Clinical trial NCT02887183
Conditions: Heart Failure
Keywords: Heart failure Reduced left ventricular ejection fraction HFrEF NT-proBNP Cardiac remodeling sacubitril/valsartan KCCQ biomarkers
Sponsor: Novartis Pharmaceuticals
Start date: 2016-10-25; Completion date: 2018-10-22
Enrollment: 794 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study was to determine early and more chronic changes in concentrations of biomarkers related to mechanisms of action (MOA) and effects of sacubitril/valsartan therapy over a period of 12 months, and correlated these biomarker changes with cardiac remodeling parameters, patient-reported outcomes and cardiovascular outcomes.

Detailed description:

Arms: arm 1: Subjects received sacubitril/valsartan (LCZ696) on Day 1. The initial dose was determined by the investigator and per the approved indication described in the United States prescribing information/package insert (USPI). The three doses available were: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg (Dose Level 3).

Titration of the dosage were performed per USPI at 2 to 4 week intervals as clinically tolerated until maximal tolerated or target dosage was achieved. Target dosage was sacubitril/valsartan 97/103 mg twice daily.
Interventions: intervention 1: LCZ696 (sacubitril/valsartan)
Intervention descriptions: intervention 1: LCZ696 (sacubitril/valsartan) was supplied as unscored, ovaloid, film-coated oral tablets in the strengths of 24/26 mg, 49/51 mg, 97/103 mg to be taken twice daily (bid)

Protocol documents:
Prot_000.pdf: 
US Clinical Development and Medical Affairs, Novartis Pharmaceuticals
LCZ696
sacubitril/valsartan
Clinical Trial Protocol CLCZ696BUS13 / NCT02887183
A 52 week, open label evaluation of the effects of 
sacubitril/valsartan (LCZ696) therapy on biomarkers, 
myocardial remodeling and patient-reported outcomes in 
heart failure with reduced left ventricular ejection fraction 
(PROVE-HF)
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.1 (February 2016)
Document type:
Amendment Protocol Version 03
Version number:
v03 (Clean)
Development phase:
IV
Release date:
27-Feb-2018


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................8
Amendment 3 ......................................................................................................................9
Protocol summary..............................................................................................................12
1
Introduction .......................................................................................................................18
1.1
Background............................................................................................................18
1.2
Purpose ..................................................................................................................20
2
Study objectives and endpoints .........................................................................................20
2.1
Primary objective(s)...............................................................................................20
2.2
Secondary objective(s)...........................................................................................20
20
3
Investigational plan ...........................................................................................................21
3.1
Study design...........................................................................................................21
3.2
Rationale for study design .....................................................................................22
23
3.4
Rationale for choice of comparator .......................................................................23
3.5
Risks and benefits..................................................................................................24
4
Population..........................................................................................................................24
4.1
Inclusion criteria ....................................................................................................24
4.2
Exclusion criteria...................................................................................................25
5
Treatment...........................................................................................................................26
5.1
Study treatment......................................................................................................26
5.1.1
Investigational drug...............................................................................26
5.1.2
Additional treatment..............................................................................27
5.2
Treatment assignment............................................................................................27
5.3
Treatment blinding.................................................................................................27
5.4
Treating the subject................................................................................................27
5.4.1
Subject numbering ................................................................................27
5.4.2
Dispensing the study drug.....................................................................28
5.4.3
Handling of study and additional treatment..........................................28
5.4.4
Instructions for prescribing and taking study treatment........................28
5.4.5
Permitted dose adjustments and interruptions of study treatment 
based on safety and tolerability.............................................................29


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5.4.6
Rescue medication ................................................................................31
5.4.7
Concomitant medication .......................................................................31
5.4.8
Prohibited medication ...........................................................................32
5.4.9
Emergency breaking of assigned treatment code..................................32
5.5
Study completion and discontinuation...................................................................32
5.5.1
Study completion and post-study treatment..........................................32
5.5.2
Discontinuation of study treatment .......................................................32
5.5.3
Withdrawal of informed consent...........................................................33
5.5.4
Lost to follow-up...................................................................................33
5.5.5
Early study termination by the sponsor.................................................34
6
Visit schedule and assessments .........................................................................................34
6.1
Information to be collected on screening failures..................................................38
6.2
Rescreening............................................................................................................38
6.3
Subject demographics/other baseline characteristics.............................................38
6.4
Treatment exposure and compliance .....................................................................38
6.5
Efficacy..................................................................................................................38
6.5.1
Heart failure signs and symptoms.........................................................39
39
6.5.3
Biomarkers in full subject population...................................................40
40
6.5.5
Appropriateness of efficacy assessments..............................................40
6.6
Safety.....................................................................................................................40
6.6.1
Physical examination ............................................................................41
6.6.2
Vital signs..............................................................................................41
6.6.3
Height and weight .................................................................................41
6.6.4
Angioedema ..........................................................................................41
6.6.5
Laboratory evaluations..........................................................................42
6.6.6
Pregnancy and assessments of fertility .................................................43
6.6.7
Appropriateness of safety measurements..............................................43
6.7
Other assessments..................................................................................................43
6.7.1
The Kansas City Cardiomyopathy Questionnaire (KCCQ-23).............43
6.7.2
Echocardiogram ....................................................................................43
6.7.3
Resource utilization...............................................................................44
7
Safety monitoring..............................................................................................................45
7.1
Adverse events.......................................................................................................45
7.2
Serious adverse events...........................................................................................46


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7.2.1
Definition of SAE .................................................................................46
7.2.2
SAE reporting........................................................................................47
7.3
Renal safety monitoring.........................................................................................48
7.4
Reporting of study treatment errors including misuse/abuse ................................48
7.5
Pregnancy reporting...............................................................................................49
8
Data review and database management.............................................................................49
8.1
Site monitoring ......................................................................................................49
8.2
Data collection.......................................................................................................50
8.3
Database management and quality control............................................................50
8.4
Data Monitoring Committee..................................................................................50
8.5
Angioedema Adjudication Committee ..................................................................50
8.5.1
Composition and Purpose .....................................................................50
8.5.2
Overview of Site Responsibility ...........................................................50
9
Data analysis......................................................................................................................51
9.1
Analysis sets ..........................................................................................................51
9.2
Subject demographics and other baseline characteristics......................................52
9.3
Treatments .............................................................................................................52
9.4
Analysis of the primary variable(s) .......................................................................52
9.4.1
Variable(s).............................................................................................52
9.4.2
Statistical model, hypothesis, and method of analysis..........................52
9.4.3
Handling of missing values/censoring/discontinuations.......................53
9.4.4
Sensitivity analyses ...............................................................................53
9.5
Analysis of secondary 
 variables ..................................................53
9.5.1
Secondary variables ..............................................................................53
54
9.5.3
Resource utilization...............................................................................55
9.5.4
Pharmacokinetics ..................................................................................55
9.5.5
DNA......................................................................................................55
9.5.6
Biomarkers............................................................................................55
9.5.7
PK/PD ...................................................................................................55
9.6
Other safety variables ............................................................................................55
9.7
Interim analyses.....................................................................................................56
9.8
Sample size calculation..........................................................................................56
10 Ethical considerations........................................................................................................56
10.1
Regulatory and ethical compliance........................................................................56
10.2
Informed consent procedures.................................................................................56


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10.3
Responsibilities of the investigator and IRB/IEC..................................................57
10.4
Publication of study protocol and results...............................................................57
10.5
Quality Control and Quality Assurance.................................................................57
11 Protocol adherence ............................................................................................................58
11.1
Protocol amendments.............................................................................................58
12 References .........................................................................................................................59
13 Appendix 1: Clinically notable laboratory values.............................................................61
14 Appendix 2: Specific Renal Alert Criteria and Actions....................................................62
15 Appendix 3: Treatment guidelines for hyperkalemia (serum potassium greater than 
or equal to 5.5 mEq/L).......................................................................................................63
16 Appendix 4: Guidelines for the management of blood pressure .......................................65
17 Appendix 5: Guidelines for the management of renal dysfunction...................................66
18 Appendix 6: Kansas City Cardiomyopathy Questionnaire ...............................................67
List of tables
Table 5-1
Open label treatment epoch...................................................................26
Table 5-2
Treatment dose levels epoch.................................................................27
Table 5-3
Safety and tolerability guidance for dose adjustments..........................30
Table 5-4
Prohibited medication ...........................................................................32
Table 6-1
Assessment schedule.............................................................................35
Table 6-2
Echocardiogram Assessments...............................................................44
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................49
Table 14-1
Specific Renal Alert Criteria and Actions.............................................62
List of figures
Figure 3-1
Study design..........................................................................................22


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List of abbreviations
AAC
Angioedema Adjudication Committee
ACE
angiotensin converting enzyme
ACEI
angiotensin converting enzyme inhibitor
AE
adverse event
ALT
Alanine Aminotransferase
ARNI
Angiotensin receptor neprilysin inhibitor
AST
Aspartate Aminotransferase
BID
Twice a day
BNP
B-type natriuretic peptide
BUN
Blood urea nitrogen
cGMP
Cyclic guanosine monophosphate
CHF
Chronic heart failure
CFR
US Code of Federal Regulations
CRF/eCRF
(electronic) Case Report/Record Form
CRO
Contract Research Organization
CRT-D
Cardiac resynchronization therapy defibrillator 
CRT-P
Cardiac resynchronization therapy pacemaker
CV
cardiovascular
DBP
diastolic blood pressure
DM
diabetes mellitus
DMC
Data Monitoring Committee
DS&E
Drug Safety & Epidemiology
Echo
echocardiogram
EDC
Electronic Data Capture
eGFR
estimated glomerular filtration rate
EOS
End of study
FAS
Full analysis set
GCP
Good Clinical Practice
HF
heart failure
HFrEF
Heart failure with reduced ejection fraction
hs-Troponin
high sensitivity troponin
HTN
Hypertension
ICF
Informed consent
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
KCCQ
Kansas City Cardiomyopathy Questionnaire
LA
Left atrial
LAVi
Left atrial volume index
LVEF
Left ventricular ejection fraction


