitril/valsartan 
97/103mg BID
Tablet
Oral use
Double Blind 
supply; 
bottles
Sponsor 
(global) 
Sacubitril/valsartan 
matching placebo
Tablet
Oral use
Double Blind 
supply; 
bottles
Sponsor 
(global)
Valsartan 40mg BID
Tablet
Oral use
Double Blind 
supply; 
bottles
Sponsor 
(global) 
Valsartan 80mg BID
Tablet
Oral use
Double Blind 
supply; 
bottles
Sponsor 
(global) 
Valsartan 160mg BID
Tablet
Oral use
Double Blind 
supply; 
bottles
Sponsor 
(global) 
Valsartan matching 
placebo
Tablet
Oral use
Double Blind 
supply; 
bottles
Sponsor 
(global) 
Table 6-2
Treatment Dose Levels
Dose Level
Sacubitril/valsartan
Valsartan
1
24/26 mg [50mg] BID
40 mg BID
2
49/51 mg [100mg] BID
80 mg BID
3
97/103 mg [200 mg] BID
160 mg BID
Each participating hospital will be provided with the patient’s initial supply of study 
medication. Bottles will be numbered and assigned via an Interactive Response Technology 
(IRT).
Sacubitril/valsartan dose or valsartan dose levels may be increased to the targeted desired dose 
of 97/103 mg twice daily or valsartan 160 BID on an every 2-week basis or earlier if based on 
clinical need and investigator judgment.  Every effort should be made to titrate to and maintain 
patients on the target dose level, as tolerated by the patient.
Patients not tolerating the target dose of sacubitril/valsartan 97/103 mg BID or valsartan 160 
mg BID will be titrated down to the lower dose level (including active medication and matching 
placebos), at the investigator’s discretion, based on the defined safety and tolerability criteria. 
Per the guidance in Section 6.4.1, every attempt should be made to uptitrate again is the patient’s 
status allows.
All study sites will be provided with a Treatment Manual describing the treatment packaging 
and treatment instructions.


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6.1.1
Treatment arms/group
Patients will be randomized in a 1:1 ratio to receive treatment with either sacubitril/valsartan or 
valsartan.  
6.1.2
Treatment duration
The planned duration of treatment is up to approximately 20 months of double-blind treatment 
and the last patient randomized will be followed for a minimum of 8 weeks. Patients may be 
discontinued from treatment earlier due to unacceptable toxicity, disease progression and/or if 
treatment is discontinued at the discretion of the investigator or the patient.  Every attempt 
should be made to maintain patients on the target study drug dose level for as long as possible 
throughout the study.  
6.1.3
Concomitant therapy
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled in the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the patient was enrolled into the study must be recorded on the appropriate Case Report 
Forms.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started. If the patient is already 
enrolled, contact Novartis to determine if the patient should continue participation in the study.
6.1.3.1
Permitted concomitant therapy requiring caution and/or action
Other heart failure and cardiovascular medication
If a patient’s condition warrants any change in concomitant heart failure or cardiovascular 
medications, changes may be made at the investigator’s discretion.
Oral diuretics may be used and may be adjusted throughout the study duration at the discretion
of the investigator.
Medications known to raise potassium levels
Potassium sparing diuretics, potassium supplements, aldosterone antagonists, and any other 
medications known to raise potassium levels should be used with caution while the patient is 
receiving study medication due to the increased possibility of hyperkalemia. Potassium levels 
should be monitored regularly especially in those who are receiving these medications.
Concomitant administration of renin inhibitors, such as aliskiren, is prohibited.
Phosphodiesterase-5 (PDE-5) inhibitors
PDE-5 inhibitors should be used with caution while the patient is receiving study medication 
due to the increased possibility of occurrence of hypotension.


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6.1.4
Prohibited medication
Use of the treatments displayed in the table below is NOT allowed after the baseline phase. 
Please note the list of prohibited medication is not exhaustive. If you have any questions, the 
medical monitor should be contacted. 
Table 6-3
Prohibited medication 
Medication
Prohibition 
period
Action taken
Any ACEIs Inhibitor
Duration of 
study
Discontinue study drug. The open label ACEI
must be stopped for ≥36 hours prior to re-initiation of 
study drug
Any Angiotensin Receptor 
Blocker
Duration of 
study
Discontinue study drug. The open label ARB must
be stopped prior to re-initiation of study drug
Aliskiren (in patients with 
concurrent diabetes or those 
with renal impairment [eGFR 
< 60 mL/min/1.73 m²])
Duration of 
study
Discontinue study drug. The open label renin
inhibitor must be stopped prior to re-initiation of
study drug
Nesiritide and intravenous 
nitrates
Duration of 
study
Do not randomize. If hospitalized, either interrupt or 
discontinue study treatment. Concomitant 
administration of sacubitril/valsartan with nesiritide 
and intravenous nitrates has not been studied. Oral, 
topical and sublingual nitrates are permissible.
Bile acid sequestering 
agents (such as 
cholestyramine or colestipol)
Duration of 
study
Switch to alternate agent to avoid interference with 
study drug absorption. If use of alternate agent is not 
appropriate, do not randomize or discontinue study 
drug treatment.
ACEIs and ARBs
Patients’ pre-study ACEIs/ARBs will be replaced with the study medication.
The concomitant use of open label ACEIs or ARBs is strictly prohibited while the patient is 
receiving study medication. If the investigator believes that addition of an ACEI or ARB is 
necessary, then study drug must be discontinued. Study medication should be stopped 36 hours 
prior to addition of open label ACEI. If not already treated with aldosterone antagonist, 
consideration should be given to adding this therapy rather than an ACEI or and ARB, while 
monitoring renal function.
Nesiritide and intravenous nitrates
The concomitant admission of sacubitril/valsartan with nesiritide and intravenous nitrates has 
not been studied. Concomitant use of nesiritide will not be permitted during the study.
Other medications
Bile acid sequestering agents such as cholestyramine or colestipol are prohibited to avoid 
interference with study drug absorption.


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6.1.5
Rescue medication
At any time during the study investigators have the option to discontinue patients from study 
treatment if they develop signs and symptoms of worsening heart failure for which the 
investigator would like to administer appropriate therapy.

Appropriate adjustments, intensifications, or additions to concomitant medications 
should be considered before deciding to withdraw the patient from study treatment.

Patients CANNOT receive ACEIs and/or ARBs during the study. These 
medications can ONLY be administered if the investigator believes that the 
patient needs to be withdrawn from study treatment so that they may be treated 
with these therapies due to signs and symptoms of worsening heart failure.

If the investigator has not made the decision to permanently discontinue study 
treatment, then the patient can resume study treatment as long as the 36-hours ACEI
washout was observed.

A 36-hour wash-out period is required if the investigator chooses to withdraw 
the patient  from study treatment and switch to ACEI due to symptoms of 
worsening heart failure.

Use of rescue medication must be recorded on the appropriate Concomitant 
Medications eCRF.
Investigators will use clinical judgment to determine if patient’s condition requires closer 
monitoring. Unscheduled visits are permitted as needed.
6.2
Patient numbering, treatment assignment, randomization
6.2.1
Patient numbering
Each patient is uniquely identified in the study by a Patient Number (Patient No.), that is 
assigned when the patient is first enrolled for screening and is retained as the primary identifier 
for the patient throughout his/her entire participation in the trial. The Patient No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential 
patient number suffixed to it, so that each patient is numbered uniquely across the entire 
database. Upon signing the informed consent form, the patient is assigned to the next sequential 
Patient No. available by the investigator. The investigator or his/her staff will contact the IRT
and provide the assigned patient study identification number along with the requested 
identifying information for the patient to register them into the IRT. The site will enter this 
number on the electronic case report form (eCRF) in the electronic data capture system (EDC).   
6.2.2
Treatment assignment, randomization
At randomization visit, all eligible patients will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The investigator or his/her delegate will contact 
the IRT after confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT 
will assign a randomization number to the patient, which will be used to link the patient to a 
treatment arm and will specify a unique medication number for the first package of study 
treatment to be dispensed to the patient.


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The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of patient numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 
Global Clinical Supply (GCS) using a validated system that automates the random assignment 
of medication numbers to bottles containing the study treatment.
The randomization scheme for patients will be reviewed and approved by Novartis. 
Initial dose at randomization will be determined based on the patient’s previous dose of or lack 
of ACEi/ARB immediately prior to current WHF event (HFpEF decompensation), or at the time 
of post-decompensation randomization.  Dose adjustments to lower dose levels may be made 
at any time at both scheduled and unscheduled visit only if clinically indicated for blood 
pressure control or tolerability reasons. Dose adjustments to increase dose levels may be made 
at any time at both scheduled and unscheduled visits based on clinical need or investigator 
judgment.
Subsequent supplies of study drug will be assigned in the following manner. The investigator 
or his or her delegate will call the IRT and provide the patient’s number. The IRT will ask the 
caller whether there is a change in the dose level of the study drug. If the caller indicates that 
there is no change in the dose level, the IRT will provide the unique medication numbers of the 
study drug with the same dose level that was dispensed at the previous dispensing. If the caller 
indicates that the dose level has changed since the last dispensing, the IRT will ask the caller 
which dose level should be dispensed.  The caller will enter the dose level to dispense or whether 
no study drug should be dispensed (in case of study drug withdrawal). If applicable, the IRT 
will provide the unique medication numbers for the study drug supplies that should be dispensed 
at the new dose level. 
6.3
Treatment blinding
Patients, investigator staff, persons performing the assessments, and Clinical Trial Team (CTT)
will remain blind to the identity of the treatment from the time of randomization until database 
lock, using the following methods: (1) Randomization data are kept strictly confidential until 
the time of unblinding, and will not be accessible by anyone else involved in the study with the
exception of the IRT provider generating the randomization code, members of the Data 
Monitoring Committee (DMC) and the independent biostatistician and programmer assigned to 
the DMC.  (2) The identity of the treatments will be concealed by the use of study treatment 
that are all identical in packaging, labeling, schedule of administration, appearance, taste and 
odor.
Unblinding may be considered in the case of patient emergencies.  It is highly recommended 
that the investigator/site coordinator contact the Novartis Medical Monitor to discuss any 
unblinding concerns, as most often, study treatment discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a study person who presents with an 


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emergency condition.  Full unblinding will occur at the conclusion of the study, after database 
lock.
6.4
Dose modification
6.4.1
Dose modifications
For patients who do not tolerate the protocol-specified dosing schedule, dose interruptions 
and/or reductions are either recommended or mandated in order to allow patients to continue 
the study treatment.
Deviations to mandatory dose interruptions and/or reductions are not allowed. Permanent 
treatment discontinuation is mandatory for specific events listed in Section 9.1.1.
These dose changes must be recorded on the appropriate case report form (CRF).
Every attempt should be made to maintain patients on the target study drug dose level for as 
long as possible throughout the study.  If, however, in the opinion of the investigator, a patient
is unable to tolerate the protocol-specified target dose, the investigator should consider whether 
dose adjustments of concomitant medications may rectify the situation before reducing the dose 
of study treatment. If adjustment of the concomitant medications is not possible or does not 
alleviate the side effects of concern, the investigator may down-titrate the dose of the study drug 
to the previous dose level. If needed, the study drug may be stopped completely, if this occurs, 
the patient should return to the clinic as soon as possible, after discontinuation of study drug, 
for an end of study visit.  Patients may restart their current dose of study drug following an 
interruption of treatment, based on investigator judgment.  
Study drug dose level adjustments should be mainly based on overall safety and tolerability 
with special focus on:

Hyperkalemia

Symptomatic hypotension

Clinically significant decrease in eGFR/increase in serum creatinine (defined as a 
serum creatinine of ≥0.5mg/dl with at least a 25% decrease in eGFR)

Angioedema
These changes must be recorded on the appropriate CRF. Every attempt should be made to 
titrate to and maintain patients on target study drug Dose Level 3 for as long as possible 
throughout the study. If, however, in the opinion of the investigator, a patient is unable to 
tolerate the protocol-specified target dose, the investigator will manage the patient’s treatment 
according to the below guidelines:
Steps:
1. Adjust Concomitant Medications

Dose adjustments/elimination of concomitant medications may remedy the situation 
before reducing the dose of study treatment. If adjustment of the concomitant 
medications is not possible or does not alleviate the side effects of concern, THEN;


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2. Adjust Study Treatment Dose Level

Down-titrate study treatment to the previous dose level. The patient may continue 
receiving the lower dose level for a recommended period of 1 to a maximum of 4 
weeks.

A re-challenge to titrate back up to the target dose level should be attempted at 2 
weeks, or when patient is deemed stable. THEN:
3. Further Adjust Study Treatment Dose Level

If tolerability issues are not alleviated despite down-titration by one dose level, the 
investigator may down-titrate further to the next lower study treatment dose level. The 
patient may continue receiving the lower dose level for a recommended period of 1 to 
a maximum of 4 weeks. See Step 5.

Again, once stable, the patient should be re-challenged with up-titration to the next 
higher dose level in an attempt to gradually bring the patient back to the target study 
treatment dose level (Dose Level 3).

The investigator may choose the next dose level for down- or up-titration according to 
his or her clinical judgment.
4. Stopping Study Treatment

If needed, the study treatment may be stopped completely, however, every effort must 
be made to complete an end of study visit and obtain follow up health status 
information and NT-proBNP for any patient that withdraws from the study. 
5. Study drug restart after temporary treatment interruption

Once the investigator considers the patient’s condition appropriate for receiving the 
study drug, the investigator should re-start the patient on study treatment at the most 
appropriate and allowable dose level per his/her medical judgment.

If tolerated, the patient should be titrated up to the next dose level every 1 to 4 weeks, 
as per the investigator’s judgment.

In some instances, Dose Level 1 or 2 could be maintained if the investigator considers 
that the patient’s condition would not allow any further up-titration to the target dose 
of study medication (Dose Level 3). In this case, it would be acceptable to maintain 
the patient at Dose Level 1 or 2, whichever is the higher and tolerated dose level by 
the patient, but reasons for not getting to Dose Level 3 need to be captured in the 
eCRF.

Should the patient not tolerate the re-start study drug dose level, he/she may be down-
titrated again (if appropriate) or discontinued from study treatment.
Patients re-started on the study drug will retain their original randomization and study 
identification numbers.
The IRT must be contacted to register any changes in the patient’s study treatment dose level, 
including in cases of temporary and permanent withdrawal or re-start of the study drug, and to 
obtain the medication numbers of the study drug supplies required for the new study treatment 
dose level. All dose changes and interruptions must also be recorded on the appropriate eCRF.


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Study visits should occur as close as possible to the pre-defined visit and time schedule 
described in Table 8-1. The timeframe between the regular visits should be maintained as 
scheduled, irrespective of the number of unscheduled visits that may be performed in between, 
or dose interruptions that may occur.
In case of pregnancy discovered during the study, the patient should be instructed to stop taking 
the study drug immediately. 
6.4.2
Follow-up for angioedema
Angioedema is a type of abrupt swelling that occurs under the skin and/or mucous membranes 
and is often localized to the head, neck, throat, and/or tongue, but may occur elsewhere, 
including the genitalia and intestines.  Severe cases may be associated with airway compromise.  
It is important that the investigator pays special attention to any swelling or edema that may 
resemble angioedema or angioedema-like events that may be reported by patients.  If such an 
event occurs, the investigator will complete a Questionnaire for an Angioedema-like Event form 
(provided by Novartis) to summarize the event, its treatment and its ultimate outcome.  
The investigator may be also contacted by Novartis regarding AEs that may resemble an 
angioedema-like event.  A list of terms that are considered ‘angioedema-like’ will be provided 
to sites in a manual.  
Details on the procedures for reporting angioedema events will be provided to investigators in 
a manual.
6.5
Additional treatment guidance
6.5.1
Treatment compliance
Compliance will be assessed by the investigator and/or study personnel at each visit (including 
during pandemic-related virtual visits, when applicable) using pill counts and information 
provided by the care giver. This information should be captured in the source document at each 
visit. Patient compliance should be at least 80%. The investigator and/or study personnel will 
counsel the patient if compliance is below 80%. Study drug accountability will also be 
determined by the site monitor while performing routine site visits and at the completion of the 
study.
Duration of double-blind study drug exposure will be calculated based upon the start and stop 
dates recorded in the eCRF.
6.5.2
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a patient, he/she must provide the 
requested patient identifying information and confirm the necessity to break the treatment code 


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for the patient. The investigator will then receive details of the investigational drug treatment 
for the specified patient and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the Clinical Trial Lead that the code
has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide:

protocol number

patient number
In addition, oral and written information to the patient must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time.
6.6
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section.  
A unique medication number is printed on the study medication label.  Investigator staff will 
identify the study medication bottles to dispense to the patient by contacting the IRT and 
obtaining the medication number(s). The study medication has a 2-part label (base plus tear-off 
label), immediately before dispensing the medication bottle to the patient, site personnel will 
detach the outer part of the label from the packaging and affix it to the source document.
During the COVID-19 pandemic that limits or prevents on-site study visits, delivery of IP 
directly to a participant’s home is generally permitted in the event the Investigator has decided 
that an on-site visit by the participant is no longer appropriate or possible, and that it is in the 
interest of the participant’s health to administer the study treatment even without performing an 
on-sitevisit. Implementation will needto bediscussed with Novartis. The dispatch ofIP from the 
site to the participant’s home remains under the accountability of the Investigator. Each 
shipment/provisioning will be for a maximum of 4-months supply. In this case,regular phone 
calls or virtual contacts are suggested per Investigator discretion based on patient stability and 
status until the participants can again visit the site.
6.6.1
Handling of study treatment and additional treatment
6.6.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, 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, all study treatment must be stored according to the 
instructions specified on the labels and in the Investigator’s Brochure. Clinical supplies are to 
be dispensed only in accordance with the protocol. Technical complaints are to be reported to 
the respective Novartis US Quality Assurance.


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The investigator must maintain an accurate record of the shipment and dispensing of 
investigational and comparator treatment in a drug accountability log. Monitoring of drug 
accountability will be performed by field monitors during site visits or remotely and at the 
completion of the trial. Patients will be asked to return all unused investigational or comparator 
treatment and packaging at the end of the study or at the time of discontinuation of treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused investigational and comparator treatment, packaging, drug labels, and a 
copy of the completed drug accountability log according to the instructions provided by 
Novartis or its agents.
6.6.2
Instruction for prescribing and taking study treatment
All medication for the duration of the study will be provided by Novartis. Eligible patients will 
be randomized via IRT to either sacubitril/valsartan or valsartan. 
Patients will be provided with sufficient medication to last until the next scheduled visit. In 
order to adequately blind the study, patients will be required to take a total of two tablets (one 
tablet from the sacubitril/valsartan / sacubitril/valsartan matching placebo bottle and one tablet 
from the valsartan/valsartan matching placebo bottle) twice a day for the duration of the study.
Initial dose at randomization will be determined based on the patient’s previous dose of or lack 
of ACEi/ARB immediately prior to current WHF event (HFpEF decompensation), or at the time 
of post-decompensation randomization. 

For patients who were not being treated with ACEi/ARB at the time of presentation to 
hospital, or at the time of post-decompensation randomization, the starting dose 
should be dose level 1. 

For patients with an estimated GFR of >20 to <30 mL/min/1.73 m2, regardless of 
ACEi/ARB dose at the time of presentation to hospital or post-decompensation
randomization, should be initiated at dose level 1. 

Those patients previously treated with low dose of ACEi/ARB (Table 6-4) should be 
initiated at dose level 1. 

For patients previously treated with high dose ACEi/ARB (Table 6-4), the starting 
dose is dose level 2. 
Table 6-5 summarizes the starting dose of study medication based on RASi stratum at time of 
patient presentation to the hospital, or at the time of post-decompensation randomization.
The target dose for sacubitril/valsartan is 97/103 mg BID and for valsartan is 160 mg BID (dose 
level 3). Every attempt should be made to titrate to and maintain patients on the target study 
drug dose level for as long as possible throughout the study. However, maximal doses for study 
medication will be determined by the investigator based upon the patient’s clinical status. It is 
recommended that patients remain at each dose level during up-titration for 1 to 2 weeks such 
that patients initiated at dose level 1 reach target dose in 2 to 4 weeks and those patients initiated 
at dose level 2 reach target dose in 1 to 2 weeks. In certain circumstances, longer up-titration 
periods may be required as deemed necessary by the investigator. 


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If patients cannot tolerate the target dose of study medication (dose level 3), down titration to a 
lower dose is allowed (see Section 6.4). Patients should be re-challenged to the target dose of 
study medication when their condition permits up-titration based on their systolic blood 
pressure (SBP), eGFR, potassium values, and at the investigator’s discretion. However, patients 
can remain at low doses (level 1 or 2), based on their tolerability and clinical judgment of the 
investigator.
Up titration may be done prior to the week 1 visit at the investigator’s discretion i.e., if 
concerned about managing hypertension. 
Table 6-4
Definition of low and high total daily doses for commonly used ACEIs 
and ARBs
ACEi/ARB 
Low RASi stratum
(total daily dose)
High RASi stratum
(total daily dose)
ACEis
Enalapril 
≤ 10 mg
> 10 mg
Benazepril
≤ 20 mg
> 20 mg
Captopril
≤ 100 mg
> 100 mg
Fosinopril
≤ 20 mg
> 20 mg
Lisinopril
≤ 10 mg
> 10 mg
Moexipril
≤ 7.5 mg
> 7.5 mg
Perindopril
≤ 4 mg
> 4 mg
Quinapril
≤ 20 mg
> 20 mg
Ramipril
≤ 5 mg
> 5 mg
Trandolapril
≤ 2 mg
> 2 mg
ARBs
Candesartan
≤ 16 mg
> 16 mg
Eprosartan
≤ 400 mg
> 400 mg
Irbesartan
≤ 150 mg
> 150 mg
Losartan
≤ 50 mg
> 50 mg
Olmesartan
≤ 10 mg
> 10 mg
Telmisartan
≤ 40 mg
> 40 mg
Valsartan
≤ 160 mg
> 160 mg
Table 6-5
Starting dose of study medication
RASi stratum at time of presentation to hospital or 
at the time of post-decompensation randomization*
Starting dose level of study medication
Patients not being treated with ACEi/ARB at the time of 
presentation to hospital or at the time of out-of-hospital 
randomization
Dose level 1


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Estimated GFR >20 and <30 mL/min/1.73 m2, regardless 
of ACEi/ARB dose at the time of presentation to hospital 
or post-decompensation randomization
Dose level 1
Low dose ACEi/ARB
Dose level 1
High dose ACEi/ARB
Dose level 2
* A 36-hour washout of prior ACEi treatment is required before administering sacubitril/valsartan. Eligible patients hospitalized for 
ADHF will be randomized no earlier than 36 hours after presentation with acute decompensated heart failure while still hospitalized 
and no later than 30 days post-decompensation (with a 36 hour-washout period from their last outpatient ACEi dose).
Dose adjustments to lower dose levels may be made at any time at both scheduled and 
unscheduled visits only if indicated for blood pressure control/tolerability reasons.
Study medication should be taken with a glass of water with or without food. If the patient
misses taking any study drug dose, he/she should take it as soon as possible, unless it is almost 
time for the following scheduled dose. In this case, the patient should skip the missed dose and 
return back to his/her regular study drug administration schedule. 
All bottles of study treatment assigned by the IRT will be recorded in the IRT system. 
The investigator should promote compliance by instructing the patient to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety and the validity of the study. The patient should be instructed to contact the investigator 
if he/she is unable to take the study treatment as prescribed for any reason. 
7
Informed consent procedures
Eligible patients may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the patient's representative(s) gives consent (if allowed according 
to local requirements), the patient must be informed about the study to the extent possible given 
his/her understanding. If the patient is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
During the COVID-19 pandemic that may challenge the ability to obtain a standard written 
informed consent due to limits that prevent an on-site visit, the Investigator may conduct the 
informed consent discussion remotely (e.g. telephone, videoconference). Guidance issued by 
local regulatory bodies on this aspect prevail and must be implemented and appropriately 
documented (e.g. the presence of an impartial witness, sign/dating separate ICFs by trial 
participant and person obtaining informed consent, etc).
For continuity of trial procedures, the Investigator may continue to conduct the informed 
consent discussion remotely as described above for the remainder of the trial, or as otherwise 
described by local regulatory bodies.
Informed consent must be obtained before conducting any study-specific procedures (e.g., all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the patient source documents.