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LVEDVi
Left ventricular end diastolic volume index
LVESVi
Left ventricular end systolic volume index
LV
Left ventricular
mm Hg
millimeter mercury
MoA
Mechanism of action
MUGA
multi gated acquisition scan 
NEP
Neutral endopeptidase
NP
Natriuretic peptide
NT-proBNP
N-terminal pro-brain natriuretic peptide
NYHA
New York Heart Association
PCI
Percutaneous coronary intervention
Pg/ml
Picogram per milliliter
RAAS
Renin angiotensin aldosterone system
SAE
Serious Adverse Event
SBP
Systolic blood pressure
sST2
Soluble ST2
SUSAR
Suspected Unexpected Serious Adverse Reactions
UNL
Upper limit of normal
USPI
United States prescribing information/package insert
VAD
Ventricular assistance device 
WoC
Withdrawal of Consent


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Glossary of terms
Cohort 
A specific group of subjects fulfilling certain criteria
Control drug
Drugs(s) 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
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 
mg once a day, 75 mg twice a day)
Enrollment
Point/time of subject entry into the study at which informed consent must 
be obtained (e.g. prior to starting any of the procedures described in the 
protocol)
Epoch
Replaces the term “Period” 
previously used for NOVDD 
studies
A portion of the study which serves a specific purpose. Typical epochs 
are: screening/recruitment, wash-out, treatment, and follow-up
Investigational drug
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.”
Medication pack number
A unique identifier on the label of each investigational drug package
Part 
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in subjects with 
established disease and in those with newly-diagnosed disease.
Subject/subject ID 
A unique number assigned to each subject upon signing the informed 
consent 
Study drug/ treatment
Any single drug or combination of drugs administered to the subject as 
part of the required study procedures; includes investigational drug (s), 
placebo/comparator active drug run-ins or background therapy
Study Treatment 
Discontinuation (TD)
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study
Withdrawal of consent 
(WoC)
Withdrawal of consent from the study is defined as when a subject does 
not want to participate in the study any longer, and does not want any 
further visits or assessments, and does not want any further study 
related contact, and does not allow analysis of already obtained biologic 
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Amendment 3
Rationale for amendment
The purpose of Amendment 3 is to remove the interim analysis that was to occur after 300 
subjects completed the study. Due to the speed of enrollment into the study, an interim 
analysis is no longer as feasible or as informative since this analysis would be performed after 
all of the patients had already been enrolled, and only 3 to 4 months prior to study completion.
All relevant section(s) of the protocol are updated to reflect the removal of the interim 
analysis.
Additionally, other administrative changes include the following:

Under List of Abbreviations added “EOS” End of Study.

Section 6; Table 6-1 Assessment Schedule added (EOS) under visit number 10 to align 
with section 5.5.2.
Summary of previous amendment 02 (June 2017)
The purpose for Amendment 2 is to add 3 additional exclusion criteria:

Subjects with a heart transplant or ventricular assistance device (VAD) or intent to 
transplant (on transplant list) or implant a VAD.

Subjects with a cardiac resynchronization therapy devices (CRT-P/CRT-D) implanted
within 6 months of screening visit.

Subjects currently taking inotropic agents.
All relevant section(s) of the protocol are updated to reflect the 3 additional exclusion criteria.
Additionally, other administrative changes include the following:

Administrative changes such as the correction of typographical error have been made 
throughout the protocol.

Clarified inclusion criteria #3 and #6 and exclusion #3 and #11.

Section: 5.4.5: was edited to add clarification to the study titration.

Section: 6, Table 6-1: Added Dosage Administration record, angioedema and footnote for 
Assessing CV events.
Summary of previous amendment 01(September 2016)


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The purpose for Amendment 1 is to allow for the collection of serum pregnancy testing at 
both visits 8 and 9 to account for pregnancy testing being performed approximately every 90 
days.
All relevant sections(s) of the protocol are updated to reflect the additional collection of serum 
pregnancy tests.
Additionally, other changes include the following:

List of Abbreviations: added MUGA  multi gated acquisition scan 

Protocol title was update to include “PROVE-HF”.

Protocol Summary: Population and Key Inclusion Criteria #3 was updated to include 
HFrEF ≤40% subjects who are candidates for on-label sacubitril/valsartan treatment per 
standard of care; added Inclusion criteria #5:  LVEF ≤40% via any local measurement 
within the past 6 months using echocardiography, multi gated acquisition scan (MUGA), 
CT scanning, MRI or ventricular angiography provided no subsequent study documenting 
an EF of >40%. If the EF measurement is expressed as a value range, the average of the 
range endpoint values should be used as the EF and deleted exclusion #7, subjects are 
require to have a 36-hour washout post-dose of sacubitril/valsartan.

Protocol Summary: Key exclusion Criteria updated to include exclusion #4 Current or 
prior treatment with sacubitril/valsartan and #7 was reworded to say “Subjects with 
diabetes mellitus who are taking aliskiren.”

Protocol Summary: Data Analysis was updated to include the word “clinical”.
 
 

Section 3.1: Study Design: under screening epoch paragraph was reworded to say 
“Subjects will be considered eligible if they are identified as clinically appropriate HFrEF 
subjects and who are candidates for on-label sacubitril/valsartan treatment per the USPI 
prescribing information”; under screening epoch sentences 3-5 were moved to section 3.1 
under Baseline (Day 1). Under Screening epoch: was reworded to say “Subjects will be 
screened to assess eligibility requirements and to confirm that subjects meet all study entry 
criteria and Figure 3-1 was updated to align with study design, deleted 36 hour washout of 
ACEi prior to baseline.

Sections 4 and 4.1 was updated to include ≤40% to HFrEF and LVEF ≤40% via any local 
measurement within the past 6 months using echocardiography, multi gated acquisition 
scan (MUGA), CT scanning, MRI or ventricular angiography provided no subsequent 
study documenting an EF of >40%. If the EF measurement is expressed as a value range, 
the average of the range endpoint values should be used as the EF.

Section 4.2 was updated to deleted previous exclusion #4, subjects are require to have a 
36-hour washout post-dose of sacubitril/valsartan and updated to include exclusion #4, 
“Current or prior treatment with sacubitril/valsartan; and #7 was reworded to say 
“Subjects with diabetes mellitus who are taking aliskiren.”


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
Section 5.4.4 was updated to “These subjects will be instructed to wait 36 hours from their 
last dose of ACEis before taking their first dose of sacubitril/valsartan.

Section 5.5.3 was updated to replace “Withdrawal of Informed Consent” with “Study 
Completion”.

Table 6-1: Assessment schedule was updated to include protocol number in header 
CLCZ696BUS13, updated Safety Laboratory (chemistry/hematology) to align with 
section 6.5.5.1 and 6.5.5.2; Drug Accountability was update from x to s; being captured on 
source document and added a column for Unscheduled Visit. Added a row to “Assess of 
Cardiovascular events” to align with section 8.6. 

Section 6.2 was changed from “date of birth” to “year of birth” to match electronic data 
capture.

Section 6.4.2 was added to include “Cardiovascular Events”  

Section 6.5.5.3 was updated by replacing “central lab” with “local lab”; adding “glucose” 
to ketones; and adding: “Microscopy and WBC and RBC sediments will also be assessed 
in case of an abnormal dipstick test (central lab).”

Section 6.5.6 Pregnancy/Assessments of fertility was updated to add visits 8 and 9 to 
serum pregnancy.

Section 9.5.1 Secondary variables #3 was updated to add the word “clinical”.

Section 8.6: was removed since a CV events adjudication committee is not required.

List of abbreviations: added AAC (Angioedema Adjudication Committee).


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Protocol summary
Protocol number
LCZ696BUS13
Title
A 52 week, open label evaluation of the effects of sacubitril/valsartan 
(LCZ696) therapy on biomarkers, myocardial remodeling and patient-
reported outcomes in heart failure with reduced left ventricular ejection 
fraction (PROVE-HF). 
Brief title
Effects of sacubitril/valsartan (LCZ696) in heart failure subjects treated as 
per standard of care.
Sponsor and Clinical 
Phase
Novartis 
Clinical Phase IV
Investigation type
Drug
Study type
Interventional, Open-label
Purpose and 
rationale
The purpose of this study is to determine early and more chronic changes 
in concentrations of biomarkers related to mechanisms of action (MOA) 
and effects of sacubitril/valsartan therapy over a period of 12 months, and 
correlate these biomarker changes with cardiac remodeling parameters, 
patient-reported outcomes and cardiovascular outcomes.
This protocol will allow for evaluation of improved understanding of the 
interplay between sacubitril/valsartan and biomarkers, remodeling and 
outcomes, and will carefully assess such relationships within important 
cohorts of subjects, such as those with low NT-proBNP/BNP at baseline, 
those naïve to HF therapy, as well as those that are unable to achieve 
target dose of sacubitril/valsartan.
This protocol will also generate a biorepository of well-handled and 
carefully considered biomarkers, which will allow a better understanding of 
sacubitril/valsartan MOA
Primary Objective(s) 
The primary objective of this study is to examine the association between 
change in concentration of NT-proBNP and change in structural cardiac 
measurements (LV end systolic and diastolic volume indices, LVEF, and 
LA volume index) from baseline to one year.
Secondary 
Objectives
Examine the association between change in concentration of  NT-proBNP 
and change in structural cardiac measurements (LV end systolic and 
diastolic volume indices, LVEF, and LA volume index) from baseline to 6 
months overall in subgroups of interest, these subgroups are:
1.
Subjects with HFrEF and “low” NT-proBNP (<600 if not 
hospitalized or <400 if hospitalized) or “low” BNP (<150 if not 
hospitalized, <100 if hospitalized) at baseline (Ambrosy, 2012).