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Eligible patients enrolled in the Original Protocol (Version 00) must sign a new informed 
consent form to participate in Amendment 1 (Protocol Version 01). Eligible patients are defined 
as those currently enrolled in the double-blind treatment period of the Original Protocol at the 
time of each site’s Amendment 1 IRB approval.  
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the patient
informed consent and should be discussed with the patient during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the patient.
Women of childbearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
Male patients must be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information.
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval.
8
Visit schedule and assessments
The Assessment Schedule (Table 8-1) lists all of the assessments and when they are performed
for participants consented to Protocol Amendment V04.  See Section 16.5 Appendix 5 for 
Expanded Assessment Schedule, which includes visit assessments for Protocol Amendment 
V04 and previous protocol amendment versions. All data obtained from these assessments must 
be supported in the patient’s source documentation.
Patients should be seen for all visits/assessments as outlined in the assessment schedule (Table 
8-1) or as close to the designated day/time as possible. Missed or rescheduled visits should not 
lead to automatic discontinuation. Patients who prematurely discontinue the study for any 
reason should be scheduled for a visit as soon as possible, at which time all of the assessments 
listed for the final visit will be performed. At this final visit, all dispensed investigational 
product should be reconciled, and the adverse event and concomitant medications recorded on 
the CRF.
If the COVID-19 pandemic limits or prevents on-site study visits, alternative methods of 
providing continuing care may be implemented. V i r t u a l  v i s i t s  [ e . g .  phone calls, video 
visits (preferred)] or visits by site staff/home nursing service to the participant´s home 


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depending on local regulations and capabilities, can replace on-site study visits, for the duration 
of the pandemic until it is safe for the participant to visit the site again.


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Table 8-1
Assessment Schedule
Period
Screening
Double-Blind Treatment 
(84 week)
Visit Name 
Screening 
Randomizati
on/Baseline 
Study 
Completion/
End of 
Study
Visit Number
Visit 1
Visit 2
Visit 3
Visit 5
Visit 7
Visit 11
Visit 13
Visit 15
Visit 16
Visit 17
Week
(Day)
[Day -30
to -1.5 
(36hours)]
0 
(Day 1)
1 
(Day 7)
4 
(Day 28)
8
(Day 56)
24
(Day 168)
40
(Day 280)
56
(Day 392)
68 
(Day 476) 
84
(Day 588)
Information and 
informed consent
S
Inclusion/exclusion 
criteria
X
X
Demography / 
Medical history
X
Heart failure and 
CV disease history
X
ECG
X
Physical Exam
S
S
S
S
S
S
S
S
Height
X
X
Weight
X
X
X
X
X
X
X
X
X
X
Waist/hip 
circumference
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
HF signs and 
symptoms and 
NYHA classification
X
X
X
X
X
X
X
X
X
X
Heart failure and 
CV medications
X
X4
X
X
X
X
X
X
X
X


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Period
Screening
Double-Blind Treatment 
(84 week)
Visit Name 
Screening 
Randomizati
on/Baseline 
Study 
Completion/
End of 
Study
Visit Number
Visit 1
Visit 2
Visit 3
Visit 5
Visit 7
Visit 11
Visit 13
Visit 15
Visit 16
Visit 17
Week
(Day)
[Day -30
to -1.5 
(36hours)]
0 
(Day 1)
1 
(Day 7)
4 
(Day 28)
8
(Day 56)
24
(Day 168)
40
(Day 280)
56
(Day 392)
68 
(Day 476) 
84
(Day 588)
Chemistry labs
X
X
X
X
X
X
X
X
X
X
Hematology labs
X
X
X
X
X
X
X
X
Hemoglobin A1C
X
X
eGFR
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
Pregnancy Test2
X
X
X
X
X
X
X
X
X
IRT
X
X
X
X
X
X
X
X
X
X
Randomization
X
Plasma NT-
proBNP or BNP 
X5
X
X
X
X
hs-Troponin
X
X
X
Drug accountability
X
X
X
X
X
X
X
X
Dispense study 
treatment 
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
PPD


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Protocol No. CLCZ696DUS01
Period
Screening
Double-Blind Treatment 
(84 week)
Visit Name 
Screening 
Randomizati
on/Baseline 
Study 
Completion/
End of 
Study
Visit Number
Visit 1
Visit 2
Visit 3
Visit 5
Visit 7
Visit 11
Visit 13
Visit 15
Visit 16
Visit 17
Week
(Day)
[Day -30
to -1.5 
(36hours)]
0 
(Day 1)
1 
(Day 7)
4 
(Day 28)
8
(Day 56)
24
(Day 168)
40
(Day 280)
56
(Day 392)
68 
(Day 476) 
84
(Day 588)
Adverse events / 
Serious Adverse 
events
X
X
X
X
X
X
X
X
X
X
Angioedema 
assessment
X
X
X
X
X
X
X
X
X
X
Thank You letter
X
X
Study completion –
randomized 
treatment
X
Post study 
completion follow 
up
S6
PPD


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Protocol No. CLCZ696DUS01
Period
Screening
Double-Blind Treatment 
(84 week)
Visit Name 
Screening 
Randomizati
on/Baseline 
Study 
Completion/
End of 
Study
Visit Number
Visit 1
Visit 2
Visit 3
Visit 5
Visit 7
Visit 11
Visit 13
Visit 15
Visit 16
Visit 17
Week
(Day)
[Day -30
to -1.5 
(36hours)]
0 
(Day 1)
1 
(Day 7)
4 
(Day 28)
8
(Day 56)
24
(Day 168)
40
(Day 280)
56
(Day 392)
68 
(Day 476) 
84
(Day 588)
X = assessment to be recorded in the clinical database or received electronically from a vendor
S = assessment to be recorded in the source documentation and in the database
 
2 All female patients of childbearing potential will have a serum pregnancy test (hCG) performed at Visit 1 (local lab). A urine pregnancy test will be conducted in the local laboratory for 
remaining visits
4 CV medications will be recorded at time of hospital discharge.
5 BNP or NT-proBNP will be assessed at Visit 1 via local laboratory. Only NT-proBNP will be assessed via central laboratory for Visits 2, 3, 5 and 7.
6 Health status phone call 4 weeks after study completion.
P


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8.1
Screening
A patient who enters screening but is determined not to be eligible will be considered a screen 
failure. The investigator may consider re-screening the patient at a later time if he/she believes 
that the patient’s condition has changed and they may potentially be eligible. In this case, a new 
patient number will be allocated to the subject and he/she will need to re-perform all Visit 1 
procedures. A patient may be re-screened once. A minimum of 24 hours must elapse between 
screen failure and re-screening. The patient must provide new written informed consent before 
they are re-screened.
8.1.1
Information to be collected on screening failures
Patients who sign an informed consent form and subsequently found to be ineligible prior to 
randomization will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate Case Report Form. The demographic information, informed 
consent, Inclusion/Exclusion pages and Protocol Amendment Log must also be completed for 
screen failure patients. No other data will be entered into the clinical database for patients who 
are screen failures, unless the patient experienced a serious adverse event during the screening 
phase (see SAE section for reporting details). If the patient fails to be randomized, the IRT must 
be notified within 2 days of the screen fail that the patient was not randomized.
Patients who are randomized and fail to start treatment, e.g. patients randomized in error, will 
be considered an early terminator. The reason for early termination should be recorded on the 
appropriate Case Report Form. 
8.2
Patient demographics/other baseline characteristics
Patient demographic and baseline characteristic data to be collected on all patients include: date 
of birth, age, sex, race, ethnicity and source of patient referral.  Relevant medical history/current 
medical condition data includes data collected up to the point in which informed consent is 
signed. Where possible, diagnoses and not symptoms, will be recorded. HF medications will be 
recorded in eCRFs separately from other medications. Likewise, detailed HF history and other 
relevant CV medical history will be recorded on eCRFs separately from other medical history.
8.3
Efficacy
The efficacy endpoints are:
Primary variable:

Time averaged proportional change in NT-proBNP from baseline to Weeks 4 and 8
Secondary variables:

The composite hierarchical outcome consisting of: a) time to CV death, b) number and 
times of HF hospitalizations during follow-up, c) number and times of urgent HF visits 
during follow-up, and d) time averaged proportional change in NT-proBNP (from baseline 
to Weeks 4 and 8) using win ratio analysis of composite hierarchical outcome


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!
The cumulative number of composite events, i.e., the composite events of CV death, total 
HF hospitalizations, and total urgent HF visits for a given subject, over time.
!
The incidences of a composite endpoint of worsening renal function (renal death, reaching 
ESRD, or > 50% decline in eGFR relative to baseline)
!
Change in NT-proBNP from baseline to Week 8 
!
Change from baseline in hs-Troponin (high sensitivity) at Weeks 4 and 8
!
Dosing levels, discontinuations, and the incidence of adverse events of special interest 
during treatment
8.3.1
Heart failure signs and symptoms
Signs and symptoms of heart failure will be reviewed by the investigator at all in-person visits 
during the study. The signs and symptoms evaluation may include, but are not limited to, 
paroxysmal nocturnal dyspnea, fatigue, edema, dyspnea at rest, dyspnea upon effort, orthopnea, 
rales, jugular venous distention, presence of a third heart sound. NYHA classification will be 
assessed and documented at each visit.
8.3.2
Estimated glomerular filtration rate (eGFR)
The eGFR to determine eligibility of the patient for screening into the trial will be calculated at 
Visit 1 from the serum creatinine concentration measured at the local laboratory. The eGFR 
will be further calculated from creatinine concentration measured at Visits 2, 3, 5, 7, 11, 13, 15, 
and 16 (randomization, Weeks 1, 4, 8, 24, 40, 56, and 68), and end of study (Week 84) at the 
central laboratory. The eGFR calculation will be based on the Abbreviated Modification of Diet 
in Renal Disease (MDRD) study equation (Levey, et al 2007).
PPD


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8.3.3
Biomarkers
BNP or NT-proBNP will be measured in all patients by using the local laboratory at Visit 1 to 
determine eligibility. NT-proBNP will be measured in all patients using the central laboratory 
at Visits 2 (randomization), 3, 5, and 7 (Weeks 0, 1, 4, and 8 respectively).
 
 
 
During the COVID-19 pandemic that limits or prevents on-site study visits, or if visits by site 
staff to a participant’s home are not feasible, the collection of standard chemistry and 
hematology samples may be modified by Novartis and will be communicated to the Investigator.
For the primary endpoint biomarkers (Weeks 4 and 8), alternative methods of collecting and 
ensuring shipment of biomarkers to the central laboratory should be implemented.  Alternative 
methods must comply with guidance issued by local regulatory bodies and be discussed with
Novartis.
 
 
 
Evaluation of neprilysin measurement at baseline as a predictor of clinical outcome may be 
added depending on availability of a validated assay and sample handling requirements. The 
list may be changed or expanded further as new relevant biomarkers may be discovered during 
this study and after its completion. As such, serum and plasma will be bio-banked for analysis 
of yet to be identified diagnostic biomarkers.  Details of sample collection, handling and 
shipment will be provided to investigators in the laboratory manual.
8.3.4
Appropriateness of efficacy assessments
The selected efficacy variables for this study including changes in NT-proBNP and other 
biomarkers concentrations, as well as heart failure signs and symptoms are standard for the 
evaluation of therapeutic agents in a heart failure population.
8.4
Safety
!
Incidence of worsening renal function, defined as an increase in serum creatinine of 
≥0.5mg/dl and worsening of the eGFR by at least 25% 
!
Incidence of symptomatic hypotension 
!
Incidence of hyperkalemia (Potassium >5.5 mEq/l)
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Incidence of angioedema 
Safety assessments will consist of monitoring and recording of all adverse events and serious 
adverse events, evaluation of hematology, blood chemistry and urine values, regular 
measurement of vital signs and the performance of physical examinations.
During the COVID-19 pandemic that limits or prevents on-site study visits, regular phone or 
virtual calls should occur for safety monitoring and discussion of the participant´s health status 
until the participant can again visit the site. If a participant cannot visit the site to have 
pregnancy tests done, a home urine pregnancy or central lab pregnancy test kit may be used.
Relevant participants can perform the urine pregnancy test at home at the time of the scheduled visit 
and report the result to the site. It is important that participants are instructed to perform the urine 
pregnancy test first and only if the test result is negative proceed with the administration of the
study treatment. A communication process should be established with the participant so that the
site is informed of the pregnancy test results.
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to AE section.
Table 8-2
Assessments & Specifications 
Assessment
Specification
Physical 
examination
A complete physical exam will be performed at Visits 1, 5, 7, 11, 13, 15, 16 and 17
(physical exam at visit 2 to be performed only if randomization visit is done on a 
different calendar date than screening).  It will include the examination of general 
appearance, skin, neck, eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities, and vascular and neurological examinations. If indicated 
based on medical history, and/or symptoms, rectal, external genitalia, breast and 
pelvic exams will be performed.
Information for all physical examinations must be included in the source 
documentation at the study site (with the exceptions of pandemic-related virtual 
visits mentioned above). Significant findings that are present prior to the informed 
consent must be included in the Relevant Medical History/Current Medical 
Conditions screen on the patient’s eCRF. Significant findings made after informed 
consent which meet the definition of an adverse event must be recorded on the 
Adverse Event eCRF.
Vital signs
Vital signs will be assessed at every in-person visit, and in cases where the COVID-
19 pandemic limits or prevents on-site study visits,.  This will include blood pressure 
and pulse measurements.  BP will be measured using a standard 
sphygmomanometer with an appropriately sized cuff and the non-dominant arm in 
the sitting position after 5 minutes of rest.  Every effort should be made to use the 
same arm for the patient for all vital signs assessments and where possible, the 
same person doing the assessment.  For virtual visits, documentation of any vital 
signs available (e.g. home BP cuff results) should be recorded in the eCRF.
Height and 
weight
Height in centimeters if possible will be measured at Visits 1 and 2. Body weight to 
the nearest 0.1 kg without shoes, will be measured at Visits 1, 2, 3, 5, 7, 11, 13, 
15, 16 and 17. 


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Assessment
Specification
Waist/hip 
circumference
Waist/hip circumference to the nearest centimeter will be measured at Visit 1.
Angioedema
Angioedema is a type of abrupt swelling that occurs under the skin and/or mucous 
membranes and is often localized to the head, neck, throat, and/or tongue, but may 
occur elsewhere, including the genitalia and intestines. Severe cases may be 
associated with airway compromise. Although, the mechanism is not fully 
understood, bradykinin has been implicated as the putative mediator. Therefore, 
medications that raise the levels of endogenous bradykinin by inhibiting the 
enzymes responsible for its breakdown, such as ACE, aminopeptidase P, and 
NEP, may result in this potentially dangerous side effect. All suspected cases of 
angioedema, regardless of suspected causality, must be reported. The 
Angioedema Questionnaire must be completed and the Clinical Trial Lead or their 
designee must be notified.
If the angioedema event meets SAE criteria, the investigator must ensure that an 
SAE form is completed and submitted to Novartis Drug Safety and Epidemiology. 
8.4.1
Laboratory evaluations
The local hospital and/or clinic laboratory will be used for all laboratory evaluations required 
to determine eligibility. If eligibility laboratory assessments were not done during the patient’s 
hospitalization, samples should be collected and sent to the local laboratory. A central 
laboratory will be used for analysis of all collected specimens from baseline through the final 
visit. Details on the collections, shipment of samples and reporting of results by the central 
laboratory will be provided to investigators in the laboratory manual.  Results from the local 
hospital laboratory will be recorded in the eCRF.
Clinically notable laboratory findings are defined in Appendix 1.
Local laboratory assessments may be performed on an as-needed basis for unscheduled visits. 
Laboratory values that exceed the boundaries of a notable laboratory abnormality must be 
commented on by the investigator on the source document and additional laboratory evaluations 
should be performed, as judged appropriate by the investigator. If the laboratory abnormality 
induces clinical signs or symptoms, or requires therapeutic intervention, then the diagnosis or 
medical condition must be entered on the patient's AE eCRF. If the laboratory abnormality is 
the primary reason for an unforeseen hospitalization or otherwise fulfills the seriousness 
category of an AE, then the procedure for rapid notification of SAEs must be followed. 
Likewise, if the laboratory abnormality leads to discontinuation from the study drug 
(temporarily or permanently), the patient must be followed until the abnormality resolves or 
until it is judged to be permanent. This investigation may include continued monitoring by 
repeat laboratory testing or by performing additional laboratory tests as deemed necessary by 
the investigator or the Novartis medical monitor.


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Table 8-3
Laboratory Assessments
Test 
Category
Test Name
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential 
(Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands, Other 
(absolute value preferred , %s are acceptable), and platelet count will be measured at 
Visits 1 (local lab), 2, 7, 11, 13, 15, 16, and 17 (central lab). Hemoglobin A1c will be 
measured at Visits 2 and 17 (central lab).
Chemistry
Assessments required for eligibility that need to be measured at Visit 1 include 
creatinine, potassium, and total bilirubin. Blood urea nitrogen (BUN), glucose, 
creatinine, total bilirubin, AST (SGOT), ALT (SGPT), alkaline phosphatase, sodium, 
potassium, chloride, calcium , total protein, albumin, uric acid, and lipid profile be 
measured at Visits 1 (local lab), 2, 3, 5, 7, 9, 11, 13, 15, 16, and 17 (central lab).
Urinalysis
Dipstick-test determination of specific gravity, pH, blood, total protein, bilirubin, 
ketones, and leukocytes will be measured at Visit 2 (central lab). If dipstick is 
positive, a qualitative microscopic determination, including white blood cells high 
power field (WBCs/HPF) and red blood cells high power field (RBCs/HPF) will be 
performed.
Pregnancy 
Test
All female patients of childbearing potential will have a serum pregnancy test (hCG) 
performed at Visit 1 (local lab). In addition, these patients will have a urine 
pregnancy test conducted in the local laboratory at Visits 2, 5, 7, 11, 13, 15, 16 and 
17.  If any of these tests are positive at Visits 1 and 2, the patient should not be 
enrolled in the trial. If a patient should become pregnant during the trial, the patient 
may remain in the trial for follow-up visits but must discontinue study drug.  
8.4.2
Electrocardiogram (ECG)
A standard 12 lead ECG will be performed at Visit 1.  Interpretation of the tracing must be 
made by a qualified physician and documented on the ECG section of the CRF.  Each ECG 
tracing should be labeled with the study, subject number and date and kept in the source 
documents at the study site.  
Clinically significant abnormalities must be recorded on the CRF as either medical history 
and/or adverse events as appropriate.
8.4.3
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have a serum pregnancy test 
(hCG) performed at Visit 1 (local lab).  In addition, these patients will have a urine pregnancy 
test conducted in the local laboratory at Visits 2, 5, 7, 11, 13, 15, 16 and 17.  .  If any of these 
tests are positive at Visits 1 and 2, the patient should not be enrolled in the trial. If a patient 
should become pregnant during the trial, the patient may remain in the trial for follow-up visits 
but must discontinue study drug. 
8.4.4
Appropriateness of safety measurements
The safety assessments selected are standard for the evaluation of patients with heart failure.


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8.5
Additional assessments
Not applicable.
 
 
 
 
 
 
 
 
 
  
 
 
9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a patient occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the patient or the investigator.
The investigator must discontinue study treatment for a given patient if he/she believes that 
continuation would negatively impact the patient's well-being.
Study treatment must be discontinued under the following circumstances:
!
Patient/guardian decision
!
Pregnancy
!
Use of prohibited treatment as per recommendations in the prohibited treatment section
!
Any situation in which study participation might result in a safety risk to the patient
!
Following emergency unblinding
!
Any severe suspected drug related AE at the investigator’s discretion
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
Suspected occurrence of angioedema. A patient with any signs or symptoms of clinically 
significant angioedema should be thoroughly evaluated by the investigator to determine if 
it constitutes a reason for discontinuation of study medication.

Depending on the serum potassium, blood pressure, or eGFR, patient may need to have their 
study drug dose or the dose of another concomitant medication reduced or discontinued; or, 
if appropriate, have potentially contributing agents adjusted.   Refer to appendices for 
treatment guidelines for hyperkalemia, hypotension or renal dysfunction, respectively.
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the patient’s premature discontinuation of study treatment 
and record this information.
Patients who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see withdraw of informed consent section,). Where possible, they should return 
for the assessments indicated in the assessment schedule. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be made 
to contact the patient/pre-designated contact as specified in the lost to follow-up section. This 
contact should preferably be done according to the study visit schedule.
If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient. This telephone 
contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

new / concomitant treatments

adverse events/Serious Adverse Events
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section.
9.1.2
Withdrawal of informed consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
Every effort should be made to encourage trial continuation to collect information regarding the 
secondary clinical endpoints (CV Death, HF Hospitalization, and Urgent HF Visits) during the 
longer term follow-up (Amendment 1 and subsequent versions).


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In the situation the patient still wants to withdraw, the investigator should make a reasonable 
effort (e.g. telephone, e-mail, letter) to understand the primary reason for the patient’s decision 
to withdraw his/her consent and record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a patient’s samples until the time of withdrawal) according to applicable 
law.
For US: All biological samples not yet analyzed at the time of withdrawal may still be used for 
further testing/analysis in accordance with the terms of this protocol and of the informed consent 
form.
9.1.3
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the patient, e.g. dates of telephone 
calls, registered letters, etc. A patient should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time. 
Reasons for early termination can include:

Unexpected, significant, or unacceptable safety risk to patients enrolled in the study

Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 

Discontinuation of study drug development
In taking the decision to terminate, Novartis will always consider patient welfare and safety. 
Should early termination be necessary, patients must be seen as soon as possible and treated as 
a prematurely withdrawn patient. The investigator may be informed of additional procedures to 
be followed in order to ensure that adequate consideration is given to the protection of the 
patient’s interests. The investigator or sponsor depending on local regulation will be responsible 
for informing IRBs/IECs of the early termination of the trial.