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2.
Subjects with new onset HF and/or RAAS naïve (Fonarow, 2010). 
3.
Subjects who are not receiving the target sacubitril/valsartan dose 
(McMurray, 2014). 
Examine the association between the change in NT-proBNP concentrations 
and patient-reported outcomes from the KCCQ-23 during a year of follow 
up.
Study design
Multi-center, Open-label, single arm
Population
The study population will consist of outpatient male and female subjects, ≥ 
18 years of age, with HFrEF≤40%.  The goal is to have a total of 
approximately 830 subjects enrolled, in approximately 100 centers in the 
United States.  At the time of enrollment, subjects will have been identified 
by their primary care physician or cardiologist as a candidate for treatment 
with sacubitril/valsartan as per USPI and meeting all other inclusion and 
none of the exclusion criteria.
Key Inclusion 
criteria
Subjects eligible for inclusion in this study have to fulfill all of the following 
criteria:
1.
Written informed consent must be obtained before any assessment is 
performed.
2.
Men and women ≥ 18 years of age.
3.
LVEF ≤40% subjects who are candidates for on-label 
sacubitril/valsartan treatment per standard of care.
4.
NYHA Functional class II-IV.
5.
LVEF ≤40% via any local measurement within the past 6 months using 
echocardiography, multi gated acquisition scan (MUGA), CT scanning, 
MRI or ventricular angiography provided no subsequent study 
documenting an EF of >40%. If the EF measurement is expressed as 
a value range, the average of the range endpoint values should be 
used as the EF.
6.
If a subject is on a loop diuretic, they must be on a stable dose for 2 
weeks prior to baseline.
Key Exclusion 
criteria
1.
History of hypersensitivity to any of the study drugs, including history of 
hypersensitivity to drugs of similar chemical classes, or allergy to 
ACEIs, ARBs, or NEP inhibitors as well as known or suspected 
contraindications to the study drugs.
2.
History of angioedema drug related or otherwise.
3.
Requirement of treatment with either ACE inhibitor and/or ARB.
4.
Subjects with a heart transplant or ventricular assistance 
device (VAD) or intent to transplant (on transplant list) or 
implant a VAD.
5.
Subjects with a cardiac resynchronization therapy devices 
(CRT/CRT-D) implanted within 6 months of screening visit.
6.
Subjects who are currently taking inotropic agents.
7.
Current or prior treatment with sacubitril/valsartan.
8.
Subjects taking medications prohibited by the protocol (Section 5.4.8).


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9.
Subjects with diabetes mellitus who are taking aliskiren.
10. Use of other investigational drugs within 5 half-lives of enrollment, or 
within 30 days until the expected pharmacodynamic effect has returned 
to baseline, whichever is longer.
11. Concomitant use of nesiritide.
12. Bile acid sequestering agents such as cholestyramine or colestipol are 
prohibited to avoid interference with study drug absorption.
13. Any hospital admission/discharge related to heart failure within 2 weeks 
prior to baseline.
14. The use of outpatient or inpatient i.v. diuretic therapy within 2 weeks 
prior to baseline.
15. Enrollment in another clinical trial within 30 days of screening.
16. Potassium > 5.2 mEq/L at screening
17. History of malignancy of any organ system (other than localized basal 
cell carcinoma of the skin), treated or untreated, within one year. 
18. 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.
19. 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 and for 7 days after stopping of 
study medication. Highly effective contraception methods include:
20. Total abstinence (when this is in line with the preferred and usual 
lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception
21. Female sterilization (have had surgical bilateral oophorectomy with or 
without hysterectomy) total hysterectomy or tubal ligation at least six 
weeks before taking investigational drug. In case of oophorectomy 
alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment
22. Male sterilization (at least 6 months prior to screening). For female 
subjects on the study, the vasectomized male partner should be the 
sole partner for that subject
23. 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 investigational drug.
24. Sexually active males must use a condom during intercourse while 
taking drug and for 7 days after stopping study medication and should 
not father a child in this period. A condom is required to be used also
by vasectomized men in order to prevent delivery of the drug via 


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seminal fluid.
Study treatment
All eligible subjects will receive sacubitril/valsartan (LCZ696).  The study 
treatment will be provided for the duration of the trial from baseline (Day 1) 
through visit 10 (Day 365).
Efficacy assessments
The efficacy variables are:
Primary: 

Change in concentration of NT-proBNP from baseline to one year 

Change in LVESVi, LVEDVi, LVEF, and LA volume index (LAVi) from 
baseline to one year   
Secondary:

Change in concentration of NT-proBNP from baseline to 6 months

Change in LVESVi, LVEDVi, LVEF, and LA volume index (LAVi) from 
baseline to 6 months

Change in KCCQ-23 baseline to one year
Key safety 
assessments

Physical examinations

Monitoring of laboratory biomarkers in blood (plasma/serum)

Echocardiograms


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
Adverse event monitoring 
Other assessments

An assessment of subject reported outcomes is planned in this trial 
using Quality of life, based on the Clinical Score of the KCCQ-23.
Data analysis
Pearson’s correlation coefficient and its two-sided 95% confidence interval 
(CI) to examine the association between change in log-transformed 
NT-proBNP and LVESVi, LVEDVi, LVEF, and LAVi from baseline to 
one year and baseline to 6 months will be calculated 
Similar correlation coefficients and CIs will be calculated for the 
following subgroups:  

Subjects with de novo HF (naïve to ACE inhibitor or ARB therapy) and 
those with previously established HF.

Subjects with NT-proBNP values <600 pg/mL (or 400 pg/mL if 
hospitalized for HF within 1 year) at the time of drug initiation, and 
those with higher values.

In those not receiving the target sacubitril/valsartan dose and those
achieving target dose.

In those with an NT-proBNP concentration <1000 pg/mL at Month 12 
and those with NT-proBNP ≥1000 pg/mL at the same time point.

As a function of time from baseline to an NT-proBNP value of <1000 
pg/mL for subjects with a baseline value >=1000 pg/mL (percentiles of 
response time).

As a function of time spent with NT-proBNP concentration <1000 
pg/mL across study visits (percentiles of response time).

The primary analysis of the primary efficacy variables will be based on 
the Full Analysis Set.
An analysis of variance will be done to compare the mean change in 
the KCCQ-23 clinical summary score between the groups of subjects 
with NT-proBNP<1000 pg/mL and NT-proBNP>=1000 pg/mL at Month 
12. Propensity score adjustments will be used in the comparison of 
treatment groups.
We would like to estimate the correlation coefficient between change in 
log NT-proBNP and each structural cardiac measurement overall and 
in each subgroup of interest with a precision (half-width of the 
confidence interval (CI)) of at least 0.15 for a 2-sided 95% CI. The 
subgroups of interest are:  (1) subjects with HFrEF and “low” NT-
proBNP (<600 if not hospitalized or <400 if hospitalized) or “low” BNP 
(<150 if not hospitalized, <100 if hospitalized) at baseline, (2) subjects 
with new onset HF and/or RAAS naïve, and (3) subjects who are not 
receiving the target sacubitril/valsartan dose. It is estimated that these 
subgroups will represent approximately 25%, 20% and 30% of the
study population, respectively.  Assuming, the population correlation 
coefficient of -0.35 for the overall study sample and within each 
subgroup, the smallest sample size that would yield a precision of at 
least 0.15 for the estimated correlation coefficient would be n=133. 
Accounting for assumed 20% drop-out rate, 166 patients would be 
required. If the n=166 was the smallest subgroup of interest (20% of 


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the overall study population), an overall sample size of 830 would be 
required to enroll in this study. For any other subgroup with more than 
166 patients will yield precision smaller than 0.15 for the estimated 
correlation coefficient. For the overall sample size of N=830 patients 
the precision of the estimate of correlation coefficient would be 0.07 
(PASS 2008).
Key words
Heart failure, reduced left ventricular ejection fraction, cardiac remodeling 
parameters.


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1
Introduction
1.1
Background
Globally, heart failure (HF) is reaching epidemic 
proportion, leading to substantial efforts to 
understand 
the 
biology 
of 
HF, 
improve 
recognition of its presence, and more optimally 
manage subjects so-affected.  As such strides 
have been made in the study of risk factors for 
progressive HF, as well as the means by which 
to recognize and treat it.
A fundamental goal in the management of 
subjects with HF and reduced ejection fraction 
(HFrEF) is the prevention of myocardial 
remodeling.  As noted by Konstam, 2011, 
myocardial remodeling is central in the pathophysiology of advancing HF; for example, 
subjects with cardiovascular (CV) events in the Survival and Ventricular Enlargement study 
(Konstam 2011) of HFrEF demonstrated considerably greater degrees of myocardial 
remodeling compared to those without events (Figure 1).
The benefit of contemporary HF 
therapies appears to be in part 
reflective of the anti-remodeling 
benefits of such agents, including 
agents 
blocking 
the 
renin 
angiotensin 
aldosterone
system 
(Figure 2).  Unfortunately, however, 
risk 
for 
remodeling 
of 
the 
myocardium may be challenging to 
recognize.
Biomarkers 
are 
increasingly 
measured as a tool to diagnose, 
establish prognosis, as well as to 
monitor or guide HF therapy.  The 
gold standard HF biomarkers are B-
type natriuretic peptide (BNP) and its amino-terminal pro-fragment equivalent (NT-proBNP).  
Concentrations of BNP and NT-proBNP not only provide unique diagnostic information for 
HF, but also allow for an understanding of the underlying biology of HF, including 
identifying the presence and severity of myocardial remodeling.  As articulated by Yancy 
2013, both peptides have Class I, level of evidence.  A support in current clinical practice 
guidelines for diagnosis and prognosis in HF (Yancy 2013) and in 2014, more than 20 million 
measurements of these two peptides were made.  


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With well-established links between change in the natriuretic peptides during HF therapy and 
both myocardial remodeling as well as outcomes, increasingly, clinicians turn to biomarkers 
such as BNP or NT-proBNP for decision making regarding prognosis and therapy changes in 
subjects so affected (Ambrosy 2012; Januzzi 2011; Masson 2006).  
It is now widely accepted that among subjects with HFrEF an NT-proBNP concentration 
<1000 pg/mL during therapy titration is associated with significantly less likelihood for 
deleterious LV remodeling than subjects with concentrations above this value (table 1) 
(Konstam 2011), and lower NT-proBNP concentrations are also associated with better 
outcome as well, (Januzzi 2011; Masson 2006).  Furthermore, as opposed to a single 
measurement, across serial measurement, the time spent with an NT-proBNP <1000 pg/mL 
over a one year period was reported to be even more strongly associated not only with 
superior outcome (Gaggin 2013), but also with more robust improvement in LV and left atrial 
(LA) size and function (Weiner 2013).
Remodeling metrics include LVEF as 
well as measures of both systolic and 
diastolic volumes, LV end systolic 
volume index (LVESVi) and LV end 
diastolic 
volume 
index 
(LVEDVi).  
Change in each has been used as the gold 
standard for LV reverse remodeling.
Beyond the clinical value of BNP or NT-
proBNP, measurement of circulating HF 
biomarkers may also be helpful to 
understand mechanism of benefit of HF 
therapies and provide important insight 
to mechanism of action (MOA) of such 
therapies.
Preliminary studies
In the landmark Prospective Comparison of ARNI with ACEI to Determine Impact on Global 
Mortality in HF [PARADIGM-HF] (McMurray 2014) study, changes in both BNP and NT-
proBNP were seen during the sacubitril/valsartan (LCZ696) run-in period, at 4 weeks, and 8 
months (Packer 2015): treatment with sacubitril/valsartan led to substantial reduction in NT-
proBNP, thought to be reflective of benefit of the drug.  Beyond this, it is yet unclear whether 
NT-proBNP reduction predicted other favorable effects in therapy of HFrEF such as reverse 
LV remodeling.  Through inhibition of neprilysin by sacubitril active metabolite, 
sacubitril/valsartan led to a rise in BNP concentration. The ramification of such increase in 
BNP concentration relative to diagnostic and prognostic accuracy remains unclear; for 
example, it is unknown if measurement of BNP will retain association/correlation with LV 
remodeling and/or prognosis.  This may have substantial ramification regarding the future of 
BNP, the most widely measured natriuretic peptide in the United States.  
Limitations of the PARADIGM-HF biomarker experience include only limited time points for 
blood sampling, which hampers ability to examine short and longer term changes in 
biomarkers following initiation and up titration of sacubitril/valsartan.  As well, only one BNP 


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assay was assessed in PARADIGM-HF. It is thus uncertain whether other commercially 
available BNP assays utilizing different antibody pairs will demonstrate the same effect from 
neprilysin inhibition. As BNP is widely used for diagnostic and prognostic evaluation, 
understanding effects of sacubitril/valsartan on representative BNP assays is of substantial 
importance.  Furthermore, it remains unclear whether effects of sacubitril/valsartan differ on 
biomarker profiles of subjects naïve to HF therapy (“new starts”) or in those with NT-
proBNP/BNP concentrations below those used for inclusion in PARADIGM-HF.  Crucially, 
no data exist regarding effects of sacubitril/valsartan on LV remodeling.  Lastly, because of 
challenges in handling of blood samples, several candidate markers of sacubitril/valsartan 
MOA could not be measured in the PARADIGM-HF trial or biorepository.
1.2
Purpose 
The purpose of this study is to determine early and more chronic changes in concentrations of 
biomarkers related to mechanisms of action (MOA) and effects of sacubitril/valsartan therapy 
over a period of 12 months, and correlate these biomarker changes with cardiac remodeling 
parameters, patient-reported outcomes and cardiovascular outcomes.
2
Study objectives and endpoints
2.1
Primary objective(s)
The primary objective of this study is to examine the association between change in 
concentration of NT-proBNP and change in structural cardiac measurements (LV end systolic 
and diastolic volume indices, LVEF, and LA volume index) from baseline to one year. 
2.2
Secondary objective(s)

Examine the association between change in concentration of  NT-proBNP and change in 
structural cardiac measurements (LV end systolic and diastolic volume indices, LVEF, 
and LA volume index) from baseline to 6 months overall in subgroups of interest, these 
subgroups are:
1. Subjects with HFrEF and “low” NT-proBNP (<600 if not hospitalized or <400 if 
hospitalized) or “low” BNP (<150 if not hospitalized, <100 if hospitalized) at baseline 
(Ambrosy 2012).
2. Subjects with new onset HF and/or RAAS naïve (Fonarow 2010). 
3. Subjects who are not receiving the target sacubitril/valsartan dose (McMurray 2014). 

Examine the association between the change in NT-proBNP concentrations and patient-
reported outcomes from the KCCQ-23 during a year of follow up.


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3
Investigational plan
3.1
Study design
This study uses an open-label, single-arm design. The study duration is a maximum of 52 
weeks (365 days). A study cohort of approximately 830 subjects will be enrolled.  Subjects 
will be considered eligible if they are identified as clinically appropriate HFrEF subjects and
who are candidates for on-label sacubitril/valsartan treatment per the USPI prescribing 
information.
Screening epoch
Subjects will be screened to assess eligibility requirements and to confirm that subjects meet 
all study entry criteria.  At screening, safety blood and urine samples will be collected and 
submitted to the central laboratory.  
Baseline (Day 1) 
Sacubitril/valsartan will be dispensed to eligible subjects at Visit 2 (Day 1/baseline). Initial 
dosing and titration will be done according the United States Prescribing Information (USPI).
Subjects that have been treated with ACEi before the study will require a 36-hour wash out 
period before starting sacubitril/valsartan treatment.  These subjects will be instructed to wait 
36 hours from their last dose of ACEi before taking their first dose of sacubitril/valsartan. 
Their first dose of sacubitril/valsartan will therefore be approximately 36 hours from last dose 
of ACEi.
Open Label treatment epoch
The open label treatment period duration is 12 months. Visits will occur every 2 weeks until 
Visit 6 (Day 60) and then at 7, 8, 9 and 10 (end of study). 
Titration of study treatment initiated at Visit 2 (baseline) will be done according to the USPI. 
Deviation from the titration schedule or dose adjustments will only be allowed if indicated per 
protocol defined safety and tolerability criteria section 5.4.5 and investigator judgment, if the 


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investigator believes that adjustment/elimination of concomitant medications is not possible 
or does not alleviate the side effects of concern. Protocol required assessments for each visit 
will be done according to the schedule of assessments (Table 6-1).
Figure 3-1
Study design 
3.2
Rationale for study design
Open questions about sacubitril/valsartan exist; this protocol will address some of the 
important gaps in knowledge regarding this novel drug.  Measurement of biomarkers BNP 
and NT-proBNP are now routine assessments in standard care for HF subjects.  The use of 
these biomarker has a Class I, level of evidence A for prognosis in clinical practice guidelines 
(Yancy 2013).  Biomarkers (including NT-proBNP) are well-associated and correlated with 
myocardial remodeling as well (Weiner 2013).
It is understood that sacubitril/valsartan has substantial effects on NT-proBNP and BNP, but 
these effects are fundamentally different.  There is a critical need to provide greater clarity for 
clinicians on how to interpret information on both biomarkers during treatment with 
sacubitril/valsartan, given the increasing frequency of therapy monitoring with natriuretic 
peptides.  For BNP, mis-interpretation of a “rise” in the values could theoretically lead to mis-
treatment of subjects. This could also result in clinician confusion regarding 
sacubitril/valsartan (ie. - it could be thought of as “toxic” and leading to rise in BNP).  
Another possibility is frustration with either BNP or sacubitril/valsartan, creating risk that 
they may cease measuring the biomarker or using the drug).  It is unclear if BNP will impart 
useful information regarding remodeling and prognosis when subjects are treated with 
Open label treatment Epoch
Screening 
Epoch
Day -28 to 
Day -1
Day 1 to Day 365
Baseline 


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sacubitril/valsartan. It is also unclear what effect sacubitril/valsartan has on BNP using 
different BNP assays in broad clinical use.  
While sacubitril/valsartan treatment was shown in the PARADIGM-HF trial to have an early 
and sustained benefit in mortality reduction and HF hospitalization in HFrEF subjects 
compared to treatment enalapril and guideline-directed medical therapy, clinical data are 
lacking regarding whether sacubitril/valsartan therapy fosters significant LV or LA 
remodeling (McMurray 2014).  As reported by Konstam 2011 degree of myocardial 
remodeling following HF therapy strongly predicts benefit of such therapies (Konstam 2011).  
Examining the inter-relationship between biomarkers, echocardiographic remodeling, and 
clinical (and subject-reported) outcomes would provide substantial understanding regarding 
mechanism of benefit from sacubitril/valsartan therapy.
In view of this significant treatment benefit demonstrated in the PARADIGM-HF trial, 
Novartis has provided guidance for company-supported trials that the randomized period for 
assessing sacubitril/valsartan against an active comparator may not exceed 12 weeks.  The 
intermediate-term and chronic biomarker changes, as well as the structural heart reverse 
remodeling endpoints being evaluated in this trial require a study period of 12 months.  
Because this exceeds the 12 week guidance, it precludes a two arm study design with an 
active comparator, and trial needs dictate a single arm design.  
This protocol will allow for evaluation of improved understanding of the interplay between 
sacubitril/valsartan and biomarkers, remodeling and outcomes, and will carefully assess such 
relationships within important cohorts of subjects, such as those with low NT-proBNP/BNP at 
baseline, those naïve to HF therapy, as well as those that are unable to achieve target dose of 
sacubitril/valsartan.
This protocol will also generate a biorepository of well-handled and carefully considered 
biomarkers, which will allow a better understanding of sacubitril/valsartan MOA.
3.4
Rationale for choice of comparator
Not applicable.