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9.2
Study completion and post-study treatment
At the study completion/end of study visit, patients will be asked to return all remaining study 
drug.  The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. When the patient
has completed all scheduled study assessments, the investigator must call the IRT to record the 
patient completion in the IRT.
Study completion is defined as when the last patient finishes their Study Completion visit and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision (e.g. Each patient will be required to complete the study in its entirety and 
thereafter no further study treatment will be made available to them).
The PARAGON-HF Post Trial Access Program (PTA) was stopped after the results of 
PARAGON-HF became known. The primary endpoint was not met; therefore this met the pre-
specified stopping rule for the program. In view of the discontinuation of the PTA program for 
PARAGON-HF, the company, after careful deliberation, decided to close the PTA for all 
Entresto HFpEF trials, including PARAGLIDE-HF.  This means that the PTA for 
PARAGLIDE-HF, as documented in the Original Protocol Version 00, will no longer be offered 
to patients enrolled in PARAGLIDE-HF.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation patient after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual patient and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the patient during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2):


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1. The severity grade:
Mild: usually transient in nature and generally not interfering with normal activities
Moderate: sufficiently discomforting to interfere with normal activities
Severe: prevents normal activities
2. its relationship to the study treatment.  If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single patient
3. its duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not 
resolved must be reported
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. action taken regarding with study treatment
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose Reduced/increased

Drug interrupted/withdrawn
6. its outcome (i.e. recovery status or whether it was fatal)
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the patient.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator’s Brochure (IB).
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant


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
they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
the underlying disease. Alert ranges for laboratory and other test abnormalities are included in 
Appendix 1.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the patient was at 
risk of death at the time of the reaction; it does not refer to a reaction that hypothetically 
might have caused death if it were more severe (please refer to the ICH-E2D 
Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse (please refer to the ICH-
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All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.
10.1.3
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis safety within 24 hours of learning of its occurrence. Detailed instructions regarding 
the submission process and requirements are to be found in the investigator folder provided to 
each site.
SAEs occurring after the patient has provided informed consent until the time the patient is 
deemed a Screen Failure must be reported to Novartis.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 30 day period after the last study visit should only be reported 
to Novartis Safety if the investigator suspects a causal relationship to study treatment.
10.1.4
Pregnancy reporting
Pregnancies
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.


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Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment and
any pregnancy outcome. Any SAE experienced during pregnancy must be reported.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Study 
Treatment eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.
10.2
Additional Safety Monitoring
10.2.1
Reporting angioedema-like events
It is important that the investigator pays special attention to any swelling or edema that may 
resemble angioedema or angioedema-like events that may be reported by patients, including 
during pandemic-related virtual visits when video allows assessment (video is the preferred 
method for virtual visits). If such an event occurs, the investigator will complete a Questionnaire 
for an Angioedema-like Event form (provided by Novartis) to summarize the event, its 
treatment, and its ultimate outcome and communicate this report to Novartis as soon as possible. 
Occasionally, the investigator may be contacted by the Novartis regarding AEs that were 
reported on behalf of patients that may resemble an angioedema-like event. The investigator or 
his/her delegated staff must complete the required report forms and supply the required medical 


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records for such events, regardless of whether the investigator views the event in question as 
angioedema or not.
Submission of an angioedema report is not a substitution for the submission of a SAE report. If 
an angioedema-like event satisfies the definition of a SAE, the investigator must submit a SAE
report in addition to the Questionnaire for an Angioedema-like Event.
10.2.2
Data Monitoring Committee
An external data monitoring committee (DMC) independent of Novartis will be appointed to 
review the incidence of the pre-specified clinical events including major cardiac events, serious 
adverse events, the rate and distribution of adverse events, and relevant laboratory findings on 
an ongoing basis.
The membership of the DMC and the responsibilities of the DMC and Novartis will be defined 
in a separate document entitled ‘Data Monitoring Committee Charter’. The DMC Charter will 
include information about data flow, purpose and timing of DMC meetings, guidance in the 
decision making process, communication strategy, procedures for ensuring confidentiality, 
procedure to address conflicts of interest and statistical monitoring guidelines.
The DMC will review and make recommendations to the sponsor on whether and how to 
continue the protocol.
10.2.3
Steering Committee
The Steering Committee (SC) will be established comprising investigators participating in the 
trial, i.e. not being members of the DMC and Novartis/sponsor representatives from the Clinical 
Trial Team.
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the steering committee will be defined in the ‘Steering Committee Charter’.
10.2.4
Adjudication committees
Endpoint Adjudication Committee: The role of the Endpoint Adjudication Committee (EAC) 
is to ensure that all clinical outcomes are judged uniformly, using standard criteria and processes. 
The EAC will be composed of independent clinical experts to evaluate disease progression and 
harmonize endpoint assessment criteria using data provided by the sponsor.
All deaths, (re-)hospitalizations, and urgent HF visits will be adjudicated.
All personnel involved in the adjudication process will remain blinded to treatment allocation 
throughout the trial. Specific details regarding endpoint definitions can be found in the 
adjudication charter.


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11
Data collection and database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs will be built using fully validated secure web-enabled 
software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not be given 
access to the EDC system until they have been trained. Automatic validation programs check 
for data discrepancies in the eCRFs, allow modification and/or verification of the entered data 
by the investigator staff.
Data not requiring a separate written record will be defined in the protocol and the Assessment 
Schedule (Table 8-1) and can be recorded directly on the CRFs. All other data captured for this 
study will have an external originating source (either written or electronic) with the CRF not 
being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
The investigator/designee is responsible for assuring that the data entered into eCRFs are
complete, accurate, and that entry and updates are performed in a timely manner. The 
Investigator must certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the patient data for archiving at 
the investigational site.
11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) terminology.
Randomization codes and data about all study treatment (s) dispensed to the patient and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
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and statistician. Any changes to the database after that time can only be made after written 
agreement by Novartis management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis and 
UBC representative will review the protocol and data capture requirements (i.e. eCRFs) with 
the investigators and their staff. During the study, Novartis employs several methods of 
ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. The field 
monitor will visit the site to check the completeness of patient records, the accuracy of data 
capture / data entry, the adherence to the protocol and to Good Clinical Practice, the progress 
of enrollment, and to ensure that study treatment is being stored, dispensed, and accounted for 
according to specifications. Key study personnel must be available to assist the field monitor 
during these visits. Continuous remote monitoring of each site’s data may be performed by a 
centralized UBC CRA organization. Additionally, a central analytics organization may analyze 
data & identify risks & trends for site operational parameters, and provide reports to Novartis 
clinical teams to assist with trial oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient’s file. The investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed.
12
Data analysis and statistical methods
It is planned that the data from all centers that participate in this study will be combined, so 
that an adequate number of patients will be available for analysis. Unless otherwise specified, 
all statistical tests will be conducted against a two-sided alternative hypothesis, employing a 
significance level of 0.05. 
The final analysis will be conducted on all participant data at the end of the study. 
Details on data analysis will be included in the Statistical Analysis Plan (SAP) and will be 
finalized before the database lock.
Any data analysis carried out independently by the investigator should be submitted to Novartis 
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12.1
Analysis sets
The Randomized Analysis Set (RAN) consists of all randomized participants.
The Full Analysis Set (FAS) comprises all participants to whom study treatment has been 
assigned by randomization. According to the intent-to-treat principle, participants will be 
included for analysis according to the treatment they have been assigned to during the 
randomization procedure.
The Safety Set (SAF) includes all participants who received at least one dose of study treatment. 
Participants will be included for analysis according to the study treatment they received, where 
treatment received is defined as the randomized treatment if the participant took at least one 
dose of that treatment or the first study treatment received if the randomized treatment was 
never received.
The patients in this trial are divided in two groups, (1) Those who are randomized under 
Protocol Version 00 (Original Protocol patients) and (2) Those who are randomized after site 
execution of Protocol Version 01 (Amendment 1 and subsequent amendment patients).  FAS 
includes patients from both groups. See Section 3 for details.
12.2
Patient demographics and other baseline characteristics
Baseline value is the last non-missing assessment before the first administration of study drug, 
unless specified otherwise. Baseline is labeled as Week 0. Summary statistics will be provided 
by treatment group and baseline classification of in/out-of-hospital randomization.  
Continuous variables will be summarized using n, mean, standard deviation (SD), median, 
minimum, and maximum. Categorical variables will be summarized using frequency and 
percentage. Additionally, summary statistics will be provided by treatment group and in/out-
of-hospital randomization group. Geometric means will be used to summarize the NT-proBNP 
. 
Relevant medical history and current medical conditions at Baseline will be summarized by 
system organ class and preferred term, by treatment group.
The FAS will be the population for the above analyses. Summary statistics will be provided for 
Original Protocol patients, Amendment 1 patients, and all patients in FAS.
12.3
Treatments
The overall duration of treatment by study drug will be summarized by treatment group and 
in/out-of-hospital randomization category using mean, standard deviation, median, minimum, 
and maximum. Additionally, the number and percentage of participants will be summarized by 
treatment group and in/out-of-hospital randomization for duration category. Concomitant 
medications and significant non-drug therapies, prior to and after the randomization, will be 
summarized by therapeutic class, preferred term, treatment group, and in/out-of-hospital 
randomization category. The number and percentage of participants on different HFpEF 
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background medications (e.g., aldosterone antagonists, β-blockers, diuretics, digoxin) will be 
tabulated by treatment and in/out-of-hospital randomization category at Baseline and post 
randomization period. The SAF population will be used for the above analyses. 
12.4
Analysis of the primary endpoint
There is one primary endpoint.  
Definition of primary endpoint
The primary endpoint is the time averaged proportional change in NT-proBNP from Baseline 
to Weeks 4 and 8.
12.4.1
Analysis of the primary endpoint
The primary null hypothesis (H10) to be tested is that the ratio of the geometric means of NT-
proBNP (average of Weeks 4 and 8) divided by baseline for the sacubitril/valsartan and 
valsartan groups are equal versus the alternative hypothesis (H1a) that the ratio of the geometric 
means of NT-proBNP are not equal.
First, the arithmetic mean of NT-proBNP at Weeks 4 and 8 will be calculated, then the change 
from baseline in log-transformed NT-proBNP will be calculated as follows: ln (mean post dose 
value) – ln (baseline value). The natural logarithm will be used in all these calculations. This 
log-transformed value will be used as the dependent variable in the analysis of covariance 
(ANCOVA) model described below. This dependent variable is called, the time-averaged 
proportional change from baseline in logarithmic scale. The dependent variable will be analyzed 
using an ANCOVA model with treatment, in-/out-of-hospital randomization, gender, and 
baseline LVEF (<= 57%, > 57%) as fixed effect factors, age and the logarithmic baseline NT-
proBNP as covariates.
The treatment effect in terms of ratios of geometric means is estimated based on the least-
squared means (LS-means) from the ANCOVA model and the corresponding 95% two-sided 
confidence interval will be provided.  Geometric means will be calculated by exponentially 
back transforming the LS-means based on the fitted ANCOVA model.
The FAS will be used in the main analysis of the primary endpoint. 
12.4.2
Handling of missing values/censoring/discontinuations
The analysis will be performed based on all available data in the FAS. Missing values caused 
due to unevaluable samples or early discontinuations will not be imputed. If either the baseline 
value or both Weeks 4 and 8 are missing, then the patient will not be included in the analysis.
12.4.3
Sensitivity and Supplementary Analyses
Sensitivity analysis
Robustness of the primary efficacy results will be explored by developing an algorithm to 
impute missing values in the primary analysis, except the baseline value. Baseline value will 


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not be imputed. When applicable, multiple imputations technique will be considered for 
replacing the missing values. Data will be analyzed using the same ANCOVA model used in 
the primary analysis.
A second sensitivity analysis will be performed based on the Amendment 1 patients only.  The 
analysis will be performed like the main analysis of the primary endpoint.  
Additional sensitivity analysis will be performed by excluding assessments after COVID-19 
positive status (during the study) at the patient level.
Supplemental analysis
In this supplementary analysis the variable to be analyzed is: Achieving a pre-specified percent 
change from baseline in NT-proBNP (binary). Three binary outcome variables will be created 
for patients achieving a 25%, 50% and 75% decline in NT-proBNP (0-no, 1-yes). The dataset 
used in the primary analysis will be used to define these categorical variables. Also, like the 
primary analysis, the missing values will not be imputed for this analysis. Logistic regression 
model will be fitted. The odds ratio, confidence interval and p-value will be provided for each 
analysis. The dependent variable will be achieving a target decline in NT-proBNP and the 
predictor of response will be treatment group and in-/out-of-hospital randomization category.
In addition, analysis of the primary endpoint will be performed with patients randomized after 
Amendment 4 (yes, no) as an additional factor to the model mentioned in Section 12.4.1.
Subgroup analyses
A set of pre-specified subgroups will be defined in the Statistical Analysis Plan to assess 
consistency of the primary efficacy result and effect of these subgroups on NT-proBNP.
12.5
Analysis of Secondary Endpoints
12.5.1
Secondary endpoints 
1. The composite hierarchical outcome consisting of: a) time to CV death, b) number and 
times of HF hospitalizations during follow-up, c) number and times of urgent HF visits 
during follow-up, and d) time averaged proportional change in NT-proBNP (from baseline 
to Weeks 4 and 8)
2. The cumulative number of recurrent composite events overtime, i.e., the total number of 
composite events of HF hospitalizations, urgent HF visits, and CV death. 
3. Incidences of a composite endpoint of worsening renal function defined as: 

renal death

reaching end-stage renal disease (ESRD)

≥ 50% decline in estimated glomerular filtration rate (eGFR) relative to baseline
4. Proportional change in NT-proBNP from Baseline to Week 8 
5. Proportional change in hs-Troponin (high sensitivity) from baseline to Weeks 4 and 8 
6. Dosing levels and discontinuations
7. Incidence of adverse events of special interest during treatment


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
Incidence of symptomatic hypotension 

Incidence of hyperkalemia (potassium >5.5 mEq/L)  

Incidence of angioedema 

Incidence of worsening renal function, defined as an increase in serum creatinine of 
≥0.5mg/dl and worsening of the eGFR by at least 25% 
Analysis of secondary endpoint 1
This secondary endpoint will be analyzed estimating the unmatched win ratio by comparing 
every participant in the sacubitril/valsartan arm to every participant in the valsartan arm to 
determine a winner (unmatched pairing method). The estimated win ratio (the total number of 
wins in the sacubitril/valsartan arm divided by the total number of wins in the valsartan arm) 
will be calculated. The corresponding null and alternative hypotheses are:
H20: Win ratio is equal to 1, versus 
H2a: Win ratio is not equal to 1. 
A win ratio greater than 1 will be in favor of sacubitril/valsartan arm. This test will be performed 
only if the primary null hypothesis (H10) is rejected. The testing of hypothesis H20 and 
calculation of the corresponding two-sided 95% confidence intervals will be performed. 
A component will only be used as tie-breaker in the pairwise comparison between two patients 
if the comparison of components with a higher priority resulted in a tie. For component a) the 
patient with the later time to death in the common follow-up period is the winner. For 
component b) the patient with the smaller number of HF hospitalizations in the common follow-
up period is the winner. If the number of HF hospitalizations in the common follow-up period 
is tied, the patient with the later time of the last HF hospitalization in the common follow-up 
period is the winner. For component c) the same algorithm is applied as for component b). For 
component d), the patient with the larger decrease or smaller increase in the proportional change 
is considered a winner; if the ratio of the proportional changes from two patients is between 
0.75 and 1/0.75, then the pairwise comparison of the change in NT-proBNP is considered tied.
The analysis will be performed using the unmatched pair win ratio approach (Pocock et al 2012).  
Contributions of each component of the composite endpoint to total number of winners used in 
estimation of the win ratio will be reported. 
Handling of missing values/censoring/discontinuations
Time to CV death
The time from randomization to CV death will be considered as censored for analysis for 
participants who have not experienced a CV death and for whom at least one of the following 
applies at or prior to the analysis time point:

withdrawal of informed consent

loss to follow up

death from non-CV causes


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The censoring date for those participants without CV death prior to the analysis time point will 
be whichever occurs first of the following:

date of withdrawal of informed consent

date of last visit (End of Study visit)

date of death from non-CV causes
NT-proBNP measurement at Weeks 4 and 8
Cardiovascular death, HF hospitalization, and urgent HF visit are at a higher hierarchy level 
than NT-proBNP in the composite endpoint for win ratio analysis. Therefore, missing values 
due to CV death or after HF hospitalization or urgent HF visit do not affect the analysis. Missing 
NT-proBNP measurements at Weeks 4 and 8 due to other reasons (e.g., non-CV death) are 
expected to be infrequent; they may result in more ties with minimal impact on the power. No 
imputation will be done for missing NT-proBNP measurement at Weeks 4 and 8. 
Analysis of secondary endpoint 2
The cumulative number of composite events, i.e., the total number of composite events of CV 
death, recurrent HF hospitalizations, and recurrent urgent HF visits for a patient over time will 
be calculated. The time to these recurrent events will be analyzed using the semi-parametric 
proportional rates model (abbreviated as LWYY model) (Lin et al 2000). The hypotheses of 
interest are:
H30: Rate ratio of sacubitril/valsartan arm over valsartan arm equal to 1, versus 
H3a: Rate ratio of sacubitril/valsartan arm over valsartan arm not equal 1. 
A rate ratio < 1 indicates an effect in favor of sacubitril/valsartan arm. 
The FAS will be used in the main analysis of the second key secondary endpoint. 
The hypothesis (H30) will be tested and 95% confidence interval will be provided. The rate ratio 
will be estimated from the above proportional rates model through maximization of a partial 
likelihood score function and the confidence intervals will be based on the robust estimate of 
the standard errors. The number and percentage of CV events by event type will be summarized.  
The CV death will not be considered as a censoring variable, but as a composite endpoint event 
and a conditional factor in this analysis. Time to non-CV death will be considered as a censoring 
variable. Any censoring due to non-CV death is assumed to be non-dependent in the analysis. 
Analysis of secondary endpoint 3
The total number of composite events will be analyzed using a negative binomial regression 
model with the count data as the dependent variable.  Treatment group and in/out-of-hospital 
randomization as a fixed-effect factors and log (follow-up duration) as the off-set.  The model 
will be used to estimate event rates and their 95% confidence intervals by treatment group.
The time to the first composite event will be analyzed using Cox’s proportional hazard model 
with factors treatment and in/out-of-hospital randomization.  Hazard ratio for treatment and its 
95% confidence interval will be reported. 


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Analysis of secondary endpoint 4
The proportional change in NT-proBNP from Baseline to Week 8 will be analyzed using an 
ANCOVA model similar to that of the primary efficacy analysis.
Analysis of secondary endpoint 5
The proportional change in hs-Troponin (high sensitivity) from baseline to Week 4 will be 
analyzed using an ANCOVA model similar to that of the primary efficacy analysis. Log-
transformed hs-Troponin will be used for analysis.  The analysis will be repeated for Week 8.
Analysis of secondary endpoint 6
The dosing level will be summarized by treatment group and in-/out-of-hospital randomization 
status. Incidence of discontinuations (all causes) will be summarized by treatment group and 
in-/out-of-hospital randomization status. 
Analysis of secondary endpoint 7
Incidence of event will be analyzed using logistic regression model with treatment and in/out-
of-hospital randomization as fixed factors. The model will be used to estimate the odds ratio for 
treatment and its 95% confidence interval. 
The number (and proportion) of patients with adverse events of special interest will be 
summarized by treatment, primary system organ class and preferred term. All these secondary 
endpoints will be analyzed using FAS and nominal p-values will be reported.  There will be no 
adjustment for multiplicity.
12.5.2
Safety endpoints
For all safety analyses, the safety set (SAF) will be used.  All listings and tables will be 
presented by treatment group and in/out-of-hospital randomization category. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of Baseline data, will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate listing for death including on-treatment and post-
treatment deaths will be provided. In particular, summary tables for AEs will summarize only 
on-treatment events, with a start date during the on-treatment period (treatment-emergent 
AEs). 
The on-treatment period lasts from the date of first administration of study treatment to the 
last study visit.
Adverse events
All information obtained on adverse events will be displayed by treatment group and patient. 
The number (and percentage) of patients with treatment emergent adverse events (events 
started after the first dose of study medication, or events present prior to start of double-
masked treatment but increased in severity based on preferred term) will be summarized in the 
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!
By treatment, primary system organ class and preferred term.
!
By treatment, primary system organ class, preferred term and maximum severity.
!
By treatment, pre-defined topic of interest, primary system organ class and preferred 
term. 
Separate summaries will be provided for study medication related adverse events, serious 
adverse events, and other significant adverse events leading to discontinuation. 
A patient with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.
Vital signs
All vital signs data will be listed by treatment group, in/out-of-hospital randomization, patient, 
and visit/time and if ranges are available, abnormalities will be flagged. Descriptive statistics 
will be provided by treatment, and visit/time and will be presented graphically.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, in/out-of-hospital randomization, patient, 
and visit/time and if normal ranges are available abnormalities will be flagged. Summary 
statistics will be provided by treatment, in/out-of-hospital randomization, and visit/time. Shift 
tables using the low/normal/high/ classification will be used to compare baseline to the worst 
on-treatment value.
12.5.3
Biomarkers
See Sections 12.4 and 12.5 for a description of the methods used to analyze the biomarkers.  
 
 
 
 
 
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12.7
Interim analysis
There is no planned interim analysis for efficacy in the study. 
An independent Data Monitoring Committee (DMC) will be responsible for performing interim 
safety assessment using independent statistician and programmer who will not be involved in 
the trial conduct. The DMC charter will contain the committee’s responsibilities regarding the 
interim safety assessment. Details of this safety assessment will be included in the Statistical 
Analysis Plan.
Interim safety assessments are planned to be performed and results will be provided to DMC 
for their review and recommendation.  The number and/or timing of these safety assessments 
will be mentioned in the Data Monitoring Committee Charter. No adjustment of the level of 
significance will be made for these interim safety assessments.
12.8
Sample size and Power
The target sample size for this study is approximately 450 total patients (including original 
protocol and all Amendment patients), randomized in the two treatment groups in 1:1 ratio. The 
maximum planned duration of follow-up after randomization of these patients is approximately 
20 months and the planned duration of follow-up for the last patient in the group is 2 months. 
The power of the study is determined based on these 450 patients for the primary endpoint. 
Sample size for the primary endpoint
This sample size of 450 patients would have 85% power to detect a 23% reduction in the 
geometric mean of the proportional change from baseline to an average of Weeks 4 and 8 in 
NT-proBNP for the sacubitril/valsartan treatment group. This 23% reduction in geometric mean 
is equivalent to -0.2614 in natural log scale (=ln(0.77)). The power is estimated assuming a two-
sided significance level of 0.05, a common standard deviation of 0.85 for change in log 
transformed NT-proBNP and a 15% rate of missingness in NT-proBNP at both Week4 and 
Week8. nQuery Version 8.4.1.0 (2019) software package is used in calculating the power of the 
test.
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
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13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, patient recruitment procedures (e.g., 
advertisements) and any other written information to be provided to patients (e.g., patient 
materials and thank you letters). Prior to study start, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance with 
these documents and all of the instructions and procedures found in this protocol and to give 
access to all relevant data and records to Novartis monitors, auditors, Novartis Quality 
Assurance representatives, designated agents of Novartis, IRBs/IECs, and regulatory authorities 
as required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform Novartis immediately that this request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.) .
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 


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observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.
14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for patient safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
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15
References
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McCullagh P, Nelder JA. (1989) Generalized Linear Models, 2nd ed. London: Chapman and
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McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and 
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McMurray JV, Packer M, Desai AS, et al.  Angiotensin-neprilysin inhibition versus enalapril 
in heart failure. N Engl J Med 2014;371:993-1004.
Packer M, McMurray JV, Desai AS, et al.  Angiotensin receptor neprilysin inhibition 
compared with enalapril on the risk of clinical progression in surviving patients with heart 
failure. Circulation 2015;131:54-61.
Pocock, S.J., Ariti, C.A., Collier, T.J. and Wang, D., 2012. The win ratio: a new approach to 
the analysis of composite endpoints in clinical trials based on clinical priorities. European 
Heart Journal, 33(2), pp.176-182.
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Amended Protocol Version No. 04 (clean)                                                 Protocol No. CLCZ696DUS01
Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer 
M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, van Veldhuisen DJ, Zannad F, Zile MR, 
Desai AS, Claggett B, Jhund PS, Boytsov SA, Comin-Colet J, Cleland J, Düngen HD, 
Goncalvesova E, Katova T, Kerr Saraiva JF, Lelonek M, Merkely B, Senni M, Shah SJ, Zhou 
J, Rizkala AR, Gong J, Shi VC, Lefkowitz MP.  Angiotensin-Neprilysin Inhibition in Heart 
Failure with Preserved Ejection Fraction. N Engl J Med. 2019 Oct 24;381(17):1609-1620
Solomon SD, Rizkala AR, Gong J, et al.  Angiotensin receptor neprilysin inhibition in heart 
failure with preserved ejection fraction – rationale and design of the PARAGON-HF trial.  
JACC Heart Failure 2017;5:471-82.
Solomon SD, Rizkala AR, Lefkowitz MP, et al.  Baseline characteristics of patients with heart 
failure and preserved ejection fraction in the PARAGON-HF trial.  Circ Heart Fail 
2018:11:e004962  DOI-10.1161.
Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in 
heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled 
trial. Lancet 2012;380:1387-1395.
Velazquez EJ, Morrow DA, DeVore AD, Duffy CI, Ambrosy AP, McCague K, Rocha R, 
Braunwald E. Angiotensin-neprilysin inhibition in acute decompensated heart failure. NEJM 
2018 DOI:10.1056/NEJMoa1812851.
Wachter R et al. Initiation of sacubitril/valsartan in hospitalized patients with heart failure 
with reduced ejection fraction after hemodynamic stabilization: Primary results of the 
TRANSITION study. Data presented at: ESC 2018, Aug 25-29; Munich, Germany.
Yancy CW, Jessup M, Bozkurt B, et al.  2013 ACCF/AHA Guidelines for the management of 
heart failure.  Report of the American College of Cardiology Foundation/American Heart 
Association Task Force on Patient Guidelines. Circulation 2013;128:e240-e327.