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3.5
Risks and benefits
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria 
and study procedures, and close clinical monitoring.
Experience in the PARADIGM-HF trial, both in the run-in period as well as the double-blind 
randomization period, indicated that the major risks associated with the treatment of 
sacubitril/valsartan are renal dysfunction, hyperkalemia, and hypotension. Results from the 
TITRATION study indicated that subjects who are ACE or ARB naïve are at an increased risk 
of experiencing these adverse events.
In this study, the risk of experiencing renal dysfunction, hyperkalemia, and hypotension are 
mitigated by appropriate up-titration of the drug every two weeks according to the USPI.  The 
risks are further mitigated by appropriate inclusion and exclusion criteria.  Subjects entering 
into the study will have their BP evaluated and be treated with sacubitril/valsartan in 
accordance with the USPI.  
Sacubitril/valsartan may also cause angioedema. The risk of developing angioedema is 
increased if subjects take both an ACEi and sacubitril/valsartan.  To decrease this risk, all 
subjects commencing the open-label treatment period will undergo a 36 hour wash out period 
prior to starting sacubitril/valsartan to minimize the interaction between an ACEi and 
sacubitril/valsartan in potentiating the development of angioedema.
All subjects will be allowed to continue receiving the rest of their background cardiovascular 
(CV) medications throughout the study. Subjects will be enrolled only after the investigator 
has confirmed the subject is on stable treatment with guideline-directed therapy for HFrEF, 
other than ACEis and ARBs, which will ensure that subjects are receiving appropriate 
treatment for their heart failure.
In the PARADIGM-HF study, sacubitril/valsartan reduced the risk of CV death and HF 
hospitalization and due to these significant results, sacubitril/valsartan is now indicated to 
reduce these risks in subjects with chronic heart failure (NYHA class II-IV) and reduced 
ejection fraction.
4
Population
The study population will consist of outpatient male and female subjects, ≥ 18 years of age, 
with HFrEF ≤40%.  The goal is to have a total of approximately 830 subjects enrolled, in 
approximately 100 centers in the United States.  At the time of enrollment, subjects will be 
considered eligible if they are identified as clinically appropriate HFrEF subjects and eligible 
to receive sacubitril/valsartan per the USPI prescribing information., as well as meeting all 
other inclusion and none of the exclusion criteria.
4.1
Inclusion criteria
Based on the USPI for sacubitril/valsartan, subjects eligible for inclusion in this study must 
fulfill all of the following criteria at screening and baseline:
1. Written informed consent must be obtained before any assessment is performed.
2. Men and women ≥ 18 years of age.


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3. LVEF ≤ 40% subjects who are candidates for on-label sacubitril/valsartan treatment per 
standard of care.
4. NYHA Functional class II-IV.
5. LVEF ≤40% via any local measurement within the past 6 months using echocardiography, 
multi gated acquisition scan (MUGA), CT scanning, MRI or ventricular angiography 
provided no subsequent study documenting an EF of >40%. If the EF measurement is 
expressed as a value range, the average of the range endpoint values should be used as the 
EF.
6. If a subject is on a loop diuretic, they must be on a stable dose for 2 weeks prior to  
baseline. 
4.2
Exclusion criteria
Subjects fulfilling any of the following criteria, at screening and prior to dispensing of 
study drug, 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 subjects/subjects.
1. History of hypersensitivity to any of the study drugs, including history of hypersensitivity 
to drugs of similar chemical classes, or allergy to ACEIs, ARBs, or NEP inhibitors as well 
as known or suspected contraindications to the study drugs. 
2. History of angioedema drug related or otherwise.
3. Requirement of treatment with either ACE inhibitor and/or ARB.
4. Subjects with a heart transplant or ventricular assistance device (VAD) or intent to 
transplant (on transplant list) or implant a VAD.
5. Subjects with a cardiac resynchronization therapy devices (CRT/CRT-D)  implanted 
within 6 months of screening visit.
6. Subjects who are currently taking inotropic agents.
7. Current or prior treatment with sacubitril/valsartan.
8. Subjects taking medications prohibited by the protocol (Section 5.4.8).
9. Subjects with diabetes mellitus who are taking aliskiren. 
10. Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days until 
the expected pharmacodynamic effect has returned to baseline, whichever is longer.
11. Concomitant use of nesiritide.
12. Bile acid sequestering agents such as cholestyramine or colestipol are prohibited to avoid 
interference with study drug absorption.
13. Any hospital admission/discharge related to heart failure within 2 weeks prior to baseline.
14. The use of outpatient or inpatient i.v. diuretic therapy within 2 weeks prior to baseline. 
15. Enrollment in another clinical trial within 30 days of screening.
16. Potassium > 5.2 mEq/L at screening.
17. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin), treated or untreated, within one year. 


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18. 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.
19. 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 and for 7 days after stopping of study medication. Highly effective 
contraception methods include:
a. Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception
b. Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment
c. Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject
d. 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.
e. In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking investigational drug.
20. Sexually active males must use a condom during intercourse while taking drug and for 7 
days after stopping study medication and should not father a child in this period. A 
condom is required to be used also by vasectomized men in order to prevent delivery of 
the drug via seminal fluid.
5
Treatment
5.1
Study treatment
5.1.1
Investigational drug
All eligible subjects will receive open label sacubitril/valsartan. Sacubitril/valsartan is 
supplied as unscored, ovaloid, film-coated tablets in the following strengths: 
Table 5-1
Open label treatment epoch
Treatment 
Number 
of 
Subjects
Minimum 
dose
Median
Maximum 
dose
Frequency
Formulation
Admin. 
Route
Open-label, 
sacubitril/valsartan 
830
24/26 mg
49/51 mg
97/103 mg
BID
Tablet
Oral
*Investigational product labeling for sacubitril/valsartan dose levels is based on the total contribution of both components of
sacubitril/valsartan and reads, 50 mg, 100 mg and 200 mg. This is equivalent to the sacubitril/valsartan dose levels 24/26 mg, 
49/51 mg and 97/103 mg, respectively.


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Table 5-2
Treatment dose levels epoch
Dose Level
sacubitril/valsartan 
1
24/26 mg BID
2
49/51 mg BID
3
97/103 mg BID
*Investigational product labeling for sacubitril/valsartan dose levels is based on the total contribution of both components of
sacubitril/valsartan and reads, 50 mg, 100 mg and 200 mg. This is equivalent to the sacubitril/valsartan dose levels 24/26 mg,
49/51 mg and 97/103 mg, respectively.
Open-label sacubitril/valsartan will be packaged and labeled by the sponsor in accordance 
with the US Code of Federal Regulation governing handling of investigational treatments, and 
will be dispensed by the study physician.  Open-label treatment will be provided through the 
duration of the trial. Adjustment of the sacubitril/valsartan dose levels may be increased on an 
every 2-4 week basis per USPI to the desired target maintenance dose of 97/103 mg or 
increased within a 1-2 week time period based on clinical need and/or investigator judgment.
Bottles/blister packs will be numbered and assigned via an interactive voice response system 
(IRT). 
5.1.2
Additional treatment
No additional treatment beyond the investigational drug are included in this trial.
5.2
Treatment assignment
Subjects will receive sacubitril/valsartan (LCZ696) on Day 1.  The initial dose will be 
determined by the investigator and per the approved indication described in the USPI. The 
three doses available are: 24/26 mg (Dose Level 1), 49/51mg (Dose Level 2) and 97/103mg 
(Dose Level 3). 
5.3
Treatment blinding
This is an open label study.
5.4
Treating the subject
The Novartis Medical Monitor may be contacted at any time during the study regarding trial 
related medical questions or problems.  
5.4.1
Subject numbering
Each subject is uniquely identified by a Subject Number which is composed by the 4-digit site 
number (e.g., 0501, 0502 etc.) assigned by Novartis and a 3-digit sequential number assigned 
by the investigator (e.g., 001, 002, etc.). Hence a 7-digit study subject identification number, 
e.g., 0501-001. Once assigned to a subject, the Subject Number will not be reused.
Upon signing the informed consent form, the subject is assigned the next sequential number 
by the investigator. The investigator or his/her staff will contact the IRT and provide the 


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assigned subject study identification number along with the requested identifying information 
for the subject 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).
If the subject fails to be assigned to treatment for any reason, the IRT must be notified within 
2 days that the subject was not assigned to treatment. The reason for not being assigned to 
treatment will be entered on the Screening Phase Disposition eCRF.
5.4.2
Dispensing the study drug
Novartis will supply each study site with open-label treatment in clinical trial packaging.  The 
study drug packaging has a 2-part label. A unique number is printed on each part of this label 
which corresponds to one “Dose Level. Investigator staff will identify the study drug 
package(s) to dispense to the subject by contacting the IRT. Immediately before dispensing 
the package to the subject, investigator staff will detach the outer part of the label from the 
packaging and affix it to the source document (Drug Label Form) for that subject’s unique 
subject number. 
5.4.3
Handling of study and additional treatment
No additional treatment is provided as part of the study.
5.4.3.1
Handling of study treatment
Investigational 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 designees have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol. Medication labels will include storage conditions but no information about 
the subject except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Subjects will be 
asked to return all unused study treatment and packaging at each study visit and at the end of 
the study or at the time of discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
5.4.3.2
Handling of additional treatment
Not applicable.
5.4.4
Instructions for prescribing and taking study treatment
The investigator must promote compliance by instructing the subject to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the subject’s 