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Amended Protocol Version No. 04 (clean)                                                 Protocol No. CLCZ696DUS01
16
Appendices
16.1
Appendix 1: Clinically notable laboratory values and vital signs
Clinically notable laboratory abnormalities for selected tests based on a percent change from 
baseline:
Hematology
RBC count
>50% increase, >20% decrease
Hemoglobin
>50% increase, >20% decrease
Hematocrit
>50% increase, >20% decrease
WBC count
>50% increase, >50% decrease
Platelet count
>75% increase, >50% decrease
Blood Chemistry
ALT (SGPT)
>150% increase
AST (SGOT)
>150% increase
BUN
>50% increase
Creatinine
>50% increase
Total bilirubin
>100% increase
CPK
>300% increase
Alkaline phosphatase >100% increase
Potassium
>20% increase, >20% decrease
Chloride
>10% increase, >10% decrease
Calcium
>10% increase, >10% decrease
Uric acid
>50% increase


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Amended Protocol Version No. 04 (clean)                                                 Protocol No. CLCZ696DUS01
16.2
Appendix 2: Treatment guidelines for hyperkalemia (serum 
potassium greater than or equal to 5.5 mEq/L)
General principles
Elevation of potassium levels above the predefined values should be repeated and confirmed 
before any action is taken.
Any patient who experiences a potassium level ≥ 5.5 mEq/L confirmed by repeated testing after 
randomization requires regular, repeated checks of potassium concentration (beyond that 
prescribed in the protocol) until it is clear that the potassium concentration is stable and not 
rising into the range of concern (≥ 5.5 mEq/L). 
Patients with elevated potassium value will be managed according to the corrective actions 
outlined below and the investigator’s clinical judgement. Hyperkalemia should be followed 
until resolution.
Recommended corrective action for management of hyperkalemia
Serum potassium > 5.3 and less than or equal to 5.5 mEq/L

Confirm potassium concentration in a non-hemolyzed sample

Reinforce low potassium diet and restriction of food/drinks with high potassium content 
(e.g. orange juice, melon, bananas, low-salt substitutes etc.) 

Review medical regimen (including dietary supplements and over-the-counter 
medications) for agents known to cause hyperkalemia. Consider reduction in dose or 
discontinuation of these agents:

Aldosterone antagonists (if they are believed to be the most likely cause of hyperkalemia)

Potassium-sparing diuretics (e.g. amiloride and triamterene) including in combination 
products with thiazide or loop diuretics 

Potassium supplements, e.g., potassium chloride

Salt substitutes 

Non-steroidal anti-inflammatory drugs (NSAIDs)

Cyclo-oxygenase-2 (COX-2) inhibitors

Trimethoprim and trimethoprim-containing combination products, such as Bactrim® and 
Septra® (trimethoprim/sulfamethoxazole fixed combination)

Herbal Supplements:

For example, Noni juice, alfalfa (Medicago sativa), dandelion (Taraxacum officinale), 
horsetail (Equisetum arvense), nettle (Urtica dioica), milkweed, lily of the valley, Siberian 
ginseng, hawthorn berries

Repeat serum potassium measurement within 3 to 5 days

If serum potassium remains > 5.3 and ≤ 5.5 mEq/L, regularly monitor serum potassium
levels to ensure stability (suggested once monthly)


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Amended Protocol Version No. 04 (clean)                                                 Protocol No. CLCZ696DUS01

Consider down-titration of study medication, according to investigator’s medical 
judgment.
Serum potassium > 5.5 and < 6.0 mEq/L

Confirm potassium concentration in a non-hemolyzed sample 

Consider down-titration or temporarily discontinue study drug according to investigator 
medical judgment. 

Apply all measures outlined for serum potassium > 5.3 and ≤ 5.5 mEq/L

Repeat serum potassium measurement after 2-3 days

If serum potassium < 5.5 mEq/L, consider resumption of study drug at lower dose with 
repeat potassium within 5 days
Serum potassium greater than or equal to 6.0 mEq/L

Immediately discontinue study drug

Confirm potassium concentration in a non-hemolyzed sample

Urgently evaluate patient and treat hyperkalemia as clinically indicated 

Apply all measures outlined for serum potassium > 5.3 and < 6.0 mEq/L

If serum potassium < 5.5 mEq/L, consider resumption of study drug at lower dose with 
repeat potassium within 5 days


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Amended Protocol Version No. 04 (clean)                                                 Protocol No. CLCZ696DUS01
16.3
Appendix 3: Guidelines for the management of blood pressure
Guidelines
1. Investigator should monitor blood pressure closely 
2. If symptomatic hypotension occurs:
a.
Correct any treatable cause, e.g. hypovolemia
b. If hypotension persists, any antihypertensive drug and non-disease-modifying 
drugs, such as diuretics, CCBs, nitrates, and α-blockers, should be down-titrated or 
stopped first before down-titration of the study drug is considered
3. If hypotension persists, the study drug should be down-titrated or even temporarily 
withdrawn. The dose re-challenge and medication adjustment guidelines described in 
Section 6.4.1 should be adhered to as much as possible.
16.4
Appendix 4: Guidelines for the management of renal dysfunction
General principles:
Glomerular filtration rate in HF patients depends on intrinsic renal function and on a balance 
between afferent and efferent glomerular arterial tonicity. This tonicity is partly regulated by a 
stimulation of angiotensin II and could be affected by either study medication. Moreover, renal 
dysfunction may develop or may deteriorate in some patients after study drug administration. 
These recommendations have been developed to guide the investigators in managing patients 
with renal dysfunction after randomization.
Two types of response to serum creatinine increase are described:
Surveillance situation 
If, at any time after randomization, eGFR decreases by ≥ 25% from baseline (or if serum 
creatinine concentration increase to 2.5 mg/dL [221 µmol/L]), the investigator will check for 
potentially reversible causes of renal dysfunction such as:

Non-steroidal anti-inflammatory drug intake, antibiotics, or other treatments known to 
affect creatininemia

Volume decrease, including that resulting from excessive dosing of diuretics

Urinary infection

Urinary tract obstruction

Study medication
Action situation 
If a patient eGFR decreases by ≥ 40% from baseline (or if serum creatinine concentration rises 
above 3 mg/dL (265 µmol/L), the investigator will check for potentially reversible causes of 
renal dysfunction (see above).


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Amended Protocol Version No. 04 (clean)                                                 Protocol No. CLCZ696DUS01
If the investigator judges that study medication has to be stopped, he/she will have to contact 
the Novartis medical monitor or his/her designee. Thereafter, serum creatinine assessments will 
have to be repeated at least each week until levels return to acceptable values. If study 
medication was stopped, every effort will be done to restart it again, according to clinical 
conditions.


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Amended Protocol Version No. 04 (clean)
Protocol No. CLCZ696DUS01
16.5
Appendix 5: Expanded Assessment Schedule
Period
Screening
Double-Blind Treatment 
(84 week)
Visit Name 
Screening 
Randomizati
on/Baseline 
Study 
Compl
etion/
End of 
Study
Visit Number
Visit 1
Visit 2
Visit 
3
Visit 
48
Visit 5
Visit 
67
Visit 
7
Visit 
87
Visit 
98
Visit 
108
Visit 
11
Visit 
128
Visit 
13
Visit 
148
Visit 
15
Visit 
16
Visit 
17
Week
(Day)
[Day -30 
to -1.5 
(36hours)]
0 
(Day 1)
1 
(Day 
7)
2 
(Day 
14)
4 
(Day 
28)
6
(Day 
42)
8
(Day 
56)
10
(Day 
70)
12
(Day 
84)
16
(Day 
112)
24
(Day 
168)
32
(Day 
224)
40
(Day 
280)
48
(Day 
336)
56
(Day 
392)
68 
(Day 
476) 
84
(Day 
588)
Information and 
informed consent
S
Inclusion/exclusion 
criteria
X
X
Demography / 
Medical history
X
Heart failure and 
CV disease history
X
ECG
X
Physical Exam
S
S
S
S
S
S
S
S
S
S
S
S
Height
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Waist/hip 
circumference
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HF signs and 
symptoms and 
NYHA classification
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Amended Protocol Version No. 04 (clean)
Protocol No. CLCZ696DUS01
Period
Screening
Double-Blind Treatment 
(84 week)
Visit Name 
Screening 
Randomizati
on/Baseline 
Study 
Compl
etion/
End of 
Study
Visit Number
Visit 1
Visit 2
Visit 
3
Visit 
48
Visit 5
Visit 
67
Visit 
7
Visit 
87
Visit 
98
Visit 
108
Visit 
11
Visit 
128
Visit 
13
Visit 
148
Visit 
15
Visit 
16
Visit 
17
Week
(Day)
[Day -30 
to -1.5 
(36hours)]
0 
(Day 1)
1 
(Day 
7)
2 
(Day 
14)
4 
(Day 
28)
6
(Day 
42)
8
(Day 
56)
10
(Day 
70)
12
(Day 
84)
16
(Day 
112)
24
(Day 
168)
32
(Day 
224)
40
(Day 
280)
48
(Day 
336)
56
(Day 
392)
68 
(Day 
476) 
84
(Day 
588)
Heart failure and 
CV medications
X
X4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry labs
X
X
X
X
X
X
X3
X
X
X
X
X
X
Hematology labs
X
X
X
X
X
X
X
X
X
Hemoglobin A1C
X
X
eGFR
X
X
X
X
X
X
X3
X
X
X
X
X
X
Urinalysis
X
Pregnancy Test2
X
X
X
X
X
X
X
X
X
X
X
X
X
IRT
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
Plasma NT-
proBNP or BNP 
X5
X
X
X
X
hs-Troponin
X
X
X
Drug accountability
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense study 
treatment 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PPD


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Amended Protocol Version No. 04 (clean)
Protocol No. CLCZ696DUS01
Period
Screening
Double-Blind Treatment 
(84 week)
Visit Name 
Screening 
Randomizati
on/Baseline 
Study 
Compl
etion/
End of 
Study
Visit Number
Visit 1
Visit 2
Visit 
3
Visit 
48
Visit 5
Visit 
67
Visit 
7
Visit 
87
Visit 
98
Visit 
108
Visit 
11
Visit 
128
Visit 
13
Visit 
148
Visit 
15
Visit 
16
Visit 
17
Week
(Day)
[Day -30 
to -1.5 
(36hours)]
0 
(Day 1)
1 
(Day 
7)
2 
(Day 
14)
4 
(Day 
28)
6
(Day 
42)
8
(Day 
56)
10
(Day 
70)
12
(Day 
84)
16
(Day 
112)
24
(Day 
168)
32
(Day 
224)
40
(Day 
280)
48
(Day 
336)
56
(Day 
392)
68 
(Day 
476) 
84
(Day 
588)
Adverse events / 
Serious Adverse 
events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Angioedema 
assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Thank You letter
X
X
Study completion –
randomized 
treatment
X
Post study 
completion follow 
up
S6
PPD


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Amended Protocol Version No. 04 (clean)
Protocol No. CLCZ696DUS01
Period
Screening
Double-Blind Treatment 
(84 week)
Visit Name 
Screening 
Randomizati
on/Baseline 
Study 
Compl
etion/
End of 
Study
Visit Number
Visit 1
Visit 2
Visit 
3
Visit 
48
Visit 5
Visit 
67
Visit 
7
Visit 
87
Visit 
98
Visit 
108
Visit 
11
Visit 
128
Visit 
13
Visit 
148
Visit 
15
Visit 
16
Visit 
17
Week
(Day)
[Day -30 
to -1.5 
(36hours)]
0 
(Day 1)
1 
(Day 
7)
2 
(Day 
14)
4 
(Day 
28)
6
(Day 
42)
8
(Day 
56)
10
(Day 
70)
12
(Day 
84)
16
(Day 
112)
24
(Day 
168)
32
(Day 
224)
40
(Day 
280)
48
(Day 
336)
56
(Day 
392)
68 
(Day 
476) 
84
(Day 
588)
X = assessment to be recorded in the clinical database or received electronically from a vendor
S = assessment to be recorded in the source documentation and in the database
 
2 All female patients of childbearing potential will have a serum pregnancy test (hCG) performed at Visit 1 (local lab). A urine pregnancy test will be conducted in the local laboratory for 
remaining visits.
3 Limited chemistry panel. eGFR will be calculated from creatinine concentration.
4 CV medications will be recorded at time of hospital discharge.
5 BNP or NT-proBNP will be assessed at Visit 1 via local laboratory. Only NT-proBNP will be assessed via central laboratory for Visits 2, 3, 5 and 7.
6 Health status phone call 4 weeks after study completion.
7 Visits are applicable to Original Protocol Version 00, but are not applicable for patients following Amended Protocol Version 01 and all subsequent amendments.
8 Visits are applicable to Amended Protocol Version 03, but are not applicable for patients following Amended Protocol Version 04 and all subsequent amendments.
P

SAP_001.pdf: 


Novartis 
 
Page 2 
SAP Amendment 1 
 
CLCZ696DUS01 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
18-
June-
2019 
Prior to 
FPFV 
Creation of 
first version 
NA - First version 
NA 
21-
Feb-
2023 
Prior to 
database 
lock 
Protocol 
Amendment 
4.0 
Amendment 1 
The vast 
majority of 
sections have 
been impacted. 
 
 


Novartis 
 
Page 3 
SAP Amendment 1 
 
CLCZ696DUS01 
 
Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 6 
1 
Introduction ......................................................................................................................... 8 
1.1 
Study design ............................................................................................................ 8 
1.2 
Study objectives and endpoints ............................................................................. 10 
2 
Statistical methods ............................................................................................................. 12 
2.1 
Data analysis general information ......................................................................... 12 
2.1.1 
General definitions ................................................................................ 12 
2.2 
Analysis sets .......................................................................................................... 16 
2.2.1 
Subgroups of interest............................................................................. 16 
2.3 
Subject disposition, demographics and other baseline characteristics .................. 17 
2.3.1 
Subject disposition ................................................................................ 17 
2.3.2 
Subject Protocol deviations ................................................................... 19 
2.3.3 
Qualifying Hospitalization/ED Visit/Out-of-Hospital Urgent HF ........ 19 
2.3.4 
Demographics and other baseline characteristics ................................. 20 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 23 
2.4.1 
Study treatment / compliance ................................................................ 23 
2.4.2 
Prior, concomitant and post therapies ................................................... 24 
2.4.3 
Unscheduled visit mapping ................................................................... 25 
2.4.4 
Multiple assessments within visit windows .......................................... 26 
2.5 
Analysis of the primary objective .......................................................................... 26 
2.5.1 
Primary endpoint ................................................................................... 26 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 26 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 27 
2.5.4 
Sensitivity analyses 1 ............................................................................ 27 
2.5.5 
Sensitivity analyses 2 ............................................................................ 27 
2.5.6 
Sensitivity analyses 3 ............................................................................ 28 
2.5.7 
Sensitivity analyses 4 ............................................................................ 28 
2.5.8 
Supplemental analysis ........................................................................... 28 
2.5.9 
Subgroup analyses ................................................................................. 29 
2.6 
Analysis of secondary objectives .......................................................................... 29 
2.6.1 
Secondary endpoints ............................................................................. 29 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 31 
2.6.3 
Handling of missing values/censoring/discontinuations ....................... 36 
2.7 
Safety analyses....................................................................................................... 36 




Novartis 
 
Page 5 
SAP Amendment 1 
 
CLCZ696DUS01 
 
5.4 
Statistical models ................................................................................................... 53 
5.4.1 
Primary analysis .................................................................................... 53 
5.4.2 
Secondary analysis endpoint 1 .............................................................. 54 
5.4.3 
Secondary analysis endpoint 2 .............................................................. 57 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 58 
5.6 
Study background .................................................................................................. 58 
5.7 
Identification of Urgent Heart Failure Visit (Investigator Reported) .................... 59 
6 
Reference ........................................................................................................................... 60 


Novartis 
 
Page 6 
SAP Amendment 1 
 
CLCZ696DUS01 
 
List of abbreviations 
ACEi 
angiotensin converting enzyme inhibitor   
ADP 
adenosine diphosphate 
AE 
adverse event     
AESI 
adverse event of special interest  
AF 
atrial fibrillation     
ALT 
alanine aminotransferase     
ANCOVA 
analysis of covariance    
ANOVA 
analysis of variance 
ANP 
atrial natriuretic peptide    
ARB 
angiotensin receptor blocker    
AST 
aspartate aminotransferase     
ATC 
Anatomical Therapeutic Chemical    
BMI 
Body mass index    
BNP 
B-type natriuretic peptide    
BUN 
Blood urea nitrogen    
CCB 
Calcium channel blocker    
CCU 
cardiac care unit 
CI 
confidence interval 
CKD 
chronic kidney disease 
CSR 
clinical study report 
CRT 
Cardiac resynchronization therapy    
CV 
cardiovascular 
DBL 
database lock 
DBP 
diastolic blood pressure    
DMC 
Data Monitoring Committee 
DOAC 
Direct-acting oral anticoagulant 
ECG 
Electrocardiogram 
eCRF 
electronic case report form   
ED 
emergency department 
EF 
ejection fraction 
eGFR 
estimated glomerular filtration rate   
ESRD 
end-stage renal disease 
FAS 
full analysis set    
 
  
hCG 
human chorionic gonadatropin 
HF 
heart failure 
HFimpEF 
Heart failure with improved ejection fraction 
HFmrEF 
Heart failure with mildly reduced ejection fraction 
HFpEF 
Heart failure with preserved ejection fraction 
hs-Troponin 
high sensitivity troponin    
ICD 
implantable cardioverter defibrillator  
ICU 
intensive care unit 
IV 
intravenous 


Novartis 
 
Page 7 
SAP Amendment 1 
 
CLCZ696DUS01 
 
IRT 
Interactive Response Technology    
KM 
Kaplan Meier 
LS 
least squares 
LVEF 
left ventricular ejection fraction   
MedDRA 
Medical dictionary for regulatory activities  
mmHg 
millimeters of mercury   
MRA 
Mineralocorticoid receptor antagonist 
NA 
not applicable 
NT-proBNP 
N-terminal pro-brain natriuretic peptide   
NYHA 
New York Heart Association   
PT 
preferred term 
RAN 
Randomized Analysis Set 
RBC 
red blood cell    
SAE 
serious adverse event    
SAF 
Safety Set     
SAP 
Statistical Analysis Plan    
SBP 
systolic blood pressure  
SD 
standard deviation 
SGLT2i 
Sodium-glucose Cotransporter-2 inhibitor 
SGOT 
serum glutamic oxaloacetic transaminase   
SGPT 
serum glutamic pyruvic transaminase   
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event     
TFL 
Tables, Figures, Listings 
US 
United States 
WBC 
white blood cell(s)    
WHF 
Worsening heart failure 
WHO 
World Health Organization    
 
 
 


Novartis 
 
Page 8 
SAP Amendment 1 
 
CLCZ696DUS01 
 
1 
Introduction 
The statistical analysis plan (SAP) will outline in detail the analyses planned in the protocol. 
The analyses will be used to generate the clinical study report (CSR). The SAP is based on the 
Amendment Protocol Version No. 04 dated 08-Dec-2021 and the data collection tool (DCT) 
Version: EDC 2021.2.1, Date: 10 Dec 2021 . 
The details on the study background can be found in the study protocol and in the Appendix 
Section 5.6.  
1.1 
Study design 
This study will use a randomized, double-blind, double-dummy, active-controlled, parallel 
group design. The goal is to randomize approximately 450 subjects to sacubitril/valsartan or 
valsartan in a 1:1 ratio in approximately 130 centers in the United States (US) and Canada. 
There is no stratification planned.  
Subjects currently or recently taking an angiotensin converting enzyme inhibitor (ACEi): To 
provide for a necessary 36-hour washout of prior ACEi treatment before receiving 
sacubitril/valsartan, eligible subjects will be randomized no earlier than 36 hours from their last 
ACEi dose. Hospital medication administration and medication reconciliation records should 
be reviewed to confirm that eligible subjects have not received ACEi for at least 36 hours prior 
to randomization and the first dose of study medication. Due to this washout period, 
Amendment 3 and earlier versions did not allow subjects to be enrolled prior to 36 hours. 
In Protocol Amendment 04, one can be enrolled any time during the admission or worsening 
HF event as long as they have washed out from the prior/current ACEI (if applicable). 
Randomized subjects will have been hemodynamically stabilized defined in this study as: 
a) Systolic blood pressure (SBP) ≥ 100mmHg for the preceding 6 hours prior to 
randomization; no symptomatic hypotension 
b) No increase (intensification) in intravenous (IV) diuretic dose within last 6 hours prior 
to randomization 
c) No IV inotropic drugs for 24 hours prior to randomization 
d) No IV vasodilators including nitrates within last 6 hours prior to randomization 
All subjects will need to meet all inclusion and none of the exclusion criteria. 
Subjects will be randomized 1:1 to sacubitril/valsartan or valsartan. Initial dose at 
randomization will be determined based on the subject’s previous dose of or lack of 
ACEi/angiotensin receptor blocker (ARB) immediately prior to current worsening heart failure 
(WHF) event (heart failure with preserved ejection fraction (HFpEF) decompensation, or at the 
time of post-decompensation randomization.  
In this study, approximately 450 subjects across 130 sites will be recruited. The maximum 
planned duration of follow-up after randomization (for subjects enrolled under Amendment 01 
or later) is approximately 20 months; the anticipated minimum follow-up would be for 8 weeks. 