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safety and the validity of the study. The subject must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed.
All medication for the duration of the study will be provided by Novartis.  Eligible subjects 
will receive sacubitril/valsartan open label treatment on the first day of treatment at baseline 
(Day 1).
Initial dose at Day 1 will be determined by the principal investigator according to the USPI. 
Subjects that have been treated with ACEi before the study will require a 36-hour wash out 
before starting sacubitril/valsartan treatment.  These subjects will be instructed to wait 36 
hours from their last dose of ACEis before taking their first dose of sacubitril/valsartan.  Their 
first dose of sacubitril/valsartan will therefore be approximately 36 hours from last dose of 
ACEi. 
Titration of the dosage will be performed per USPI at 2 to 4 week intervals as clinically 
tolerated until maximal tolerated or target dosage is achieved.  
Study medication should be taken with a glass of water with or without food. If the subject 
misses taking any study drug dose, he/she should take it as soon as possible, unless it is within
4 hours of the scheduled dosing time. In this case, the subject should skip the missed dose and 
return back to his/her regular study drug administration schedule. 
All dosage prescribed and dispensed to the subject and all dose changes during the study must 
be recorded in the IRT and on the Dosage Administration Record eCRF.
5.4.5
Permitted dose adjustments and interruptions of study treatment
based on safety and tolerability
Every attempt should be made to maintain subjects on the target study drug dose level for as 
long a duration as possible throughout the study.  If, however, in the opinion of the 
investigator, a subject 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, interrupt study drug temporarily or permanently 
discontinue study drug at his/her discretion. Subjects may restart study drug at any dose level 
following an interruption of treatment, based on investigator judgment.  If study drug is 
permanently discontinued, the subject should return to the clinic as soon as possible to 
complete an end of study visit. 
Study drug dose level adjustments should be mainly based on overall safety and tolerability 
with special focus on hyperkalemia, symptomatic hypotension and 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).


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Table 5-3
Safety and tolerability guidance for dose adjustments
Parameter
Criteria
Potassium level
K > 5.3 mEq/L
Kidney function

eGFR reduction ≥ 35% compared to baseline; OR,
serum creatinine increase of ≥0.5mg/dl with at least a 25% 
decrease in eGFR
Blood pressure

Symptomatic hypotension or SBP ˂ 90 mmHg
Adverse events (AEs) or conditions

Postural symptoms or any conditions that preclude 
continuation according to the investigator’s judgment
All study treatment dose changes must be recorded on the Dosage Administration Record 
eCRF.
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;
2. Adjust Study Treatment Dose Level
Down-titrate study treatment at the investigator discretion to any dose level. The subject may 
continue receiving the lower dose level for a recommended period of 1 to a maximum of 4 
weeks.
Once stable, the subject should be re-challenged with up-titration to the next higher dose level 
in an attempt to gradually bring the subjects back to the target study treatment dose level 
(Dose level 3).
The investigator may choose any dose level for down-or up- titration according to his or her 
clinical judgment.
3. Study drug restart after temporary treatment interruption
Patients that have had a temporary interruption of study drug may re-start treatment at the 
most appropriate and allowable dose level per investigator medical judgment.  
If tolerated, the subject should be titrated up to any 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 
subject’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 subject at Dose 
Level 1 or 2, whichever is the higher and tolerated dose level by the subject, but reasons for 
not getting to Dose Level 3 needs to be captured in the eCRF.
Should the subject not tolerate the re-start study drug dose level, he/she may be down-titrated 
again (if appropriate) or discontinued from study treatment.


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4. Stopping Study Treatment
If needed, the study treatment may be permanently discontinued.  In this case, the subject 
should return to the clinic as soon as possible for an end of study visit. All assessments from 
the final visit (Visit 10) in the visit schedule of assessments (Table 6-1) must be completed 
and recorded in the eCRF. See Section 5.5.2.
5.4.6
Rescue medication
Subjects may receive open-label ACEIs and/or ARBs during the study ONLY if the study 
medication has been discontinued either temporarily or permanently. A 36 hour wash-out 
period is required when switching from or to an ACE inhibitor. Use of rescue medication 
must be recorded on the concomitant medication eCRF.
5.4.7
Concomitant medication 
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the subject was enrolled into the study must be recorded in the concomitant 
medications eCRF or Surgical and Medical Procedures eCRF as appropriate.
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
enrolling a subject or allowing a new medication to be started.
Other heart failure and cardiovascular medication
If a subject’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 and substances 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 subject is 
receiving study medication due to the increased possibility of occurrence of hyperkalemia
(please refer to Appendix 2). Salt substitutes containing potassium chloride are also to be 
avoided when possible.  Potassium levels should be monitored regularly especially in those 
who are receiving these medications.
Concomitant administration of renin inhibitors, such as aliskiren, is prohibited in subjects with 
diabetes mellitus.
Phosphodiesterase-5 (PDE-5) inhibitors
PDE-5 inhibitors should be used with caution while the subject is receiving study medication 
due to the increased possibility of occurrence of hypotension.


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Nesiritide and intravenous nitrates
The concomitant admission of sacubitril/valsartan with nesiritide or intravenous nitrates has 
not been studied. Given biological interaction between sacubitril and BNP, concomitant use of 
nesiritide (recombinant BNP) should be avoided during the study.
Other medications
Bile acid sequestering agents such as cholestyramine or colestipol are prohibited to avoid 
possible interference with study drug absorption.
5.4.8
Prohibited medication
Use of the treatments displayed in Table 5-4 is NOT allowed during the study.
Table 5-4
Prohibited medication
Medication
Prohibition period
Action taken
ACEIs Inhibitors:  benazepril, 
enalapril, Lisinopril, captopril, 
Ramipril, Fosinopril, Moexipril 
Quinapril, Trandolapril 
36 hours before 
Day 1 (visit 2) 
through end of 
study
discontinue study treatment
Aliskiren (only subjects with 
concurrent diabetes)
duration of study
discontinue study treatment 
Nesiritide
duration of study
discontinue study treatment
Bile Acid sequestering agents
duration of study
discontinue study treatment
5.4.9
Emergency breaking of assigned treatment code
Not applicable.
5.5
Study completion and discontinuation 
5.5.1
Study completion and post-study treatment
At the end of study visit, subjects will be asked to return all remaining study drug.  The 
investigator must provide follow-up medical care for all subjects who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.
5.5.2
Discontinuation of study treatment 
Subjects may voluntarily discontinue the study drug for any reason at any time. 
Study drug must be discontinued under the following circumstances: 

Withdrawal of consent

Pregnancy

Use of prohibited concomitant medication

Any protocol deviation that constitutes a risk to the subject

Investigator believes that continuation of study drug may be detrimental to the subject’s 
well-being


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Study medication may be discontinued at the investigator’s discretion if any of the following 
occur:

Any severe suspected drug related AE

Suspected occurrence of angioedema. A subject 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, subjects 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 subject should return to the clinic as soon as 
possible, after discontinuation of study drug, for an end of study visit.  All assessments from 
the final visit (Visit 10) in the visit schedule of assessments (Table 6-1) must be completed 
and recorded in the eCRF.  The study completion eCRF will also need to be completed. The 
investigator must determine the primary reason for the subject’s premature discontinuation of 
study treatment and record this information on the Study Completion eCRF. 
5.5.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. 
Withdrawal of consent (WoC) occurs only when a subject does not want to participate in the 
study anymore and does not want any further visits or assessments and does not want any 
further study related contacts and does not allow analysis of already obtained biologic 
material
At the time a subject withdraws consent, the investigator must make every effort (e.g. 
telephone, e-mail, letter) to determine the primary reason for this decision and record this 
information on the Study Completion eCRF. Study drug must be discontinued and no further 
assessments conducted. All biological material that has not been analyzed at the time of 
withdrawal must not be used. Further attempts to contact the subject are not allowed unless 
safety findings require communicating or follow-up.
5.5.4
Lost to follow-up 
For subjects 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 subject, e.g. dates of 
telephone calls, registered letters, etc. A subject will not be formally considered lost to follow-
up until all efforts to contact the subject have been exhausted.


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5.5.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the 
subject must be seen as soon as possible and treated as a prematurely withdrawn subject. 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 subject’s interests. The investigator 
will be responsible for informing the Institutional Review Board/Independent Ethics 
Committee (IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
All assessments are listed in Table 6-1. Assessments that are to be reported in the clinical 
database are marked with an ‘x’. Assessments that will only be reported in the source 
documentation are marked with an ‘s’. Subjects should be seen for all visits on the designated 
day or as close to it as possible, with an allowed visit window of ± 3 days for visits  3, 4, 5, 6 
and an allowed visit window of ±7 days for visits 7, 8, 9, and 10.  Eligible subjects may start 
study treatment once it is confirmed that they meet all inclusion criteria and none of the 
exclusion criteria. 
Blood and urine samples for protocol required assessments will be collected and submitted to 
the central laboratory. Any additional routine blood tests performed per standard of care (e.g. 
renal function, electrolytes) will be at the discretion of the principal investigator. 
Protocol required assessments for the baseline visit, including echocardiography, will be done 
according to the schedule of assessments (Table 6-1). 
Subjects may be contacted for safety evaluations for 30 days after the last dose. 
Documentation of attempts to contact the subject should be recorded in the source 
documentation. Unscheduled visits for safety/medication evaluation/unscheduled assessments 
are permitted at any time during the study.