Novartis 
 
Page 9 
SAP Amendment 1 
 
CLCZ696DUS01 
 
The first amended protocol (Amendment 01) extended duration of treatment from 12 weeks 
(Original Protocol) to a maximum of approximately 20 months, and increased the sample size 
to 800 subjects. The average duration of study for all participants was anticipated to be 
approximately 11 months based in modeling from December 2019.  
With Protocol Version 01 (Amendment 01) and subsequent amendments, all participants will 
be in double-blind treatment throughout the study, and there is no open label treatment phase.  
Protocol Version 00 (Original Protocol) includes participants who signed Informed Consent 
and were randomized prior to execution of Protocol Version 01 (Amendment 1). Some of these 
participants already have completed the full 8 week double-blind period and have either finished 
or already commenced the 4 weeks open-label period; these participants were not eligible for 
continuation into Amendment 1, although their data is eligible for inclusion with all participants. 
Another subset is those participants who were randomized to Protocol Version 00 who are still 
active in the 8 week double-blind period, and have not entered the open-label period. 
If these participants are interested and can provide their voluntary signature to the revised 
Informed Consent prior to completion of the double-blind period, these participants would be 
eligible to continue in Amendments 01, 02, 03 and 04 with no open-label period. Lastly, those 
participants randomized subsequently to Institutional Review Board approval of Amendments 
01, 02, 03, and 04 and the appropriate Informed Consent for the amended protocols would enter 
directly into the protocol as defined in the respective amended protocols. 
Throughout all protocol versions, the primary endpoint remains the time-averaged proportional 
change in N-terminal pro-brain natriuretic peptide (NT-proBNP) from Baseline to Weeks 4 and 
8. The most recent protocol amendment (Amendment 04) changed the sample size to 450 
subjects with 85% power, deemphasizing the statistical power for key secondary clinical 
endpoints, however clinical events will still be assessed as secondary endpoints. 
Section 1.2 shows the most recent version of the study objectives and endpoints according to 
protocol Amendment 04. 
The planned duration of treatment is up to approximately 20 months of double-blind treatment 
and the last subject randomized will be followed for a minimum of 8 weeks. Subjects may be 
discontinued from treatment earlier due to adverse event, disease progression and/or if treatment 
is discontinued at the discretion of the investigator or the subject.  
At the randomization visit, all eligible subjects will be randomized via interactive response 
technology (IRT) to one of the treatment arms. The investigator or his/her delegate will contact 
the IRT after confirming that the subject fulfills all the inclusion/exclusion criteria. The IRT 
will assign a randomization number to the subject, which will be used to link the subject to a 
treatment arm and will specify a unique medication number for the first package of study 
treatment to be dispensed to the subject. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of subject numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 


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Global Clinical Supply using a validated system that automates the random assignment of 
medication numbers to bottles containing the study treatment. 
There is no planned interim analysis for efficacy in the study. Interim safety assessments are 
planned to be performed and results will be provided to the Data Monitoring Committee (DMC) 
for their review and recommendation. The number and/or timing of these safety assessments 
will be mentioned in the DMC Charter. No adjustment of the level of significance will be made 
for these interim safety assessments. 
1.2 
Study objectives and endpoints 
 
 
Objectives 
Endpoints 
 
Primary Objective 
Endpoint for primary objective 
1 
To demonstrate the effect of sacubitril/valsartan vs. 
valsartan on time-averaged proportional change 
in NT-proBNP from Baseline to Weeks 4 and 8 in 
HFpEF patients with a WHF event (HFpEF 
decompensation) who have been stabilized for and 
initiated at the time of or within 30 days post-
decompensation 
The 
time-averaged 
proportional 
change in NT-proBNP from Baseline 
to Weeks 4 and 8. 
 
Secondary Objectives 
Endpoints 
for 
secondary 
objectives 
2 
To determine the effect of sacubitril/valsartan vs. 
valsartan on the composite hierarchical 
outcome consisting of: a) time to CV death, b) total HF 
hospitalizations, c) total urgent HF visits, and d) time-
averaged proportional change in NT-proBNP 
(from Baseline to Weeks 4 and 8) using win ratio 
methodology 
The composite hierarchical outcome 
consisting 
of: a) time to CV death, b) number 
and times of HF hospitalizations 
during follow-up, c) number and 
times of urgent HF visits during 
follow-up, and d) time-averaged 
proportional change in NT-proBNP 
(from Baseline to Weeks 4 and 8) 
3 
To assess the effect of sacubitril/valsartan vs. valsartan 
on total composite events based on 
CV death, HF hospitalizations, and urgent HF visits 
The cumulative number of recurrent 
composite events overtime, the total 
number of composite events of HF 
hospitalizations, urgent HF visits, 
and CV death.  
4 
To assess the effect of sacubitril/valsartan vs. valsartan 
on the incidences of a composite endpoint of worsening 
renal function (renal death, reaching 
ESRD, or decline in eGFR ≥ 50%) 
The incidences of a composite 
endpoint 
of 
worsening 
renal 
function, defined as: 
• 
renal death 
• 
reaching end-stage renal 
disease (ESRD) 
• 
≥ 50% decline in estimated 
glomerular 
filtration 
rate 
(eGFR) relative to Baseline 
 


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5 
To assess the effect of sacubitril/valsartan vs. valsartan 
on change in NT-proBNP from Baseline to Week 8 
Proportional change in NT-proBNP 
from Baseline to Week 8 
6 
To assess the effect of sacubitril/valsartan vs. valsartan 
on change from Baseline in hs-Troponin (high 
sensitivity) at Weeks 4 and 8 
Proportional change from Baseline 
in hs-Troponin (high sensitivity) at 
Weeks 4 and 8 
7 
 
 
 
 
 
To assess the effect of sacubitril/valsartan vs. valsartan 
on tolerability and the incidence of 
adverse events of special interest during treatment 
Dosing levels and discontinuations    
 
Incidence of symptomatic 
hypotension during treatment 
Incidence of hyperkalemia 
(potassium >5.5 mEq/L) 
Incidence of angioedema   
Incidence of worsening renal 
function, defined as an increase in 
serum creatinine of ≥0.5mg/dl and 
worsening of the eGFR by at least 
25%  


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2 
Statistical methods 
2.1 
Data analysis general information 
 
All statistical analyses outlined in this SAP will be performed by Novartis Medical & Clinical 
Solutions. SAS® version 9.3 (or higher) will be used for all analyses.  
 
Data from all centers that participate in this Protocol  Amendment 4.0 or previous versions of 
the Protocols will be combined. All data as collected to date at the time of database lock (DBL) 
will be included in the analysis. 
 
Unless otherwise specified, for continuous data, the mean, standard deviation (SD), median, 
first and third quartile, interquartile range, and minimum and maximum values will be 
presented. Minimum and maximum will be displayed to the same number of decimal places as 
raw values; mean, median, quartiles, and interquartile range will be presented to 1 additional 
decimal place; and SD to 2 additional decimal places.  
 
For categorical data, frequencies and percentages will be presented. All statistical tests will be 
conducted against a two-sided alternative hypothesis, employing a significance level of 0.05. 
Due to participants being recruited under the original protocol and participants being recruited 
under the amended protocols, there will be a mix of participants that are observed for different 
lengths of time. Therefore, exposure adjusted summaries will be presented for relevant outputs. 
There will be a mix of participants that are observed for different visits and lengths of time 
because of the recruitment under the Original Protocol Version 00 and under the amended 
protocols (01 to 04). However, all the analysis planned here will be a pooled analysis unless 
otherwise stated. 
 
Additionally, summary statistics will be provided by treatment group and Baseline 
classification of in-hospital/out-of-hospital randomization group. Geometric means will be used 
to summarize the NT-proBNP 
. 
All data will be provided in listings in addition to summaries described below.   
2.1.1 
General definitions  
Study treatment/ study drug 
• Participants recruited under the Protocol Version 00 (Original Protocol) received either 
sacubitril/valsartan or valsartan during the first 8 weeks of the study.  


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• Participants recruited under the amended protocols (01 to 04) will receive either 
sacubitril/valsartan or valsartan during the approximately 84 weeks of the study.  
• Participants recruited under Protocol Version 00 (Original Protocol) and who have not 
completed the double-blind period are eligible to continue in Amendment 01 with no open-
label period. 
Study treatment or study drug will refer to either of these 2 drugs. 
Baseline 
Baseline value is the last non-missing assessment before the first administration of study drug, 
unless specified otherwise. 
For safety labs and biomarkers, Baseline is defined as the last non-missing assessment collected 
before the first dose of study treatment, including matching placebos. For subjects not treated, 
Baseline is defined as the last non-missing assessment prior to or on the date of randomization.  
Visit 1 biomarkers will be processed by the local laboratory and can be either NT-proBNP or 
B-type natriuretic peptide (BNP) for the purposes of study screening. From Visit 2 
(Randomization/Baseline) onwards, NT-proBNP values will be based on clinical laboratory 
samples processed and assessed by the central laboratory (Visits 2, 3, 5, and 7; Weeks 0, 1, 4, 
and 8); BNP will not be collected.  
For other assessments, including those for which assessment time is collected 
(electrocardiograms (ECGs), heart failure (HF) signs and symptoms, and pregnancy tests), 
Baseline is defined as the last non-missing assessment prior to or on the start date of study 
treatment (randomization date for subjects not treated), including matching placebos. 
Date of first administration of study treatment 
Double-blind phase: The date of first administration of study treatment in the double-blind 
phase is defined as the first date a dose of study treatment is administered and recorded on 
the First Dose of Study Treatment (Visit 2) electronic case report form (eCRF).  
Open-label phase: The date of first administration of study treatment in the open-label phase 
is defined as the first date a dose of sacubitril/valsartan is administered in the open-label 
phase and recorded on the Study Treatment – Open Label eCRF. 
The double-blind phase and open-label phase is only applicable for subjects enrolled under 
original protocol version 00.  
With Protocol Versions 01, 02, 03 and 04 (Amendment 1, Amendment 2, Amendment 3, 
Amendment 4), all subjects will be in double-blind treatment throughout the study, and there is 
no open-label treatment phase.  
Date of last administration of study treatment 
Double-blind phase: The date of last administration of study treatment in the double-blind 
phase is defined as the last date a dose of study treatment is administered in the double-
blind phase and recorded on the Study Treatment – Double Blind eCRF, or earlier if 
prematurely discontinued and recorded on the Study Treatment – Double Blind eCRF.  


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Open-label phase: The date of last administration of study treatment in the open-label phase is 
defined as the last date of sacubitril/valsartan is administered in the open-label phase and 
recorded on the Study Treatment – Open Label eCRF.  
The double-blind phase and open-label phase is only applicable for subjects enrolled under 
original protocol version 00.  
With Protocol Versions 01, 02, 03, and 04 (Amendment 1, Amendment 2, Amendment 3, 
Amendment 4), all subjects will be in double-blind treatment throughout the study, and there is 
no open-label treatment phase. 
Study day 
The study day describes the day of the assessment relative to the first date of study treatment. 
The study day will be calculated as the difference between the date of assessment and the date 
of the first date of study treatment plus 1. If the date of assessment is prior to the date of the 
first date of study treatment, the study day will be negative and will be calculated as the 
difference between the date of the assessment and the date of the first date of study treatment. 
The descriptor “Study Day 0” will not be used.  
Study phase 
Double-blind phase  
Participants recruited under Protocol Version 00 (Original Protocol) will receive either 
sacubitril/valsartan or valsartan during the first 8 weeks of the study. Assessments performed 
at Weeks 1, 2, 4, 6, 8 (including, but not limited to, vital signs) are assigned to the double-blind 
phase for summarization purposes. Unscheduled assessments are not assigned to a study phase 
for purposes of by-visit summaries.  
Participants recruited under the amended protocols (verisons 01, 02, 03) and those participants 
recruited under Protocol Version 00 (Original Protocol) who opted to continue in an amendment 
protocol will receive either sacubitril/valsartan or valsartan during the approximately 84 weeks 
of the study. The assessments performed at Weeks 1, 2, 4, 6, 8, 10, 12, 16,  24, 32, 40,  48, 56, 
68 or 84 (including, but not limited to, vital signs). 
Participants recruited under the amended Protocol Version 04, assessments performed at Weeks 
1, 4, 8, 24, 40, 56, 68 or 84 (including, but not limited to, vital signs) are assigned to the double-
blind phase for summarization purposes. Unscheduled assessments are not assigned to a study 
phase for purposes of by-visit summaries. 
For summarization of adverse events (AEs), notable vital signs and laboratory abnormalities, 
worsening renal function, defined as an increase in serum creatinine of ≥ 0.5mg/dL and 
worsening of the eGFR by at least 25%, hyperkalemia (Potassium > 5.5 mEq/l), angioedema 
and symptomatic hypotension by study phase, an assessment during the double-blind phase is 
defined as any assessment obtained in the following time interval:  
• For participants recruited under the Protocol Version 00 (Original Protocol) date of first 
administration of study treatment through the date of the Week 8 visit, inclusive. For 
participants without a Week 8 visit, a projected Week 8 visit date will be derived relative to 
their treatment start date.   


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• For participants recruited under the amended protocols (versions 01, 02, 03 and 04) and 
participants recruited under Protocol Version 00 (Original Protocol) who opted to continue 
in the amended protocols date of first administration of study treatment through the date of 
the Week 84 visit, inclusive.   
Open-label phase (under the Protocol Version 00 (Original Protocol) )  
For participants recruited under the Protocol Version 00 (Original Protocol) who do not 
continue in amendment protocol assessments performed at Weeks 10 or 12 (including, but not 
limited to, vital signs) are assigned to the open label phase for summarization purposes, unless 
otherwise noted. Unscheduled assessments are not assigned to a study phase for purposes of 
by-visit summaries.  
For summarization of AEs, notable vital signs and laboratory abnormalities, and symptomatic 
hypotension by study phase, an assessment during the open label phase is defined as any 
assessment obtained in the following time interval:  
After the date of the Week 8 visit. For participants without a Week 8 visit, a projected Week 8 
visit date will be derived relative to their treatment start date.  
Participants enrolled under Protocol Version 00 (Original Protocol) who died, withdrew consent, 
or were lost to follow-up prior to or on their projected Week 8 visit date will be excluded from 
the open-label phase.  
 
End of Study (EOS)  
EOS is obtained directly from the source data. A subject can discontinue treatment  (EOT) at 
any time but continue the study, then the EOS is the study completion date. A subject who 
completes the study and has an EOS visit. If a subject discontinues the study for any reason, the 
discontinuation date is the EOS for that subject. 
Follow-up for time-to-event analyses 
For patients enrolled in the original protocol and continue to an open-label period, events are 
considered up to the end of their double-blind period (up to Week 8). For patients enrolled in 
Protocol Amendments 1-4, the events are considered up to their end of double-blind phase 
(EOS).  
In-Hospital / Out-of-Hospital Randomization Status 
The status for patient’s in-hospital/out-of-hospital randomization is collected as “In-Patient or 
Out-Patient” category and will be provided by the Interactive Response Technology (IRT).  
Year, month and week 
For reporting purposes, the rules below will be followed to convert a year, month and week to 
days. 
1 year = 365.25 days 
1 month = 30.4375 days 
1 week = 7 days 
1 day = 24 hours 


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COVID-19 pandemic phases 
The participants in this trial may be divided into 3 subsets based on the COVID-19 pandemic 
status: 
• Before pandemic set: Participants who completed (or discontinued) the trial (or completed 
study treatment period) before the pandemic start date 
• During pandemic set: Participants with at least one on-treatment assessment or treatment-
emergent event during the pandemic date 
• After pandemic set: Participants who were enrolled (based on informed consent date) in the 
study after the pandemic end date (if applicable) 
Where 01-Mar-2020 is the defined start date for the COVID-19 pandemic in the US and Canada 
according to the COVID-19 Guidance Dates by region for sensitivity analyses V5.0 (novartis.net).  
2.2 
 Analysis sets 
 
The following analysis sets will be used for the statistical reporting and analyses: 
Randomized Analysis Set (RAN) The RAN will consist of all randomized subjects. 
The Full Analysis Set (FAS) 
The FAS will consist of all subjects to whom study 
treatment has been assigned by randomization and at 
least one dose of study treatment recieved. According to 
the intent-to-treat principle, participants will be included 
for analysis according to the treatment they have been 
assigned to during the randomization procedure. 
The Safety Set (SAF) 
The SAF includes all participants who received at least 
one dose of the study treatment. Participants will be 
included for analysis according to the study treatment 
they received, where treatment received is defined as the 
randomized treatment if the participant took at least one 
dose of that treatment or the first study treatment 
received if the randomized treatment was never 
received.   
 
The subjects in this trial are divided in 2 groups, (1) those who are randomized under Protocol 
Version 00 (Original Protocol subjects) and (2) those who are randomized after site execution 
of the amended protocols (Amendment 01, 02, 03, and 04 subjects). The FAS includes subjects 
from both groups.   
2.2.1 
Subgroups of interest 
The following subgroups will be analyzed for the primary endpoint and for selected secondary 
endpoints based on clinical decision: 
1. Age group (< 65, ≥ 65 years) and (< 75, ≥ 75 years) 
2. Left ventricular ejection fraction (LVEF) categories prior to randomization: 
• > 40 to < 45% vs. ≥ 45%;  


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• > 40 to < 50% ((HFmrEF (mildly reduced) ), ≥ 50% ( (HFpEF) preserved )  
• ≥ 50 to ≤ 60% vs. >60* 
• 
>40 to ≤60 vs. > 60* 
• ≤ median vs. > median 
3. Prior use of ACEi/ARB (at the time of hospitalization) 
4. Four groups defined by the Baseline quartiles of NT-proBNP   
5. Baseline eGFR (< 45, 45 to < 60, ≥ 60 ; <30 or ≥ 30 mL/min/1.73 m2) 
6. SBP at randomization (< 110, ≥ 110 mm Hg) 
7. Race 
8. Ethnicity 
9. Atrial fibrillation (AF) vs. no AF at the time of consent 
10. Body mass index (BMI) ≥ 30 vs. BMI < 30; BMI ≤50 vs. >50 kg/m2  
11. Sex  
12. New onset HF (at the time of hospitalization) – ‘de novo heart failure’ 
13. New York Heart Association (NYHA) class at randomization 
14. Recovered EF / Improved EF (HFimpEF) (most recent left ventricular ejection fraction 
(LVEF) > 40% (within past 3 months), but history of prior documented LVEF < 40%) 
15. Time from presentation to hospital (if applicable) to randomization time  
16. Prior history of HF 
17. Prior Hospitalization for Heart Failure 
18. Duration of Heart Failure (< 12 months, 12-24 months, 24-60 months, and  >  60 months) 
19. In-hospital/out-of-hospital randomization status 
20. Structural heart disease (yes/no) 
21. Subjects without COVID-19 positive during the trial.  
22. Enrollment Country: Canada vs United States 
 
*  LVEF of >60% is defined as normal; LVEF <= 60% is defined as “below normal” 
 
See Sections 2.5 and 2.6 for further details on the primary and secondary objectives, 
respectively. 
2.3 
Subject disposition, demographics and other baseline 
characteristics 
2.3.1 
Subject disposition 
The number and percentage of subjects successfully screened will be presented. In addition, the 
reasons for screen failures will be provided. For subjects who are screened more than once, the 
information from the last screen will be used in the summary. This analysis will be performed 
on All subjects. 
Number of subjects who were randomized will be presented on screen passed subjects.  
The following categories will be summarized on RAN: 


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• Number and percentage of subjects who were treated 
• Number and percentage of subjects who prematurely discontinued study treatment during 
double-blind phase 
• Number and percentage of subjects who prematurely discontinued study treatment during 
double-blind phase, excluding deaths 
• Number and percentage of subjects who prematurely discontinued study treatment during 
open-label phase 
• Number and percentage of subjects who prematurely discontinued study treatment during 
open-label phase, excluding deaths 
• Reasons for premature discontinuation of study treatment (separately for double-blind phase 
and open-label phase) 
• Adverse Event 
• Death 
• Lost of Follow-Up 
• Study terminated by sponsor 
• Patient/Guardian decision 
• Protocol deviation 
• Physician  decision 
• Pregnancy 
Study duration in months [(date of last contact/death – date of first dose of study treatment + 
1)/30.4375]  
The following categories will be summarized by treatment group for the full study period 
(Baseline – Week 84 end)  
• Subjects who received at least 1 dose of study treatment in the study period 
• Subjects who did not receive at least 1 dose of study treatment in the study period and the 
reason 
Furthermore, it will only be feasible to determine loss to follow-up at Week 84 end.  
Subject disposition (total enrolled, total discontinued, total completed) by region (US and 
Canada) and pandemic phase will also be summarized for the RAN.   
A summary of subjects who were randomized but did not met the inclusion criteria #3 , i.e. 
subjects enrolled outside of the respective protocol window will be provided. The summary will 
include subjects randomized with/without the protocol specified enrollment window  (i.e., 
Original protocol 36H-10Days; Amendment 1-3 36H-30Days; Amendment 4 0H-30Days)  by 
original protocol and amendments by treatment for RAN.  
Additionally, listings of inclusion/exclusion criteria, screening disposition, reason for 
withdrawal of consent and study treatment disposition will be provided. 
Any visit that did not occur per protocol will be listed with the reason it was not done. 


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2.3.2 
Subject Protocol deviations 
The number and percentages of protocol deviations by category will be summarized. 
Additionally, a listing of protocol deviations during the study will also be presented. The FAS 
will be used. 
In addition pandemic related protocol deviations will be summarized by category and 
relationship. All COVID-19 related protocol deviations will also be listed. 
2.3.3 
Qualifying Hospitalization/ED Visit/Out-of-Hospital Urgent HF  
The number and percentages of the following information about subjects and their qualifying 
hospitalization visit will be summarized by treatment group. The RAN will be used. 
• Qualifying Healthcare Encounters 
• Hospitalization  
• Emergency Department (ED) Visit 
• Out-of-Hospital Urgent HF Visit 
• Subject in shock (No, Yes, Unknown) 
• Subjects receiving following treatment from qualifying hospitalization to randomization 
• Vasopressor (No, Yes, Unknown) 
• Inotrope (No, Yes, Unknown) 
• Nitroprusside (No, Yes, Unknown) 
• Nesiritide (No, Yes, Unknown) 
• IV Nitroglycerin (No, Yes, Unknown) 
• Subject cared for in the intensive care unit (ICU) (No, Yes, Unknown) 
The number and percentage (categorical variables) and descriptive statistics (continuous data) 
for information on subject qualifying hospitalization discharge will be summarized by treatment 
group. The RAN will be used. 
• Duration of qualifying hospitalization stay in days [(date:time of discharge – date:time of 
arrival)/(3600*24)] 
• Discharge disposition (Home or with family/friends, Rehabilitation facility, Skilled nursing 
facility, Death, Unknown) 
• Discharge weight (kg) 
• NYHA class (I, II, III, IV) 
• Subject experienced worsening HF since randomization (No, Yes, Unknown) 
• Subject cared for in ICU (No, Yes, Unknown) 
• Number of nights in ICU since randomization 
• Subject treated with any of the following medication classes since randomization (IV 
inotrope, IV vasopressor, Nitroprusside, IV Nitroglycerin,) 
All information relating to the qualifying hospitalization will be listed. 
With Amendment 4, not all subjects will have a qualifying hospitalization, with some qualifying 
based on a worsening HF event (e.g. ED visit or Urgent HF visit).  


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2.3.4 
Demographics and other baseline characteristics 
Demographics, baseline characteristics, and disease history are collected at the screening visit. 
Descriptive summaries and/or listings will be provided. The number and percentage 
(categorical variables) and descriptive statistics (continuous data) for the information below 
will be summarized by treatment group for both double-blind and open-label subjects. 
The FAS will be used. Summary statistics will be provided for Original Protocol subjects, and 
subjects recruited under the amended protocols, and all subjects in FAS. 
In addition, demographics and baseline characteristics may be summarized by pandemic phases 
if needed.  
2.3.4.1 
Demographics and baseline characteristics 
Demographic variables include: 
• Age (years), age group (derived; < 65 years, 65 to <75 years, and ≥ 75 years) 
• Sex (Male, Female, Unknown, Undifferentiated) 
• Race (White, Black, Asian, Native Hawaiian or Other Pacific Islander, American Indian or 
Alaska Native) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown) 
• Total subjects recruited under each country (Total recruited, Recruited in Canada, Recruited 
in the US) 
Baseline characteristic variables include: 
• Height (cm) 
• Weight (kg) 
• BMI (kg/m2) [= weight (kg)/height (m)2 from screening visit 1] 
• BMI categories (< 20, 20 to < 25, 25 to 30, ≥ 30 kg/m2) 
• Smoking history (Former, Current, Never) 
• Heart rate (beats per minute) 
• Bundle branch block (or Intraventricular conduction delay [IVCD]) present (No, Yes) 
• Bundle branch block type (Left bundle branch block, Right bundle branch block, Non-
specific IVCD) 
• NT-proBNP (pg/mL) values based on clinical laboratory samples processed and assessed 
by the central laboratory 
• NT-proBNP quartiles and IQR 
• Log-transform of NT-proBNP 
• BNP (pg/mL) (screening visit 1 only), based on clinical laboratory samples processed and 
assessed by the local laboratory 
• BNP quartiles and IQR 
• Log-transform of BNP 
• NT-proBNP (pg/mL) (screening visit 1 only), based on clinical laboratory samples 
processed and assessed by the local laboratory 


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• NT-proBNP quartiles and IQR 
• Log-transform of NT-proBNP 
2.3.4.2 
Disease characteristics 
Disease characteristic variables include: 
• Category of prior cardiovascular (CV) medication: 
 (Diuretic class (Loop diuretic, Thiazide diuretic)), Mineralocorticoid receptor antagonist 
(MRA), ACEi, ARB, Digoxin, Beta blocker, Calcium channel blocker (CCB), Long-acting 
nitrate, Anticoagulant class (Warfarin, Direct-acting oral anticoagulants (DOACs)), Aspirin, 
Statin, Non-statin lipid lowering therapy, Antiplatelet (excluding aspirin), Adenosine 
diphosphate (ADP)  antagonist), SGLT2 inhibitors with relevant Anatomical Therapeutic 
Chemical (ATC) drug class codes. 
• ACEi/ARB naïve (never exposed); Previously on ACEi/ARB but not currently taking 
(previously exposed); Currently taking (up until randomization). 
• Primary HF etiology: Ischemic; Non-ischemic 
• Hypertensive (No, Yes) 
• Diabetic (No, Yes) 
• Alcoholic (No, Yes) 
• Viral cardiomyopathy (No, Yes) 
• Infectious cardiomyopathy (No, Yes) 
• Peripartum (No, Yes) 
• Drug induced (No, Yes) 
• Other (No, Yes) 
• History of HF prior to qualifying HF event (No, Yes, Unknown) 
• Number of hospitalizations with primary diagnosis of HF within past 12 months not 
including qualifying hospitalization 
• Number of hospitalizations categories (0, 1, 2, ≥ 3, Not Applicable) 
• Total number of hospitalizations for any reason within past 12 months 
• NYHA classification approximately 1 month prior to admission of the trial (I, II, III, IV, 
Unknown) 
• Most recent left ventricular ejection fraction (LVEF) (%) 
• Left ventricular ejection fraction (LVEF) categories prior to randomization: 
• > 40 to < 45% vs. ≥ 45%;  
• > 40 to < 50% ((HFmrEF (mildly reduced) ), ≥ 50% ( (HFpEF) preserved )  
• ≥ 50 to ≤ 60% vs. >60* 
• >40 to ≤60 vs. > 60* 
• ≤ median vs. > median) 
• Left atrial enlargement defined by at least one of the following: 
- 
LA width ≥3.8 cm  
- 
LA length ≥5.0 cm  


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- 
LA area ≥20 Square Centimeter 
- 
LA volume ≥ 55 mL 28 
- 
LA volume index ≥ 29 Milliliters per Square Meter 
• Left ventricular hypertrophy (Septal thickness or posterior wall thickness ≥1.1 cm, 
• Time from hospital presentation to randomization (days) 
• Any prior EF < 40% (LVEF < 40%) (No, Yes, Unknown) 
• Presence of structural heart disease (No, Yes, Unknown) 
 
*  LVEF of >60% is defined as normal; LVEF <= 60% is defined as “below normal” 
2.3.4.3 
Cardiovascular history 
Cardiovascular history will be summarized. The following disease information will be 
collected: 
• Hypertension (No, Yes, Unknown) 
• Transient ischemic attack (No, Yes, Unknown) 
• Stroke (No, Yes, Unknown) 
• Peripheral vascular disease (No, Yes, Unknown) 
• Chronic renal insufficiency (CRI) [eGFR <60 ml/min/1.73m2 prior to qualifying 
hospitalization or WHF event] (No, Yes, Unknown) 
• Chronic kidney disease (CKD) stage (CKD Stage 3 [eGFR 30 to 59], CKD Stage 4 [eGFR 
15 to 29], CKD Stage 5 [eGFR < 15 or dialysis] and Other 
• CKD defined as either CRI=yes or CKD stages (3 or 4 or 5) =yes. (No, Yes, Unknown)  
• eGFR categories prior to randomization  
• < 60 ml/min/1.73m2  
• ≥ 60 ml/min/1.73m2 
• Arrhythmia (No, Yes, Unknown) 
• Arrhythmia type (AF, Atrial flutter, Supraventricular tachycardia, Ventricular 
tachycardia) 
• Pacemaker/Implantable cardioverter defibrillator (ICD) (No, Yes, Unknown) 
• Device type (Pacemaker [conventional], Cardiac resynchronization therapy – no ICD 
[CRT-P], Cardiac resynchronization therapy – with ICD [CRT-D], ICD only 
[single/dual], Other, Unknown) 
• Moderate to severe valvular heart disease (No, Yes, Unknown) 
• Heart disease type (Mitral regurgitation, Aortic regurgitation, Aortic stenosis, Tricuspid 
regurgitation) 
• Prior valvular heart surgery (No, Yes, Unknown) 
• Valvular surgery type (Mitral, Aortic, Tricuspid, Pulmonic) 


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2.3.4.4 
Non-Cardiovascular Medical History 
Non-cardiovascular medical history and ongoing conditions will be summarized and listed. The 
summaries will be presented by primary system organ class (SOC), preferred term (PT) and 
treatment group for both double-blind and open-label subjects. Incidence of SARS-CoV-2 
(COVID-19) infection in the subjects’ medical history will be included in the non-
cardiovascular medical history summaries and listings. Non-cardiovascular medical history and 
ongoing conditions will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) terminology (latest version at the time of data cut-off will be used).  
2.3.4.5 
Surgeries and Medical Procedures 
Surgeries and medical procedures will be listed, including the reason, start date and end date. 
Surgeries and medical procedures will be coded using MedDRA terminology (latest version at 
the time of DBL will be used). 
2.4 
Treatments (study treatment, rescue medication, 
concomitant therapies, compliance) 
The SAF will be used for all analyses associated with study treatment and medications, unless 
otherwise specified. 
2.4.1 
Study treatment / compliance 
The duration of study treatment is defined as: 
Duration (days) = (date of last study treatment – date of first study treatment) +1 
The first date of study treatment is recorded on the First Dose of Study Treatment eCRF. 
Summary statistics will be displayed for the duration of study treatment by treatment group and 
in-hospital/out-of-hospital randomization category using mean, SD, median, minimum, and 
maximum. Additionally, the number and percentage of participants will be summarized by 
treatment group and in-hospital/out-of-hospital randomization for duration category. 
The durations will also be categorized into weekly time intervals (< 7 days, 7 to < 14 days, 14 
to < 21 days, …, etc.). The number and percentage of subjects in each category will be presented. 
Total subject-days of exposure will also be summarized. 
In addition, the number and percentages of each dose level dispensed by visit will be 
summarized by treatment group. The number and percentage of the maximum dose levels 
dispensed will also be presented by treatment group. Similarly, the up-titrated doses, down-
titrated doses and unchanged doses will be summarized by visit and treatment group. The 
number and percentage of subjects who were dispensed Dose Level 3 by Week 6 will be 
summarized by treatment group. 
All information on dose administration will be listed. 
The duration of exposure by pandemic impact may also be summarized.  


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2.4.2 
Prior, concomitant and post therapies 
2.4.2.1 
Prior and concomitant medications definition 
Prior and concomitant medications will be coded according to the World Health Organization 
(WHO) Drug Reference List (latest version at the time of data cut-off will be used). Prior and 
concomitant medications are mutually exclusive, as defined below: 
• Prior medications are defined as any medication with an end date prior to the first dose of 
study treatment 
• Concomitant medications are defined as any medications taken on or after the start of study 
treatment. Prior medications that are ‘ongoing’ at the time of the first study treatment or 
whose end date is after first study treatment will be considered a concomitant medication 
The number and percentage of subjects with concomitant medications that started after study 
treatment will be summarized by ATC class, PT and study phase (refer to Section 2.1.1 for 
study phase definitions). All medications will be listed. Concomitant medications and 
significant non-drug therapies, prior to and after the randomization, will be summarized by 
therapeutic class, PT, treatment group, and in-hospital/out-of-hospital randomization category. 
The SAF population will be used for the above analyses. 
2.4.2.2 
Medications of interest 
The following medication classes of interest will be summarized by treatment group and in-
hospital/out-of-hospital randomization status at Baseline: 
• Previous use of medication, n(%) 
• Any Diuretic agent 
a) Diuretics prior to index (qualifying event) 
b) Loop diuretics 
• ACEi or ARB 
• MRA 
• BB 
• SGLT2i  
Medication names will be coded using the WHO Drug Reference List (latest version at the time 
of Database Lock will be used).  
2.4.2.3 
COVID-19 vaccination status 
COVID-19 vaccination status will be summarized by treatment group and by study phase. The 
descriptive summary will present the number and percentage of subjects who are fully 
vaccinated, partially vaccinated (received 1 out of 2 doses of vaccine, where applicable). 
Booster doses will not be included as an indication of full vaccination status, however will be 
recorded and provided.  


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Total number of COVID-19 vaccine doses (No vaccine, 1, 2, 3, 4 and 5 (if applicable)) will also 
be reported along with a complete. Listing for COVID-19 vaccination status.  
The SAF population will be used for the above analysis. 
2.4.3 
Unscheduled visit mapping 
When visit mapping are used, all visits will be re-aligned, i.e., they will be mapped into one of 
the visit windows. E.g., if the Week 4 visit of a subject is delayed and occurs on Day 46 instead 
of on Day 29, say, it will be re-aligned to visit window Week 8. In the case of major deviations 
from the visit schedule, or due to unscheduled visits, several assessments of a subject may fall 
in a particular visit window (either scheduled or unscheduled). Statistical approaches to handle 
multiple assessments in a given visit window are specified below in Section 2.4.4. 
An unscheduled visit will be mapped according to the following visit windows: 
For subjects recruited under Original protocol (00) to Amendment 01-03: 
Visit Name Visit Number Target Day (Study Days) 
Visit Window (Study Days) 
Week 1 
Visit 3 
7 
2 to 10 
Week 2 
Visit 4 
14 
11 to 21 
Week 4 
Visit 5 
28 
22 to 35 
Week 6 
Visit 6 
42 
36 to 49 
Week 8 
Visit 7 
56 
50 to 63 
Week 10 
Visit 8 
70 
64 to 77 
Week 12 
Visit 9 
84 
78 to 98 
Week 16 
Visit 10 
112 
99 to 140 
Week 24 
Visit 11 
168 
141 to 196 
Week 32 
Visit 12 
224 
197 to 252 
Week 40 
Visit 13 
280 
253 to 308 
Week 48 
Visit 14 
336 
309 to 364 
Week 56 
Visit 15 
392 
365 to 434 
Week 68 
Visit 16 
476 
435 to 532 
Week 84 
Visit 17 
588 
>532; 
Visit Schedule to be followed for subjects recruited under protocol Amendment 04: 
 
Visit Name Visit Number Target Day (Study Days) 
Visit Window (Study Days) 
Week 1 
Visit 3 
7 
2 to 17 
Week 4 
Visit 5 
28 
18 to 42 
Week 8 
Visit 7 
56 
43 to 112 
Week 24 
Visit 11 
168 
113 to 224 
Week 40 
Visit 13 
280 
225 to 336 
Week 56 
Visit 15 
392 
337 to 434 
Week 68 
Visit 16 
476 
435 to 532 
Week 84 
Visit 17 
588 
>532 


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2.4.4 
Multiple assessments within visit windows 
When there are multiple assessments in a particular visit window, the following rules are applied 
to select one value “representing” the subject in summary statistics in a visit window. 
In cases where there are multiple assessments in the Screening period, the value closest to the 
baseline will be considered for the analysis. 
For baseline assessment definition see Section 2.1.1. For post-baseline visit windows with 
multiple assessments, the following applies (unless otherwise specified): 
1. for quantitative variables, the closest to the actual visit is chosen (if two assessments have 
the same distance, then the earlier one will be chosen);  
2. for qualitative variables, the worst record is selected. It is noted that in the analyses 
performed, worst case is always well defined. 
2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint 
The primary endpoint is the comparison of the time-averaged proportional change from 
Baseline in NT-proBNP between sacubitril/valsartan and valsartan to Week 4 and 8.  
Primary analysis timepoint will be the change from Baseline to averages of Week 4 and 8.  
The analysis of the primary endpoint will be based on the FAS. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The primary analysis to address the primary objective will be based on the following estimand:  
Estimand 1 
Population: Defined through the appropriate inclusion/exclusion criteria to reflect the targeted 
study population currently hospitalized for or within 30 days of a WHF event (HFpEF 
decompensation). A WHF event (HFpEF decompensation) is defined as a hospitalization, 
emergency department (ED) visit or out-of-hospital urgent HF visit, all requiring IV diuretics.  
Endpoint: Time-averaged proportional change between Baseline and weeks 4 and 8 in NT-
proBNP 
Treatment: The randomized treatment sacubitril/valsartan or valsartan 
Intercurrent event: Using a treatment policy strategy to handle the intercurrent event of 
treatment discontinuation. 
Summary measure: Difference between treatment in ratios of geometric means  
The primary null hypothesis to be tested is the ratio of the geometric means of NT-proBNP 
(average of Weeks 4 and 8 divided by Baseline) for the sacubitril/valsartan and valsartan 
treatment groups are equal (H10) versus the alternative hypothesis that the ratio of the geometric 
means of NT-proBNP are not equal (H1a).  
For NT-proBNP, the time-averaged proportional change from Baseline in a natural logarithmic 
scale will be analyzed using an ANCOVA model using data from Weeks 4 and 8 with treatment, 


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in-hospital/out-of-hospital randomization status, gender, and Baseline LVEF (≤ Median, > 
Median) as fixed effect factors, age and the logarithmic Baseline NT-proBNP as covariates.  
The values from Weeks 4 and 8 will be averaged and the change from Baseline in log 
transformed NT-proBNP will be calculated as follows: 
ln(average post dose value) – ln (baseline value) 
The estimated treatment effect in terms of ratios of geometric means, based on the least-squares 
(LS) means from the model, and the corresponding two-sided 95% confidence intervals (CIs) 
will be presented. 
The geometric means (presented as a ratio to Baseline) will be calculated by exponentially back 
transforming the LS means based on the ANCOVA model as follows: 
exp(LS mean) 
The FAS will be used for the primary endpoint analysis. 
2.5.3 
Handling of missing values/censoring/discontinuations 
The analysis will be performed based on all available data in the FAS. Missing values caused 
due to unevaluable samples or early discontinuations will not be imputed.  
Also, NT-proBNP from unscheduled visits will not be used for the analysis.  
2.5.4 
Sensitivity analyses 1 
Robustness of the primary efficacy results will be explored by multiple imputation assuming 
MAR i.e., missing at random algorithm to impute missing values in the primary analysis, except 
the Baseline value. Baseline value will not be imputed.  
To investigate the sensitivity of the analysis results based on the MAR assumption, we will 
perform an analysis using a pattern mixture model approach which assumes, besides the 
imputation with 0 for the NT-proBNP values after death. This sensitivity analysis would first 
create multiple (100) imputations of missing NT-proBNP values under a MAR assumption, 
resulting in multiple (100) complete data sets. The imputation model assumes a multivariate 
normal model for the 3 NT-proBNP measurements at baseline, Week 4 and Week 8. To the 
resulting 100 datasets, the original analysis model described above will be fitted, yielding 100 
sets of parameter estimates and associated covariance matrices. These are then combined by 
using Rubin’s rules to derive overall estimates, and confidence intervals that adequately reflect 
missing data uncertainty as well as associated p-values.  
The sensitivity analysis to address the primary objective will be based on the same primary 
estimand. 
2.5.5 
Sensitivity analyses 2 
A second sensitivity analysis will be performed based on the subjects recruited under  
Amendment 1 to Amendment 4 protocol versions. The analysis will be performed like the main 
analysis of the primary endpoint. 


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The sensitivity analysis to address the primary objective will be based on the same primary 
estimand. 
The analysis will be performed based on all available data in the FAS. Missing values caused 
due to unevaluable samples or early discontinuations will not be imputed. 
2.5.6 
Sensitivity analyses 3 
A third sensitivity analysis will be performed by excluding assessments after COVID-19 
positive status at the subject level. The analysis will be performed similar to the main analysis 
of the primary endpoint. 
The sensitivity analysis to address the primary objective will be based on the same primary 
estimand. 
The analysis will be performed based on all available data in the FAS. Missing values caused 
due to unevaluable samples or early discontinuations will not be imputed. 
2.5.7 
Sensitivity analyses 4 
A fourth sensitivity analysis will be performed on all the subjects randomized in the study with 
and without the prespecified enrollment windows specified in the respective protocol (00, 1-4). 
The analysis will be performed similar to the main analysis of the primary endpoint. 
The sensitivity analysis to address the primary objective will be based on the same primary 
estimand. 
The analysis will be performed on 2 sub populations: 
1. 
Outside enrollment window : This will consist of all subjects randomized in the 
study who did not meet the inclusion criteria #3, for the respective pre-specified 
protocol enrollment window ( protocol versions, 00, 1 – 4). No statistical 
analysis will be performed if the total number of subjects are less than 5 for this 
subgroup. 
2. 
Within enrollment window : This will consist of the total FAS population 
excluding the subjects enrolled outside enrollment window. 
The analysis will be performed based on all available data in the FAS. Missing values caused 
due to unevaluable samples or early discontinuations will not be imputed.  
2.5.8 
Supplemental analysis 
In this supplementary analysis the variables to be analyzed are: Achieving a pre-specified 
percent change from Baseline in NT-proBNP (binary). Three binary outcome variables will be 
created for subjects achieving a 25%, 50% and 75% decline in NT-proBNP (0-no, 1-yes). The 
dataset used in the primary analysis will be used to define these categorical variables using the 
NT-proBNP. Logistic regression model will be fitted. The odds ratio, CI and p-value will be 
provided for each analysis. The dependent variable will be achieving a target decline in NT-
proBNP and the predictor of response will be treatment group and in-hospital/out-of-hospital 
randomization status. 


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In addition, an analysis of the primary endpoint will be performed with subjects randomized to 
Amendment 4 (yes, no) as an additional factor to the model mentioned in Section 2.5.2.  
The supplemental analysis will be based on the following estimand. 
Estimand  
Population: Defined through the appropriate inclusion/exclusion criteria to reflect the targeted 
study population currently hospitalized for or within 30 days of a WHF event (HFpEF 
decompensation). A WHF event (HFpEF decompensation) is defined as a hospitalization, ED 
visit or out-of-hospital urgent HF visit, all requiring IV diuretics. 
Endpoint: Dichotomized (25%, 50% and 75% reduction) change from Baseline in NT-proBNP 
from Weeks 4 and 8 
Treatment: The randomized treatment sacubitril/valsartan or valsartan 
Intercurrent event: Using a treatment policy strategy to handle the intercurrent event of 
treatment discontinuation. 
Summary measure: Difference between treatment in odds ratio  
The values from Weeks 4 and 8 will be averaged and the change from Baseline in NT-proBNP 
will be calculated and the reductions categorized.  
The analysis will be performed based on all available data in the FAS. Missing values caused 
due to unevaluable samples or early discontinuations will not be imputed. 
2.5.9 
Subgroup analyses 
All subgroups as defined in Section 2.2.1 will be analyzed for the primary endpoint.  
The subgroup analysis will be based on the same primary estimand. 
• The analyses will be performed like the main analysis of the primary endpoint with the 
addition of an interaction term for the subgroup and treatment.  
An interaction p-value will be generated from a likelihood ratio test comparing the interaction 
model to the model without the interaction.  
• Forest plots will be produced including interaction p-values for treatment by subgroup 
interactions. 
2.6 
Analysis of secondary objectives 
All analyses will be performed on the FAS, unless otherwise specified. 
2.6.1 
Secondary endpoints 
Secondary endpoints include the following: 
1. The composite hierarchical outcome consisting of a) time to CV death, b) number and times 
of HF hospitalizations during follow-up, c) number and times of urgent HF visits during 
follow-up, and d) time-averaged proportional change in NT-proBNP (from Baseline to 
Weeks 4 and 8) 


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2. The cumulative number of recurrent composite events overtime, ie, the total number of 
composite events of HF hospitalizations, urgent HF visits, and CV death. 
3. Incidences of a composite endpoint of worsening renal function defined as: 
• renal death 
• reaching end-stage renal disease (ESRD) 
• ≥ 50% decline in estimated glomerular filtration rate (eGFR) relative to baseline 
4. Proportional change in NT-proBNP from Baseline to Week 8 
5. Proportional change in hs-Troponin (high sensitivity) from Baseline to Weeks 4 and 8 
6. Dosing levels and discontinuations 
7. Incidence of adverse events of special interest during treatment 
• Incidence of symptomatic hypotension 
• Incidence of hyperkalemia (potassium > 5.5 mEq/L) 
• Incidence of angioedema 
• Incidence of worsening renal function, defined as an increase in serum creatinine of 
≥0.5mg/dl and worsening of the eGFR by at least 25%  (based on central laboratory 
data). 
All these secondary endpoints will be analyzed using FAS and nominal p-values will be 
reported. There will be no adjustment for multiplicity.  
2.6.1.1 
Adjudication of Events 
Among the secondary variables above, some of them or their components need to be adjudicated 
to confirm the reported types and occurrences based on a unified criteria for analyses. The 
adjudication of these events is based on an adjudication process through an independent 
Endpoint Adjudication Committee (EAC). The role of the EAC is to ensure that all clinical 
outcomes are judged uniformly, using standard criteria and processes. Specific details regarding 
endpoint definitions can be found in the adjudication charter (ref  CEC Charter, final version 
16 July 2021). 
All deaths, (re-)hospitalizations, and urgent HF visits will be adjudicated. The following events 
will be assessed by the EAC during the study: 
• DEATH; 
o Cardiovascular Death 
• 
Fatal Myocardial Infarction (MI) 
• 
Heart Failure Death 
• Sudden Death 
• 
Presumed Sudden Death 