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Table 6-1
Assessment schedule
Schedule of Assessments
Visit number
1
2
3
4
5
6
7
8
9
10/
EOS
Unscheduled
Visit◊
Period
Screening
Baseline
Titration / Maintenance
Day
Day -28 to 
Day -1
Day 1
14
30
45
60
90
180
270
365
Inclusion/Exclusion
X
X
Informed Consent
X
Demographics
X
Medical History
X
HF Signs/Symptoms and 
NYHA Classification
X
X
X
X
X
X
X
X
X
X
X
Complete Physical 
Examination
s
s
s
s
s
s
s
s
s
Limited Cardiovascular 
Physical examination1
s
s
Vital signs
X
X
X
X
X
X
X
X
X
X
X
Height 
X
Weight
X
X
X
X
X
X
X
X
X
X
X
Safety Laboratory 
(Chemistry/Hematology) 5
X
X
X
X
X
X
X
X
X
X
X
Laboratory (per protocol) 
Renal 
function/Potassium6,7
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Adverse Events/Serious 
Adverse Events
X
X
X
X
X
X
X
X
X
X
X


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Schedule of Assessments
Visit number
1
2
3
4
5
6
7
8
9
10/
EOS
Unscheduled
Visit◊
Period
Screening
Baseline
Titration / Maintenance
Day
Day -28 to 
Day -1
Day 1
14
30
45
60
90
180
270
365
Angioedema assessment
X
X
X
X
X
X
X
X
X
X
Blood for Biomarkers (all 
subjects)6,7,8
X
X
X
X
X
X
X
X
X
X
Urine  for Biomarkers (all 
subjects) 6,8
X
X
X
X
X
X
X
X
X
X
Serum pregnancy test 2
X
X
X
X
X
X
Urine Pregnancy tests 3
X
X
X
Echocardiogram
X
X
X
X
Dipstick urinalysis4
X
X
X
X
KCCQ-23
X
X
X
X
X
X
X
X
X
Dispensation of 
medication9
X
X
X
X
X
X
X
X
X
Drug accountability
s
s
s
s
s
s
s
s
s
s
Dosage Administration 
Record
X
X
X
X
X
X
X
X
X
IRT Call
X
X
X
X
X
X
X
X
X
X
X
Screening Disposition
X
Study completion/early 
termination in IRT
X
X
X
X
X
X
X
X
X
X
X


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Schedule of Assessments
Visit number
1
2
3
4
5
6
7
8
9
10/
EOS
Unscheduled
Visit◊
Period
Screening
Baseline
Titration / Maintenance
Day
Day -28 to 
Day -1
Day 1
14
30
45
60
90
180
270
365
* S: to be documented in the source data.
◊Unscheduled Visit Assessments marked with (x) are optional procedures that may be performed at the investigator’s discretion, or if the subject 
withdraws early from treatment or study.
1. Limited Cardiovascular Physical Exam to be completed at Days 14 and 45 (Visits 3 and 5).
2.  A serum pregnancy test is not required for a woman who is sterile or who is post-menopausal. All serum pregnancy tests will be sent to the central 
laboratory.
3.  Urine pregnancy test will be performed on site for the visits 1 and 2.
4.  Urine dipstick. If positive, send full urinalysis to central laboratory.
5.  Abbreviated chemistry panel includes electrolytes and creatinine.
6.  Must be strictly processed and stored according lab manual instructions and timelines.
7.  Includes cardiac, renal, and drug mechanism of action biomarkers.
8.  Includes urinary biomarkers such as cGMP.
9.  36-hr washout required pre-dose at visit 2 (baseline) to avoid drug-drug interaction between ACEis and NEPi.
 
 


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6.1
Information to be collected on screening failures
All subjects who have signed informed consent but not entered into the next epoch will have 
the study completion page for the screening epoch, demographics, inclusion/exclusion, and 
serious adverse event (SAE) data collected. Adverse events that are not SAEs will be 
followed by the investigator and collected only in the source data.
6.2
Rescreening
Rescreening may be allowed under certain conditions.  Request from the investigator/site staff 
to rescreen patients will be handled on a case-by-case basis with Clinical Trial Lead approval 
required before proceeding with the rescreening.  Rescreening cannot be done if a patient was 
previously enrolled in the study.
If a patient rescreens for the study, the patient must sign a new informed consent (ICF) and be 
issued a new patient number prior to any screening assessments being conducted under the 
new patient number.  The date of the new informed consent signature must be entered on the 
Informed Consent eCRF to correspond to the new patient number.
6.3
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data to be collected on all subjects include: 
year of birth, age, sex, race, ethnicity and source of subject referral. Relevant medical 
history/current medical condition data includes data until the start of study drug. Where 
possible, diagnoses and not symptoms, will be recorded. HF medications and other CV 
medications will be recorded on eCRFs designed to facilitate separation from non-CV 
medications. Likewise, detailed HF history and other relevant CV medical history will be 
recorded on eCRFs separately from relevant non-CV medical history.
6.4
Treatment exposure and compliance
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts and information provided by the care giver. This information should be captured in the 
source document at each visit. Subject compliance should be at least 80% during the titration 
and maintenance treatment period. The investigator and/or study personnel will counsel the 
subject 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 the study titration and maintenance study drug exposure will be calculated based 
upon the start and stop dates recorded in the Dosage Administration Record eCRF.
6.5
Efficacy
The efficacy variables are:
Primary:

Change in concentration of NT-proBNP from baseline to one year 

Change in LVESVi, LVEDVi, LVEF, and LA volume index (LAVi) from baseline to 
one year   


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Secondary:

Change in concentration of NT-proBNP from baseline to 6 months

Change in LVESVi, LVEDVi, LVEF, and LA volume index (LAVi) from baseline to 
6 months

Change in KCCQ-23 baseline to one year
6.5.1
Heart failure signs and symptoms
Signs and symptoms of heart failure will be reviewed by the investigator at all 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 scored at each visit.
Novartis’ reporting guidelines for AE and SAE as outlined in Section 7.1 and Section 7.2
must be followed, independent from the circumstance that an event is also reported as a
cardiovascular event.


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6.5.3
Biomarkers in full subject population
Blood and urine samples for analysis of stable biomarkers related to heart failure or study 
drug mechanism of action will be collected in all subjects at Visits 2, 3, 4, 5, 6, 7, 8, 9 and 10 
as indicated in Table 6-1.  Biomarkers will be used to elucidate the effect of study drug as 
well as to explore drug effect and may also be used to determine event risk. Blood biomarkers 
may include, but are not limited to: NT-proBNP, high sensitivity Troponin, and sST2. Urine 
biomarkers may include, but are not limited to, cGMP.  Biomarker values will be blinded to 
the site and the Novartis clinical study team. The list of blood and urine biomarkers may 
change during the course of the study as new or more relevant biomarkers related to heart 
failure or study drug mechanism are determined.  Biomarker analysis may also occur 
retrospectively after study close using samples that are biobanked with biomarker decisions 
dependent on study outcome and/or new biomarkers relevant to heart failure or the study drug.  
Details of sample collection, handling and shipment will be provided to investigators in the 
laboratory manual.
6.5.5
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.
6.6
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)

Incidence of angioedema 


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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.
6.6.1
Physical examination
A complete physical exam will be performed at visit 1 (screening), visit 2 (baseline), visit 4 
(Day 30), visit 6 (Day 60), 7 (Day 90), 8 (Day 180), 9 (Day 270), and 10 (Day 365). 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. 
Limited cardiovascular physical examination will be performed at visit 3 (Day 14) and visit 5 
(Day 45), except where a complete physical examination is required (see above), and will 
include the examination of vital signs (systolic and diastolic blood pressure, pulse and 
respiration rate), heart and lung sounds, jugular venous distension, and extremities.
Signs and symptoms of heart failure will be reviewed by the investigator at all 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 scored at each visit.
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that were present prior to the subject providing written 
informed consent for the study must be included in the Relevant Medical History/Current 
Medical Conditions eCRF. Significant findings made after the subject provides written 
informed consent for the study which meet the definition of an adverse event must be 
recorded on the Adverse Event eCRF.
6.6.2
Vital signs 
Vital signs will be assessed at every visit. This will include blood pressure, pulse and 
respiration measurements. BP will be measured using a standard sphygmomanometer with an 
appropriate 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 subject for all vital signs assessments 
and where possible, the same person doing the assessment.
6.6.3
Height and weight
Height in centimeters if possible, body weight to the nearest 0.1 kg without shoes will be 
measured at visit 1. Body weight (to the nearest 0.1 kilogram (kg) in indoor clothing, but 
without shoes) will be measured at every visit.
6.6.4
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 


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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 
eCRF must be completed and the Novartis Medical Monitor 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.  In addition, all 
angioedema events will be adjudicated as described in Section 8.5.1
6.6.5
Laboratory evaluations
A central laboratory will be used for all laboratory evaluations with the exception of the urine 
pregnancy test (hCG) performed at visit 1 (screening) and visit 2 (baseline) at the site, 
required to determine eligibility and analysis of all collected specimens from screening 
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.      
Clinically notable laboratory findings are defined in Appendix 1.
For laboratory values that exceed the boundaries of a notable laboratory abnormality 
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 AEs 
screen of the subject's 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 
subject 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.
6.6.5.1
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and 
platelet count will be measured at all visits: 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 (central lab).
6.6.5.2
Clinical chemistry
Blood urea nitrogen (BUN), glucose, creatinine, total bilirubin, AST (SGOT), ALT (SGPT), 
alkaline phosphatase, sodium, potassium, chloride, calcium, hemoglobin A1C, total protein, 
albumin, uric acid, and lipid profile will be measured at all Visits 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10  
(central lab).
6.6.5.3
Urinalysis
Dipstick-test determination of specific gravity, pH, blood, total protein, bilirubin, glucose
ketones, and leukocytes will be measured at Visits 1, 7 and 10 (local lab). Microscopy and 


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WBC and RBC sediments will also be assessed in case of an abnormal dipstick test (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.
6.6.6
Pregnancy and assessments of fertility
All female subjects of childbearing potential will have a urine pregnancy test (hCG) 
performed at Visits 1 and 2 (site).  In addition, these subjects will have a serum pregnancy test 
performed at visits 2, 7, 8, 9 and 10 (central Lab). If any of these tests are positive, the subject 
must be discontinued from the study.
6.6.7
Appropriateness of safety measurements
The majority of safety assessments selected for this study are standard for this 
indication/subject population.  They include the monitoring and recording of all adverse 
events and serious adverse events, evaluation of hematology, blood chemistry and urine, 
regular measurements of vital signs and the performance of physical examinations.
6.7
Other assessments
6.7.1
The Kansas City Cardiomyopathy Questionnaire (KCCQ-23)
The KCCQ-23 is a self-administered questionnaire and requires, on average, 4-6 minutes to 
complete. It contains 23 items, covering physical function, clinical symptoms, social function, 
self-efficacy and knowledge, and Quality of Life (QoL), each with different Likert scaling 
wording, including limitations, frequency, bother, change in condition, understanding, levels 
of enjoyment and satisfaction. A change of 5 points on the scale scores, either as a group 
mean difference or an intra-individual change appears to be clinically significant, based on 
comparisons of changes in the scale scores to clinical indicators and subject global reports of 
change. The KCCQ is a valid, reliable and responsive health status measure for subjects with 
CHF and may serve as a clinically meaningful outcome in CV clinical research, subject 
management and quality assessment Green et al 2000.
The HF symptoms and physical limitation domains scores show the best correlation for 
improvements following a CHF exacerbation Green et al 2000. Thus, one of the secondary 
endpoints is a clinical summary score based on the HF symptoms and physical limitation 
domains scores of the KCCQ. 
 