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• 
Presumed Cardiovascular Death 
• 
Fatal Stroke 
• 
Fatal Pulmonary Embolism 
• 
Cardiovascular Procedure-Related Death 
• 
Other Cardiovascular Death 
o Non-Cardiovascular Death 
o Undetermined Cause of Death 
• HOSPITALIZATIONS: 
o Cardiovascular (CV) hospitalization 
• 
Hospitalization for Heart Failure 
• 
Possible Hospitalization for Heart Failure 
• 
Cardiovascular Hospitalization for a reason other than Heart Failure  
• 
Cardiovascular Hospitalization that cannot be further classified  
o Non-Cardiovascular (non-CV) Hospitalization 
o Undetermined Cause of Hospitalization    
• URGENT HEART FAILURE VISITS 
Urgent Heart Failure visits as defined in EAC charter :  
Urgent, unscheduled office/practice or emergency department visit for heart failure 
management not requiring overnight hospitalization and associated with all of the 
following: 
1. New or worsening signs and symptoms of heart failure, defined by the same 
criteria as for the heart failure hospitalization end point above and 
2. Intravenous therapy directed at heart failure management 
2.6.2 
Statistical hypothesis, model, and method of analysis 
2.6.2.1 
Analysis of secondary endpoint 1 
The composite hierarchical outcome consisting of below 4 variables 
a) time to CV death (Adjudicated by EAC), 
b) number and times of HF hospitalizations during follow-up (Adjudicated by EAC - only 
the confirmed events will be considered, i.e. HF hospitalizations meeting PARAGLIDE-HF 
criteria),  
c) number and times of urgent HF visits during follow-up (Adjudicated by EAC), and  
d) time-averaged proportional change in NT-proBNP (from baseline to Weeks 4 and 8) 


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This secondary efficacy endpoint of the composite hierarchical outcome will be analyzed 
estimating the unmatched win ratio by comparing every participant in the sacubitril/valsartan 
arm to every participant in the valsartan arm to determine a winner (unmatched pairing method). 
The estimated win ratio (the total number of wins in the sacubitril/valsartan arm divided by the 
total number of wins in the valsartan arm) will be calculated. The corresponding null and 
alternative hypotheses are: 
H20: Win ratio is equal to 1, verses 
H2a: Win ratio is not equal to 1. 
A win ratio greater than 1 will be in favor of sacubitril/valsartan arm. The testing of hypothesis 
H20 and calculation of the corresponding two-sided 95% CIs will be performed.  
A component will only be used as tie-breaker in the pairwise comparison between two subjects 
if the comparison of components with a higher priority resulted in a tie. For component a) the 
subject with the later time to CV death is the winner. For component, b) the subject with the 
smaller number of HF hospitalizations in time at risk that is common for both subjects (for 
definition see Section 2.6.2.1.1) is the winner. If the number of HF hospitalizations in the time 
at risk is common for both subjects it is tied, the subject with the later time of the last HF 
hospitalization is the winner. For component c) the same algorithm is applied as for component 
b). For component d), the subject with the larger decrease or smaller increase in the proportional 
change is considered a winner; if the ratio of the proportional changes from two subjects is 
between 0.75 and 1/0.75, then the pairwise comparison of the change in NT-proBNP is 
considered tied. This proportional change is equivalent to ± 0.2876 on the natural log scale 
ln(0.75) and ln(1/0.75). 
The analysis will be performed using the unmatched pair win ratio approach. Contributions of 
each component of the composite endpoint to the total number of winners used in the estimation 
of the win ratio will be reported. More details on win ratio approach are in Section 5.4.2 
2.6.2.1.1 Handling of missing values/censoring/discontinuations 
For the calculation of the win-ratio an initial time “at risk” (follow-up) for each subject will be 
calculated as number of days from treatment start date to their attained: 
– Date of last visit (End of Study visit) 
– Date of death from any cause 
– Date of withdrawal of informed consent 
– Date of loss to follow up 
CV death events 
In the case of CV death in one or both subjects the following censoring rules will be applied: 
• If a CV death occurs in both subjects then all time at risk will be considered and the 
subject with the latest time to CV death will be considered the winner 
• If a CV death occurs in one subject and it occurs before the second subject time at risk is 
censored then the subject who does not experience the CV death will be considered the 
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• If a CV death occurs in one subject and it occurs after the second subject time at risk is 
censored then the pair will be considered a tie 
Note: for this event deaths from non-CV causes will be censored. 
HF hospitalization events and urgent HF visits 
For these events only those that occur in the time at risk that is common for both subjects in the 
pair will be used for analysis to define win or tie. For example, if subject 1 of a pair has 145 
days at risk and subject 2 has 126 days only events that occur days 1-126 are considered.   
Time-averaged proportional change in NT-proBNP (from baseline to Weeks 4 
and 8) 
If the NT-proBNP value is missing for one or both subjects in the pair then the pairwise 
comparison of the change in NT-proBNP is considered tied. 
2.6.2.1.2 Sensitivity Analysis: 
Three sensitivity analyses are planned for secondary endpoint 1. 
• The primary analysis of the win ratio will be repeated but will also include HF 
hospitalizations that are adjudicated as Possible HF Hospitalization (i.e. are insufficient data 
to meet PARAGLIDE-HF criteria) in addition to confirmed HF hospitalizations. 
• The primary analysis of the win ratio will be repeated but data for CV death, HF 
hospitalizations and urgent HF visits will be based on investigator reporting and not 
adjudicated data.  
• The primary analysis of the win ratio will be repeated but data that occurs after diagnosis as 
COVID-19 positive will be censored at the subject level.  
2.6.2.2 
Analysis of secondary endpoint 2 
The cumulative number of recurrent composite events over time, i.e., the total number of 
composite events of  
a) CV death (Adjudicated by EAC), 
b) HF hospitalizations (Adjudicated by EAC - only the confirmed events will be 
considered, i.e. HF hospitalizations meeting PARAGLIDE-HF criteria),   
c) Urgent HF visits (Adjudicated by EAC), 
The FAS will be used in the main analysis of the secondary endpoint 2. 
The cumulative number of composite events, ie, the total number of composite events of CV 
death, recurrent HF hospitalizations, and recurrent urgent HF visits for a subject over time will 
be calculated. The time to these recurrent events will be analyzed using the semi-parametric 
proportional rates model (abbreviated as LWYY model)(Lin 2000). The hypotheses of interest 
are: 
H30: Rate ratio of sacubitril/valsartan arm over valsartan arm equal to 1, versus 


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H3a: Rate ratio of sacubitril/valsartan arm over valsartan arm not equal 1. 
A rate ratio < 1 indicates an effect in favor of sacubitril/valsartan arm. 
The hypothesis (H30) will be tested, and 95% CIs will be provided. The rate ratio will be 
estimated from the above proportional rates model with treatment and in-hospital/out-of- 
hospital randomization as fixed factors through maximization of a partial likelihood score 
function. The CIs will be based on the robust estimate of the standard errors. The number and 
percentage of CV events by event type will be summarized. 
Censoring Variables: 
The CV death will not be considered a censoring variable, but a composite endpoint event and 
a conditional factor in this analysis. Time to non-CV death will be considered as a censoring 
variable. Any censoring due to non-CV death is assumed to be non-dependent in the analysis. 
2.6.2.2.1 Sensitivity Analysis: 
Four sensitivity analyses are planned for secondary endpoint 2. 
• The primary analysis of the LWYY model will be repeated but will also include HF 
hospitalizations that are adjudicated as Possible HF Hospitalization (i.e. are insufficient data 
to meet PARAGLIDE-HF criteria) in addition to confirmed HF hospitalizations meeting 
PARAGLIDE-HF criteria  
• The primary analysis of the LWYY model will be repeated but data for CV death, HF 
hospitalizations and urgent HF visits will be based on investigator reporting and not 
adjudicated data. 
• The primary analysis of the Secondary endpoint 2 will be repeated with Kaplan-Meier 
estimates for time to the first composite event by the treatment group, in tables and graphs. 
• The primary analysis of the LWYY model will be repeated but data that occurs after 
diagnosis with COVID-19 positive will be censored at the subject level. 
2.6.2.3 
Analysis of secondary endpoint 3 
Incidences of a composite endpoint of worsening renal function are defined as: 
• renal death (from AE data) 
• reaching end-stage renal disease (ESRD) (Sustained eGFR <15mL/min/m2, chronic 
dialysis, or renal transplant) 
• ≥ 50% decline in estimated glomerular filtration rate (eGFR) relative to baseline 
[using central laboratory measurements (scheduled or unscheduled visits)] 
Among the variables above, none of their components will be adjudicated. The Investigator-
reported AE and central laboratory data will be used to identified event of interest in this 
secondary endpoint 3. 
ESRD is defined as one of the following:  


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• 
Initiation of dialysis (e.g., hemodialysis, peritoneal dialysis, or continuous eno-
venous hemodialysis) after randomization (post-baseline). [from the procedure (PR) 
data] 
• 
A drop in eGFR from baseline (randomization, i.e. Visit 2) to a value <15 
mL/min/1.73m2 on two consecutive central laboratory measurements [scheduled or 
unscheduled visits] separated by ≥ 30 days. This event will be identified 
programmatically by the programming team.  
• 
Occurrence of kidney transplantation. [from the procedure (PR) data] 
The main analysis of the total number of composite events will be performed using a negative 
binomial regression model with the count data as the dependent variable. Treatment group and 
in-hospital/out-of-hospital randomization as fixed-effect factors and log (follow-up duration) 
as the off-set. The model will be used to estimate event rates and their 95% CIs by treatment 
group.  
2.6.2.3.1 Sensitivity Analysis: 
Three sensitivity analyses are planned for secondary endpoint 
• The time to the first composite event will be analyzed using Cox’s proportional hazard 
model with factors treatment and in-hospital/out-of-hospital randomization. Hazard ratio 
for treatment and its 95% CIs will be reported. 
• The Kaplan-Meier estimates for time to the first composite events will be provided by the 
treatment group, in tables and graphs. 
• The primary analysis of secondary endpoint 3 will be repeated but data that occurs after 
diagnosis  as COVID-19 positive will be censored at the subject level.  
2.6.2.4 
Analysis of  secondary endpoint 4 
The proportional change in NT-proBNP from Baseline to Week 8 will be analyzed using an 
ANCOVA model similar to the primary efficacy analysis.  
• The primary analysis of secondary endpoint 4 will be repeated but data tha occurs after 
diagnosis  as COVID-19 positive will be censored at the subject level.  
2.6.2.5 
Analysis of secondary endpoint 5 
The proportional change in high-sensitivity Troponin (hs-Troponin) from Baseline to Week 4 
will be analyzed using an ANCOVA model similar to that of the primary efficacy analysis. Log 
transformed hs-Troponin will be used for analysis. The analysis will be repeated for Week 8. 
• The primary analysis of secondary endpoint 4 will be repeated but data that occurs after 
diagnosis  as COVID-19 positive will be censored at the subject level.  
2.6.2.6 
Analysis of secondary endpoint 6 
The dosing level will be summarized by treatment group and in-hospital/out-of hospital  
randomization status.  


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Incidence of discontinuations (all causes) will be summarized by treatment group and in-
hospital/out-of-hospital randomization status.  
• The primary analysis of secondary endpoint 6 will be repeated but data tha occurs after 
diagnosis  as COVID-19 positive will be censored at the subject level.  
2.6.2.7 
Analysis of secondary endpoint 7 
Incidence of below adverse events of special interest (AESI) during treatment will be 
considered. 
• Incidence of symptomatic hypotension (Collected in AESI CRF)    
• Incidence of hyperkalemia (potassium >5.5 mEq/L) (Collected in AESI CRF)     
• Incidence of angioedema (Collected in AESI CRF)   
• Incidence of worsening renal function, defined as an increase in serum creatinine of 
≥0.5mg/dl and worsening of the eGFR by at least 25% [using Central Lab data from 
same scheduled or unscheduled visits] 
Incidence of adverse events of special interest (AESIs) will be analyzed using a logistic 
regression model with treatment and in-hospital/out-of-hospital randomization as fixed factors. 
The model will be used to estimate the odds ratio for treatment and its 95% CIs.  
• The number (and proportion) of subjects with AESI will be summarized by treatment.  
• The primary analysis of secondary endpoint 7 will be repeated but data that occurs after 
diagnosis as COVID-19 positive will be censored at the subject level.  
2.6.3 
Handling of missing values/censoring/discontinuations 
The analysis will be performed based on all available data in the FAS and based on likelihood 
method with an assumption of missing at random for missing data. 
2.7 
Safety analyses 
For all safety analyses, the SAF will be used. All listings and tables will be presented by 
treatment group and in-hospital/out-of-hospital randomization category. 
Safety summaries (tables, figures) include only data from the on-treatment period with the  
exception of Baseline data, which will also be summarized where appropriate (eg, change from 
Baseline summaries). In addition, a separate listing for death including on-treatment and post 
treatment deaths will be provided. In particular, summary tables for AEs will summarize only 
on-treatment events, with a start date during the on-treatment period (treatment-emergent AEs 
(TEAEs)). The on-treatment period lasts from the date of first administration of study treatment 
to the last study visit. 
2.7.1 
 Adverse events 
2.7.1.1 
Coding of adverse events 
Adverse events will be coded using the latest version of MedDRA terminology at the time of 
DBL. 


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2.7.1.2 
General rules for AE reporting 
All information obtained on AEs will be displayed by treatment group and subject. 
The number (and percentage) of subjects with TEAEs (events started after the first dose of study 
medication, or events present prior to start of double-masked treatment but increased in severity 
based on PT) will be summarized in the following ways: 
• By treatment, primary SOC and PT. 
• By treatment, primary SOC, PT and maximum severity. 
• By treatment, pre-defined topic of interest, primary SOC and PT. 
Separate summaries will be provided for study medication-related AEs, serious adverse events 
(SAEs), and other significant AEs leading to discontinuation. 
A subject with multiple adverse events within a primary SOC is only counted once towards the 
total of the primary SOC. 
2.7.1.3 
Treatment-emergent adverse events 
AE summaries will include all TEAEs. TEAEs are defined as AEs starting on or after the first 
day of study treatment. All AEs will be listed. AEs starting prior to the first day of study 
treatment (non-TEAEs) will be flagged in the listings. 
All TEAEs will be summarized by study phase as defined in Section 2.1.1. 
TEAEs will be summarized by presenting the number and percentage of subjects having at least 
1 TEAE, having at least 1 TEAE in each primary SOC, and for each PT using MedDRA coding.  
A subject with multiple occurrences of a TEAE will be counted only once in the AE category. 
Separate summaries will be presented by SOC, PT and severity. A subject with multiple 
severities for an AE will be summarized under the worst severity recorded for the event. 
Any information collected will be listed as appropriate. 
2.7.1.4 
Adverse event summaries 
The following summary tables will be provided: 
• AEs, regardless of study treatment relationship, by primary SOC, PT and maximum severity 
• Most frequent (≥5%) AEs, regardless of study treatment relationship, by PT 
• AEs, related to study treatment reported by investigator , by primary SOC and PT 
• SAEs, regardless of study treatment relationship, by primary SOC and PT 
• SAEs, related to study treatment reported by investigator, by primary SOC and PT 
• SAEs occurring with a frequency of ≥0.5%, regardless of study treatment relationship, by 
PT 
• SAEs, regardless of study treatment relationship, by primary SOC, PT, and seriousness 
criteria 
• AEs leading to discontinuation, regardless of study treatment relationship, by primary SOC 
and PT 


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• AEs requiring dose adjustment or study treatment interruption, regardless of study treatment 
relationship, by primary SOC and PT 
• AEs requiring additional therapy, regardless of study treatment relationship, by primary 
SOC and PT 
• Death resulting from AEs, regardless of the study treatment relationship, by primary SOC 
and PT 
2.7.1.5 
Adverse events of special interest / grouping of AEs 
Separate summaries will be provided for AEs related to all angioedema, elevated creatinine, 
hyperkalemia, symptomatic hypotension. The summaries will be presented by primary SOC, 
PT and worst severity. 
In addition, suspected or confirmed SARS-CoV-2 infections will be listed.  
Additionally, a sensitivity analysis will be performed on the AESIs for subjects randomized to 
sacubitril/valsartan. The number and percentages of AESIs occurring prior to the active dose of 
sacubitril/valsartan will be presented along with the number and percentages of AEs of special 
interest occurring on or after the active dose of sacubitril/valsartan during the study. The 
following definitions will be used: 
Angioedema: 
AE prior to active study treatment = if event occurred within 1 day of dosing as recorded on 
the Angioedema Assessment Visit 2 (randomization) 
AE after active study treatment = if event occurred after 1 day of dosing as recorded on the 
Angioedema Assessment Visit 2 (randomization) 
Symptomatic hypotension: 
AE prior to active study treatment = First dose date ≤ event   
AE after active study treatment = event ≤ Last dose date of medication 
Elevated creatinine: 
AE prior to active study treatment = First dose date:time of study treatment ≤ event 
AE after active study treatment = event ≤ Last dose date:time of  medication  
Hyperkalemia: 
AE prior to active study treatment = First dose date:time of study treatment ≤ event 
AE after active study treatment = event ≤ Last dose date:time of  medication 
2.7.1.6 
Exposure Adjusted Adverse Events 
The following Exposure adjusted incidence rate of adverse events will be presented by study 
phase and treatment group: 
• Exposure-adjusted incidence rate of adverse events by preferred term 


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• Exposure-adjusted incidence rate of study treatment related adverse events by primary 
system organ class and preferred term 
• Exposure-adjusted incidence rate of adverse events leading to permanent study 
treatment discontinuation by primary system organ class and preferred term 
• Exposure-adjusted incidence rate of serious adverse events by primary system organ 
class and preferred term 
• Exposure-adjusted incidence rate of deaths by primary system organ class and preferred 
term 
The exposure adjusted incidence rate (IR) will be derived by the number of subjects with an 
event divided by the corresponding sum of the exposure duration for all subjects, where duration 
of exposure in Subject Treatment Years (STY) is counted up to the first qualifying event (or 
end of time at risk for subjects without event).  
Incidence rate will be set to the 100 STY and only on treatment events (TEAE) will be included.  
2.7.2 
Deaths (EAC Adjudicated) 
All subject deaths will be adjudicated by EAC. Subject deaths will be summarized by total (all-
cause), primary cause of death, type of cardiovascular death and type of non-cardiovascular 
death and will be presented by study phase (see Section 2.1.1 for study phase definitions). A 
subject listing of all deaths with recorded principal cause of death will be provided. All subjects 
in the SAF will be included for the above analysis.  
• A KM curve will be presented for all-cause deaths.  
2.7.3 
Laboratory data 
All laboratory data will be listed by treatment group, in-hospital/out-of-hospital randomization, 
subject, and visit/time and if normal ranges are available abnormalities will be flagged.  
Shift tables using the low/normal/high/ classification will be used to compare Baseline to the 
worst post Baseline value. The number and percentage of subjects with laboratory values will 
be presented by low/normal/high (low and high) classifications to compare Baseline to worst 
post Baseline value. 
In addition, laboratory values and the change from Baseline for each parameter by visit will be 
summarized by treatment group sacubitril/valsartan. In the event that there are multiple 
laboratory values within a visit, the worst value will be summarized. 
A summary of hyperkalemia labs by visit will also be presented by treatment group. The highest 
potassium value for the event and any potassium re-test results will be descriptively summarized. 
Similarly, creatinine labs will also be presented by visit, treatment group. The highest creatinine 
value for the event and any creatinine re-test results will be descriptively summarized. 
Listings of all laboratory values will be provided. Separate listings for hyperkalemia labs, 
creatinine labs, and pregnancy tests will also be provided. Any notable laboratory abnormalities 
will also be flagged. 


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2.7.3.1 
Laboratory Assessments 
 
Hematology  
Hemoglobin, hematocrit, red blood cell (RBS) count, white blood cell (WBC) count with 
differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands, Other 
(absolute value preferred , %s are acceptable), and platelet count will be measured at Visits 1, 
2, 7, 11, 13, 15, and 17 (central lab). Hemoglobin A1c will be measured at Visit 2 and 17 (central 
lab). 
Chemistry  
Assessments required for eligibility that need to be measured at Visit 1 include creatinine, 
potassium, and total bilirubin. Blood urea nitrogen (BUN), glucose, creatinine, total bilirubin, 
AST (SGOT), ALT (SGPT), alkaline phosphatase, sodium, potassium, chloride, calcium , total 
protein, albumin, uric acid, and lipid profile be measured at Visits 1 (local lab), 2, 3, 5, 7, 9, 11, 
13,  15, 16  and 17 (central lab). 
 
Urinalysis  
Dipstick-test determination of specific gravity, pH, blood, total protein, bilirubin, ketones, and 
leukocytes will be measured at Visit 2 (central lab). If dipstick is positive, a qualitative 
microscopic determination, including WBCs high power field and RBCs high power field will 
be performed. 
 
Pregnancy Test 
All female subjects of childbearing potential will have a serum pregnancy test (hCG) performed 
at Visit 1 (local lab). In addition, these subjects will have a urine pregnancy test conducted in 
the local laboratory at Visits 2, 5, 7, 11, 13, 15, 16, and 17. If any of these tests are positive at 
Visits 1 and 2, the subject should not be enrolled in the trial. If a subject should become pregnant 
during the trial, the subject may remain in the trial for follow-up visits but must discontinue 
study drug. 
2.7.4 
Other safety data 
2.7.4.1 
Electrocardiogram and cardiac imaging data 
A standard 12 lead ECG will be performed by Visit 1. ECG data will be collected at Visit 1 will 
also be listed along with the summary statistics.  
2.7.4.2 
Vital signs 
All vital signs (SBP and diastolic blood pressure (DBP) (mmHg), pulse rate (sitting/beats per 
minute), weight (kg), height (cm), BMI (kg/m2) and waist/hip circumference) will be 
descriptively summarized at each visit by treatment group. Change from Baseline will also be 
presented, excluding height and waist/hip circumference. 
A separate summary table will be presented with the number and percentages of subjects having 
notable vital signs based on changes relative to Baseline values (see Section 2.1.1 for study 
phase definitions and Section 5.3.3 for the list of notable vital signs). 


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The number and percentages of subjects having symptomatic hypotension will also be 
summarized. The following variables associated with symptomatic hypotension will also be 
presented: symptoms occurring while standing, any treatment or medication change as a result 
of episode, lowest documented SBP, SBP position, lowest documented DBP and DBP position. 
A listing for symptomatic hypotension will also be presented. 
2.7.4.3 
Heart Failure Event 
Any new HF event information will be collected and listed. The following will be presented: 
• Type of event (HF hospitalization [hospital stay ≥24 hours], HF ED visit, Urgent/unplanned 
HF office visit, Worsening HF during the index hospitalization [qualifying HF event], None 
of the aforementioned types occurred with, or apply to, this HF event) 
• Symptoms of worsening HF (Dyspnea – [Dyspnea at rest, Dyspnea on exertion, Orthopnea, 
Paroxysmal nocturnal dyspnea, Tachypnea], Decreased exercise tolerance [reduced ability 
to perform activities that induce physical exertion due to dyspnea or fatigue], Fatigue [lack 
of energy, extreme tiredness, inability to complete usual activities], Worsening end-organ 
perfusion – [Confusion (thought to be from low cardiac output), Reduced urine output], 
Symptoms of volume overload – [Lower extremity swelling, Increased abdominal 
distension)], Other) 
• Physical exam signs of worsening HF (Peripheral edema, Increased abdominal distension 
or ascites [in the absence of hepatic disease], Pulmonary rales/crackles, Elevated jugular 
venous pressure and/or hepatojugular reflux, New or worsening 3rd heart sound, Clinically 
significant weight gain thought to be related to fluid retention [>3 to 4 lbs. in 3 to 4 days], 
Other) 
• Laboratory evidence of worsening HF (Increased NT-proBNP [> 2,000 pg/mL], 
Radiographic evidence of pulmonary congestion, Right heart catheterization with 
pulmonary capillary wedge pressure ≥18 mmHg, central venous pressure ≥12 mmHg, or a 
cardiac index of < 2.2 L/min/m2, Other) 
• Increased or additional therapy (No, Yes, Unknown) 
• Therapy type (Augmentation of oral diuretic therapy with additional diuretic; Initiation 
of intravenous diuretic; Uptitration of intravenous therapy, if already on therapy; 
Initiation of inotrope, or vasodilator therapy; Initiation of percutaneous mechanical 
circulatory support; Initiation of temporary surgical support [extracorporeal membrane 
oxygenation or temporary surgical ventricular assist device  ie, centrimag]; 
Implantation of durable left ventricular assist device; Listed for heart transplantation) 
• Evidence of cardiogenic shock (No, Yes, Unknown) 
• Blood sample collected for BNP or NT-proBNP (No, Yes, Unknown) 
• BNP result (pg/mL) 
• NT-proBNP result (pg/mL) 
• Contributors/precipitants of worsening HF (Medication nonadherence, Dietary indiscretion, 
Acute coronary syndrome, Other systemic illness – [Respiratory infection, Urinary tract 
infection, Other]) 


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2.7.4.4 
HF Signs and Symptoms 
• NYHA Classification (Class I: no limitation of physical activity; Class II: slight limitation 
of physical activity; Class III: marked limitation of physical activity; Class IV: unable to 
carry out any physical activity without discomfort). 
• Paroxysmal nocturnal dyspnea (Absent, Present) 
• Dyspnea at rest (Absent, Present) 
• Dyspnea on effort (Absent, Present; if Present: Mild, Moderate, Severe)  
• Fatigue (Absent, Present) 
• Orthopnea (Absent, Present; if Present: 1 pillow (10cm elevation); 2 pillows (20 cm 
elevation); >2 pillows (>20 cms elevation)) 
• Jugular venous distention (Absent, Present, Not Available; if Present: <6 cm; 6 to 10 
cm; >10 cm) 
• Edema (Absent, Present; if Present: Trace; 1+; 2+; 3+; Feet and Ankles (no/yes); Lower 
legs of thighs (no/yes); Sacrum (no/yes)) 
• Rales (Absent, Present; if Present: Rales <1/3; Rales 1/3 to 2/3; Rales > 2/3) 
• Third heart sound (Absent, Present, Not Available) 
2.7.4.5 
Hospitalization 
Information related to hospitalization will be listed. The following will be presented: 
• Type of hospitalization (Elective, Planned, Unplanned) 
• Reason for hospitalization (refer to eCRF for list of reasons) 
• Subject discharged (No, Yes, Unknown) 
• Duration of hospitalization in days [date of discharge – date of admission + 1] 
• Subject admitted to ICU or Coronary Care Unit (CCU) (No, Yes, Unknown) 
• Number of days in ICU or CCU 
• Discharge disposition (Home or with family/friends, Rehabilitation facility, Skilled nursing 
facility, Death, Unknown) 
All hospitalizations (Cardiovascular (CV) Hospitalization, Non-Cardiovascular (non-CV 
Hospitalization and Undetermined Cause of Hospitalization)) will be adjudicated by the Events 
Adjudication Committee at Brigham and Women’s Hospital. 
Information on time from index hospitalization to randomization will be summarized.  
2.7.4.6 
Angioedema 
Data collected from the Questionnaire for Angioedema-Like Event at Screening, 
Randomization and Follow-up visits will be summarized. Separate summaries will be produced 
for all angioedema events. The number and percentage for categorical variables and summary 
statistics for continuous variables of the following will be presented by visit, treatment group 
and open-label sacubitril/valsartan: 
• Outcome (Not recovered/Not resolved, Recovered/Resolved, Recovering/Resolving, 
Recovered/Resolved with Sequelae, Fatal, Unknown) 


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• Duration of angioedema in days [end date – start date + 1] 
• Timing of event (After first dose, after multiple doses, dose not given) [not asked at 
screening] 
• Study medication discontinued due to event (No, Yes, Unknown) 
• Event occurred within 1 day of dosing (Within 1 day of dose but less than or equal to 1 
hour, within 1 day of dose but greater than 1 hour, After 1 day of dosing, Unknown) 
• History of prior angioedema or angioedema like event (No, Yes, Unknown) 
• If yes, medications taken at time of previous event: 
• ACE inhibitor (No, Yes, Unknown) 
• ARB (No, Yes, Unknown) 
• Renin inhibitor (No, Yes, Unknown) 
• Other medications (No, Yes, Unknown) 
• Presence of hereditary angioedema (No, Yes, Unknown) 
• Any family members with history of angioedema-like events (No, Yes, Unknown) 
• Signs and symptoms for current event 
• Shortness of breath/dyspnea (No, Yes, Unknown) 
• Difficulty swallowing/dysphagia (No, Yes, Unknown) 
• Difficulty speaking/dysarthria (No, Yes, Unknown) 
• Pain on swallowing/odynophagia (No, Yes, Unknown) 
• Stridor (No, Yes, Unknown) 
• Abdominal pain (No, Yes, Unknown) 
• Other (No, Yes, Unknown) 
• Edema present (No, Yes) 
• Periorbital edema (No, Yes, Unknown) 
• Head edema (No, Yes, Unknown) 
• Neck edema (No, Yes, Unknown) 
• Lip edema (No, Yes, Unknown) 
• Tongue edema (No, Yes, Unknown) 
• Throat edema (No, Yes, Unknown) 
• Submandibular edema (No, Yes, Unknown) 
• Genitalia edema (No, Yes, Unknown) 
• Extremities edema (No, Yes, Unknown) 
• Other (No, Yes, Unknown) 
• Previous edematous episodes (No, Yes, Unknown) 
• Number of previous edematous episodes 
• ACEi taken in the past (No, Yes, Unknown) 
• ACEi taken during trial participation after Screening (No, Yes, Unknown) [not asked at 
Screening] 


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• Dose changed within 2 days of event (No, Yes, Unknown) 
• ARB taken in the past (No, Yes, Unknown) 
• ARB taken during trial participation after screening (No, Yes, Unknown) [not asked at 
Screening] 
• Dose changed within 2 days of event (No, Yes, Unknown) 
• Subject suffering from influenza, common cold or upper respiratory tract infection (No, Yes, 
Unknown) 
• Medication allergies (No, Yes, Unknown) 
• Food allergies (No, Yes, Unknown) 
• Potential causes of angioedema-like event 
• Food (No, Yes, Unknown) 
• Insect bite (No, Yes, Unknown) 
• Animal exposure (No, Yes, Unknown) 
• Medication (No, Yes, Unknown) 
• Dental work (No, Yes, Unknown) 
• Pollen (No, Yes, Unknown) 
• Dust (No, Yes, Unknown) 
• Concomitant disease (No, Yes, Unknown) 
• Idiopathic (No, Yes, Unknown) 
• Other (No, Yes, Unknown) 
• Medical intervention (No, Yes) 
• Administration of H-1 blocker (No, Yes) 
• Administration of H-2 blocker (No, Yes) 
• Administration of steroids (No, Yes) 
• Administration of epinephrine (No, Yes) 
• Admission to hospital (No, Yes) 
• Admission to the emergency room (No, Yes) 
• Endotracheal intubation (No, Yes) 
• Tracheostomy (No, Yes) 
• Discontinuation of ACE inhibitor (No, Yes) 
• Discontinuation of ARB (No, Yes) 
• Other 
All assessment data will be listed as collected in the CRF.  
2.8 
Pharmacokinetic endpoints   
Not applicable. 






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2.13 
Interim analysis 
There is no planned interim analysis for efficacy in the study.  
Interim Safety Assessment  
An independent DMC will be responsible for performing interim safety assessment using 
independent statistician and programmer who will not be involved in the trial conduct. The 
DMC charter will contain the committee’s responsibilities regarding the interim safety 
assessment. Details of this safety assessment will be included in the DMC-SAP.  
Interim safety assessments are planned to be performed and results will be provided to DMC 
for their review and recommendation. There are 3 DMC planned and the timing of these safety 




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o If the year is the same as the year of first study treatment, then the day and month 
of the start date of treatment will be assigned to the missing fields. 
o If the year is prior to the year of first study treatment, then December 31 will be 
assigned to the missing fields. 
o If the year is after the year of first study treatment, then January 1 will be 
assigned to the missing fields. 
• 
Missing month only 
o Treat day as missing and replace both month and day according to the above 
procedure. 
• 
Missing day only 
o If the month and year are the same as the year and month of first study treatment, 
then the start date of treatment will be assigned to the missing day. 
o If the month and year are before the year and month of first study treatment, then 
the last day of the month will be assigned to the missing day. 
o If the month and year are after the year and month of first study treatment, then 
the first day of the month will be assigned to the missing day. 
If the imputed start date result is after the stop date (and the stop date is complete), the imputed 
start date will be reset to the stop date. 
The following algorithm should be used to estimate stop dates for which only partial 
information is known: 
• 
Missing year 
o Date left missing. 
• 
Missing month 
o Impute ‘December’. 
• 
Missing day 
o Impute ‘last date of that month’. 
5.1.3 
Concomitant medication date imputation 
The following algorithm should be used to estimate start dates for which only partial 
information is known: 
• 
Missing day and month 
o If the year is the same as the year of first study treatment, then the day and month 
of the start date of treatment will be assigned to the missing fields. 
o If the year is prior to the year of first study treatment, then December 31 will be 
assigned to the missing fields. 
o If the year is after the year of first study treatment, then January 1 will be 
assigned to the missing fields. 


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• 
Missing month only 
o Treat day as missing and replace both month and day according to the above 
procedure. 
• 
Missing day only 
o If the month and year are the same as the year and month of first study treatment, 
then the start date of treatment will be assigned to the missing day. 
o If the month and year are before the year and month of first study treatment, then 
the last day of the month will be assigned to the missing day. 
o If the month and year are after the year and month of first study treatment, then 
the first day of the month will be assigned to the missing day. 
If the imputed start date result is after the stop date (and the stop date is complete), the imputed 
start date will be reset to the stop date. 
The following algorithm should be used to estimate stop dates for which only partial 
information is known: 
• 
Missing year 
o Date left missing. Consider the medication to have been received at all periods 
after that period determined by the start date. 
• 
Missing month 
o Impute ‘December’. 
• 
Missing day 
o Impute ‘last date of that month’. 
5.1.3.1 
Prior therapies date imputation 
The same imputation as concomitant medication will be used. See Section 5.1.3. 
5.1.3.2 
Post therapies date imputation 
The same imputation as concomitant medication will be used. See Section 5.1.3. 
5.1.3.3 
Other imputations 
Not applicable 
5.2 
AEs coding/grading 
The United BioSource Company, UBC coding team will code the AE terms using MedDRA 
terminology (v19.0 or later). If any terms are not coded, the data management team will issue 
queries to sites to update the AE term appropriately. 


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5.3 
Laboratory parameters derivations 
5.3.1 
Laboratory grading 
The collected laboratory values will be summarized by severity (low/normal/high) and not 
converted to Common Terminology Criteria for Adverse Events grades. 
5.3.2 
Notable laboratory values 
Clinically notable laboratory abnormalities for selected tests based on a percent change from 
Baseline: 
Hematology 
RBC count 
>50% increase, >20% decrease 
Hemoglobin  
>50% increase, >20% decrease 
Hematocrit 
>50% increase, >20% decrease 
WBC count 
>50% increase, >50% decrease 
Platelet count 
>75% increase, >50% decrease 
Blood Chemistry 
 
ALT (SGPT) 
>150% increase 
AST (SGOT) 
>150% increase 
BUN 
>50% increase 
Creatinine  
>50% increase 
Total bilirubin 
>100% increase 
CPK 
>300% increase 
Alkaline phosphatase 
>100% increase 
Potassium  
>20% increase, >20% decrease 
Chloride  
>10% increase, >10% decrease 
Calcium  
>10% increase, >10% decrease 
Uric acid 
>50% increase 
5.3.3 
Clinically notable changes in vital signs 
               Vital Sign (unit)                                 Clinically notable criteria 
 Weight (kg)                                                   decrease > 7% from Baseline 
                                                                       increase > 7% from Baseline 
 
Sitting systolic blood pressure (mmHg)        <90 and decrease from baseline of >20 
                                                                      >180 and increase from baseline of >20 
 


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Sitting diastolic blood pressure (mmHg)       <50 and decrease from baseline of >15 
                                                                      >105 and increase from baseline of >15 
Pulse (bpm)                                                  <50 and decrease from baseline of > 15 
                                                                      >120 and increase from baseline of >15 
 
5.4 
Statistical models 
5.4.1 
Primary analysis 
The null hypothesis for the primary analysis is the ratio of the geometric means of NT-proBNP 
for the sacubitril/valsartan and valsartan groups are equal. For NT-proBNP, the time-averaged 
proportional change from Baseline in a natural logarithmic scale will be analyzed using an 
analysis of covariance (ANCOVA) model with treatment, in-hospital/out-of-hospital 
randomization status, gender, and baseline LVEF (≤ Median, > Median) as fixed effect factors, 
age and the logarithmic Baseline NT-proBNP as covariates. 
The general form for the ANCOVA model is: 
 
yij = μ + τi + B(xij − 𝑥𝑥̅i ) + ϵij 
 
PROC MIXED in SAS will be used for the analysis. The LSMEANS option will be used with 
options of CL to output the confidence limits. 
proc mixed data=<........>; 
class treatment in-hospital/out-of-hospital gender baseLVEF; 
model chg = treatment in-hospital/out-of-hospital gender baseLVEF age base NT-
proBNP; 
lsmeans treatment / OM pdiff cl; 
run; 
where, 
treatment = treatment the subject is randomized to 
in-hospital/out-of-hospital = whether the subject randomized in hospital or out of hospital 
gender = gender of the subject 
baseLVEF = Baseline LVEF (≤ Median, > Median) 
chg =  NT-proBNP, the time-averaged proportional change from Baseline in a natural 
logarithmic scale 
age = age of the subject 
baseNT-proBNP = the logarithmic Baseline NT-proBNP 


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5.4.2 
Secondary analysis endpoint 1 
The composite hierarchical outcome consisting of: a) time to CV death, b) number and times of 
HF hospitalizations during follow-up, c) number and times of urgent HF visits during follow-
up, and d) time-averaged proportional change in NT-proBNP (from Baseline to Weeks 4 and 8) 
This secondary efficacy endpoint 1analysis is described in Section 2.6.2.1. 
This hierarchical composite endpoint consists of the following four ordered components: 
a) Time to CV death,  
b) Number and times of HF hospitalizations during follow-up,  
c) Number and times of urgent HF visits during follow-up, and  
d) Time-averaged proportional change in NT-proBNP (from Baseline to Weeks 4 and 8)  


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Table 5-1 
Step wise determination of win ratio winners 
Hierarchy/Outcome 
Category 
Criteria 
Winner 
Definition 
Result 
1 Time to CV death 
A 
Both subjects experienced 
CV death 
Subject with 
longest time to 
death 
sacubitril/valsartan 
or valsartan 
winner 
B 
One subject only experienced 
CV death and it occurred 
before the censoring time of 
the other subject in the pair 
Subject who 
did not 
experience CV 
death 
sacubitril/valsartan 
or valsartan 
winner 
C 
One subject only experienced 
CV death and it occurred 
after the censoring time of 
the other subject in the pair 
N/A 
Tie 
D 
Neither subject experience 
CV death 
N/A 
Tie 
E 
For one or both subjects the 
cause of death is not known 
N/A 
Tie 
2 Number and times of 
HF hospitalizations 
during common follow-
up+* 
F 
Count of both subjects HF 
hospitalizations 
Subject with 
fewest HF 
hospitalizations 
sacubitril/valsartan 
or valsartan 
winner 
G 
If equal number of HF 
hospitalizations 
Subject with 
longer time to 
last HF 
hospitalization 
sacubitril/valsartan 
or valsartan 
winner 
H 
If counts equal and time to 
last HF hospitalization equal 
N/A 
Tie 
I 
For one or both subjects the 
number of HF 
hospitalizations is not known 
N/A 
Tie 
3 Number and times of 
urgent HF visits during 
common follow-up+** 
J 
Count of both subjects' 
urgent HF visits 
Subject with 
fewest urgent 
HF visits 
sacubitril/valsartan 
or valsartan 
winner 
K 
If equal number of urgent HF 
visits 
Subject with 
longer time to 
last urgent HF 
visit 
sacubitril/valsartan 
or valsartan 
winner 
L 
If counts equal and time to 
last urgent HF visit equal 
N/A 
Tie 
M 
For one or both subjects the 
no of urgent HF visits is not 
known 
N/A 
Tie 
N 
Subject has urgent HF visit 
after the end of another 
subject’s time at risk. 
N/A 
Tie 


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4 Time-averaged 
proportional change in 
NT-proBNP from 
Baseline to Weeks 4 and 
8*** 
O 
Compare subjects 
proportional change from 
Baseline 
Difference of 
the 
proportional 
change from 
two subjects is 
between -
0.2876 and 
0.2876 
Tie 
P 
Compare subjects 
proportional change from 
Baseline 
Difference of 
proportional 
change 
between 
subjects is < -
0.2876    
OR  >0.2876: 
The subject 
with the larger 
decrease or 
smaller 
increase is the 
winner 
sacubitril/valsartan 
or valsartan 
winner 
Q 
A comparison is not possible 
as the NT-proBNP value is 
missing for one or both 
subjects in the pair 
N/A 
Tie 
+ For these events only those that occur in the common follow-up time for both subjects in the 
pair will be used for analysis to define win or tie. For example, if subject 1 of a pair has 145 
days at risk and subject 2 has 126 days only events that occur on days 1-126 are considered. 
* Patients in categories C, D & E only are evaluated 
** Patients in categories H & I only are evaluated  
*** Patients in categories L, M & N only are evaluated 
Table 5-2 
Win Ratio Winner Categories 
Category 
Description  
Winner 
a 
Time to CV death  
sacubitril/valsartan  
b 
valsartan winner 
c 
Number and times of HF hospitalizations 
during common follow-up  
sacubitril/valsartan  
d 
valsartan winner 
e 
Number and times of urgent HF visits during 
common follow-up  
sacubitril/valsartan  
f 
valsartan winner 
g 
Time-averaged proportional change in NT-
proBNP from Baseline to Weeks 4 and 8  
sacubitril/valsartan  
h 
valsartan winner 
i 
None of the above 
None of the above 


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Let Nv and Nvs be the number of subjects on sacubitril/valsartan and valsartan treatments. Then 
one makes all Nn× Ns paired comparisons. Each pair is classified into one of categories a 
through i in Table 5-2 and will be reported. 
The trial’s composite endpoint results are summarized by Na, Nb, Nc, Nd, Ne, Nf, Ng, Nh and Ni 
the numbers of pairs in categories (a), (b), (c), (d), (e), (f), (g), (h) and (i) respectively.  
Categories (a), (c), (e) and (g) “are winners” for sacubitril/valsartan  while (b), (d), (f) and (h) 
are “losers.” 
Na + Nc  + Ne + Ng  =  Nw and Nb + Nd  + Nf + Nh  = NL are the numbers of ‘winners’ and ‘losers’ 
for the sacubitril/valsartan  and Rw = Nw/NL is the “win ratio.” 
 
We will apply a more efficient approach proposed in Bebu, I & Lachin, JM. (2015) [9] to 
calculate the p-value and 95% CI. The proposed method [9] constructs tests of significance 
and confidence intervals in the context of composite outcomes using the large sample 
distribution. 
5.4.3 
Secondary analysis endpoint 2 
The cumulative number of composite events, ie, the total number of composite events of CV 
death, recurrent HF hospitalizations, and recurrent urgent HF visits for a subject over time will 
be calculated. The time to these recurrent events will be analyzed using the semi-parametric 
proportional rates model (abbreviated as LWYY model) (Lin 2000).  
Specifically, let λi, (t,xi) be the individual rate of composite events for subject i, given that the 
subject has not died from a CV reason at time t. It is dependent on the time from randomization 
(t) and treatment group (xi). Let xi = 1 if the subject is in the sacubitril/valsartan group and xi = 
0 if the subject is in the valsartan group.  
Under the proportional rates model, the individual rate function for the composite endpoint of 
CV death and total HF hospitalizations is assumed to be, λi(t,xi) = Yi(t)λ0 (t)exp(β0 xi), where Yi 
(t) =1 if subject i is at risk for CV death, recurrent HF hospitalizations, and recurrent urgent HF 
visits at time t and λ0 (t) = 0 if subject i  is censored or died from a CV reason at time t  
The primary hypothesis to be tested is, H30: β0 = 0 versus H3a: β0 < 0, where exp(β0) is the 
relative risk or rate ratio of CV death, recurrent HF hospitalizations, and recurrent urgent HF 
visits in the sacubitril/valsartan group relative to the valsartan group given the subject has not 
died from a CV reason at time t, which is assumed to be constant over time . 
The primary hypothesis could be equivalently written as: 
H30: Rate ratio (sacubitril/valsartan)/(valsartan) = 1  
versus  
H3a: Rate ratio (sacubitril/valsartan)/(valsartan) < 1, 
A rate ratio < 1 indicates an effect in favor of sacubitril/valsartan. 
The rate ratio and its 95% CI will be estimated from the above proportional rates model through 
maximization of a partial likelihood score function. The resulting estimate of exp(β0) is identical 
to the one described by Anderson and Gill (1982), but unlike Anderson-Gill, a robust variance 


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estimator (sandwich estimator) is used to account for the dependency of within subject events. 
The number and percentage of CV events by event type will be summarized.  
The LWYY analysis can be carried out using the following SAS code: 
 
proc phreg data=primary_data covs(aggregate); 
model (time_start, time_rec)*status_rec(0)=treat/ties=efron rl; 
id usubjid; 
run; 
where primary_data is the input dataset, time_start is the previous event stop time and time_rec 
is the current event stop time, the censoring variable status_rec (0 for censored and 1 for event) 
should take the value 1 if the last event is a CV death and 0 if it is censored for 
any non-CV death reasons for the given subject; usubjid is the subject ID. 
As a supportive part of the analysis, the two components in the composite endpoint (recurrent 
HF hospitalizations, and recurrent urgent HF) will be analyzed separately to quantify the 
respective treatment effects and check the consistency between the composite and the 
components. 
For details on the steps, consider the primary endpoint analysis from  CLCZ696D2301 as 
reference.  
5.5 
Rule of exclusion criteria of analysis sets  
There is no Per Protocol Set and defined protocol deviations will not lead to exclusion from 
FAS and RAS. 
Table 5-3 
Subject Classification 
Analysis Set 
Protocol deviations ID that cause 
subjects to be excluded 
Non-protocol deviation criteria that cause subjects to 
be excluded 
RAS 
NA 
Not randomized 
 
5.6 
Study background 
In the United States, sacubitril/valsartan is approved to "reduce the risk of cardiovascular death 
and hospitalization for heart failure in adult patients with chronic heart failure", based on data 
from the PARAGON-HF trial. The indication goes on to say "benefits are most clearly evident 
in patients with a left ventricular ejection fraction (LVEF) below normal." The term "below 
normal" can vary between patients depending on age, gender, race/ethnicity, and other factors, 
with normal being defined as a LVEF of 62% (range 52-72) and 64% (range 54-74) for men 
and women, respectively. 
PARAGLIDE-HF seeks to study potential heart failure biomarker changes (NTproBNP) and 
clinical benefits of sacubitril/valsartan vs. valsartan in HFimpEF, HFmrEF, and HFpEF patients 
following a worsening heart failure event. Analyses will include multiple subgroups, including 
those with an LVEF "below normal" vs. normal, defined as >60% here using a conservative 
estimate of normal. 










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• 
Investigator-reported events from both PARAGON-HF and  PARAGLIDE-HF 
studies   
Section 3: PARAGLIDE-HF and PIONEER-HF 
In addition, an additional analysis, all subjects randomized in PARAGLIDE-HF will be 
combined with those all randomized patients from PIONEER-HF.