The KCCQ questionnaire will be completed at Visits 2, 3, 4, 6, 7, 8, 9 and 10.
The KCCQ is available in a number of validated translations. However, subjects in whose 
language a validated translation of the KCCQ is not available will be exempt from completing 
this instrument. 
6.7.2
Echocardiogram
Echocardiograms will be performed at the sites by qualified echocardiographic personnel 
(technicians or physicians) in accordance with standard echocardiographic clinical practice. 


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The baseline echocardiogram will be performed before administration of study medication. 
The echocardiographic examination required will be a modification of the standard 
echocardiographic examination, and will include the majority of standard echocardiographic 
views normally obtained for clinical practice, in addition to specific echocardiographic 
assessments designed to assess LV mass, LA volume, and diastolic function (Table 6-2). 
1. LV mass index, left atrial volume index
2. Diastolic function (lateral E’ velocity, E/E’)
3. Systolic function (ejection fraction, S’ velocity)
Table 6-2
Echocardiogram Assessments
Echocardiograms will be recorded to digital media in DICOM format (CD, or Magneto-
Optical Disc) and sent to the core laboratory for analysis. All echocardiographic 
measurements will be made at the core laboratory 
 
.
The echo data obtained during Baseline (Day 1), visit 8 (Day 180) and visit 10 (Day 365) will 
be sent to a core laboratory for evaluation and analysis.  A detailed manual of all echo 
procedures will be provided to all sites.
6.7.3
Resource utilization
Not applicable.
Echocardiographic view
Images obtained

Parasternal long axis view 

2-D image for septal and posterior wall 
thickness, volume and ejection fraction 
measures, LA size/volume

M-Mode Images 

Color flow Doppler 

Parasternal Short axis view, papillary 
muscle level 

2-D images for septal and posterior wall 
thickness

Apical 4-chamber View 

2-D images for volume and ejection fraction 
measures, LA size/volume and RV function  
Color flow Doppler for assessment of mitral 
regurgitation 

Doppler Tissue Imaging of mitral annular 
velocities 

Mitral inflow pulsed Doppler 


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7
Safety monitoring
7.1
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 subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
The occurrence of adverse events must be sought by non-directive questioning of the subject 
at each visit during the study. Adverse events also may be detected when they are volunteered
by the subject during or between visits or through physical examination findings, laboratory 
test findings, or other assessments.
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, 

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 subject with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1.
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information:

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 

no action taken (e.g. further observation only) 

[investigational] treatment dosage increased/reduced

[investigational] treatment interrupted/withdrawn

concomitant medication or non-drug therapy given 

non-drug therapy given 

subject hospitalized/subject’s hospitalization prolonged (see Section 7.2 for definition of 
SAE)


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
its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it must be followed until its resolution or until it is judged 
to be permanent, and assessment must be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the subject
informed consent and should be discussed with the subject during the study as needed. Any 
new information regarding the safety profile of the medicinal product 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 has then to be discussed with the subject.
The investigator must also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
7.2
Serious adverse events 
7.2.1
Definition of SAE 
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:

is fatal or life-threatening 

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 (specify what this includes)

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

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 

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
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All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the subject 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 Annex IV, ICH-E2D Guideline).
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 
subject or might require intervention to prevent one of the other outcomes listed above. 
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 Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.  
7.2.2
SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days [after the last study visit/ following the last 
administration of study treatment if there are post-treatment follow-up visits with no required 
procedures] must be reported to Novartis within 24 hours of learning of its occurrence. Any 
SAEs experienced after the 30 day period [after the last study visit/ following the last 
administration of study treatment if there are post-treatment follow-up visits with no required 
procedures] should only be reported to Novartis if the investigator suspects a causal 
relationship to study treatment. 
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.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to each specific 
component of study treatment, (if study treatment consists of several components) complete 
the SAE Report Form in English, and submit the completed form within 24 hours to Novartis. 
Detailed instructions regarding the submission process and requirements for signature are to 
be found in the investigator folder provided to each site. 
Follow-up information is submitted as instructed in the investigator folder. Each re-
occurrence, complication, or progression of the original event must be reported as a follow-up 
to that event regardless of when it occurs. The follow-up information should describe whether 
the event has resolved or continues, if and how it was treated, whether the blind was broken or 
not, and whether the subject continued or withdrew from study participation.


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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 Drug Safety and 
Epidemiology 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.
7.3
Renal safety monitoring 
The following two categories of abnormal renal laboratory values have to be considered 
during the course of the study:

Serum event:

confirmed (after ≥24h) increase in serum creatinine of ≥25% compared to baseline 
during normal hydration status

Urine event

new onset (≥1+) proteinuria; confirmed by doubling in the urinary albumin-creatinine 
ratio (ACR) or urinary protein-creatinine ratio (PCR) (if applicable)

new onset (≥1+), hematuria or glycosuria 
Every renal laboratory trigger or renal event as defined in Table 14-1 in Appendix 2 should be 
followed up by the investigator or designated personnel at the trial site as summarized in
Appendix 2. 
7.4
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, subject 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 collected in 
the DAR (dose administration record) eCRF 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.


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Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error 
type
Document in Dose 
Administration (DAR) 
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
7.5
Pregnancy reporting
To ensure subject 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.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
8
Data review and database management
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and (e)CRFs 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 subject records, the accuracy of entries on the (e)CRFs, 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 
monitor. 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 subject 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 


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subject's file. The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the (e)CRF entries. 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 (e)CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.
8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRFs) using fully validated software that conforms to US CFR 21Part 
11 requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected. The 
Investigator must certify that the data entered into the Electronic Case Report Forms are 
complete and accurate. After database lock, the investigator will receive copies of the subject 
data for archiving at the investigational site. 
8.3
Database management and quality control
The designated CRO staff working on behalf of Novartis will review the data entered into the 
CRFs by investigator staff for completeness and accuracy and instruct the site personnel to 
make any required corrections or additions. Queries are sent to the investigational site using 
an electronic data query. Designated investigator site staff is required to respond to the query 
and confirm or correct the data. 
8.4
Data Monitoring Committee
Not applicable.
8.5
Angioedema Adjudication Committee
8.5.1
Composition and Purpose
The Angioedema Adjudication Committee (AAC) consists of a group of experts in clinical 
angioedema who have been selected according to their educational, clinical, and research 
experience and are independent from Novartis. The purpose of the AAC is to review and to 
adjudicate all suspected angioedema events in a uniform and consistent manner and to assign 
severity for each confirmed case for the project wide sacubitril/valsartan program. The AAC 
will remain blinded to treatment allocation during the adjudication process whenever possible 
and necessary.
8.5.2
Overview of Site Responsibility
An overview of site responsibility for reporting angioedema is described below.


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At each study visit, it is important for the investigator to pay special attention to any swelling 
or edema that may resemble angioedema or angioedema-like events that may be reported by 
subjects. There will be a separate eCRF for angioedema events. If such an event occurs, the 
investigator will complete an Adjudication 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. Follow-up reports must be 
communicated to Novartis as soon as new information regarding the event becomes available. 
All hospital records related to the event must be communicated to Novartis.
Occasionally, the investigator may be contacted by Novartis, or designee, regarding AEs that 
were reported on behalf of subjects 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 records for such events, regardless of whether the investigator views the 
event in question as angioedema or not.
All angioedema reports will be forwarded to an angioedema adjudication committee by 
Novartis or designee for assessment.
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 Adjudication Questionnaire for an Angioedema-like Event.
Please refer to the Angioedema Adjudication Site Manual for additional details regarding the 
process for documenting and reporting angioedema-like events.
9
Data analysis
A designated Contract Research Organization will perform the statistical analysis.
It is planned that the data from all centers that participate in this protocol will be combined, so 
that an adequate number of subjects will be available for analysis.
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation
Unless otherwise specified, all statistical tests will be conducted against a two-sided 
alternative hypothesis, employing a significance level of 0.05.
Efficacy, safety, and other data will be summarized.  For continuous variables, summary 
statistics (mean, standard deviation, median, 25th and 75th percentiles, interquartile range, 
minimum, and maximum) at each time point and for change from baseline to each time point 
will be reported by treatment group.  Discrete variables will be summarized by frequencies 
and percentages.
9.1
Analysis sets 
The following subject sets will be used for the statistical reporting and analyses:
The Treatment Set will consist of all eligible subjects.


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The Full Analysis Set (FAS) will consist of all subjects with the exception for those subjects 
who have not been qualified for study treatment and have not received study drug, but have 
been inadvertently entered into the study. Efficacy  variables  will  be  analyzed  based  on  
the  FAS  as  the  primary set.
The Safety Set (SAF) will consist of all subjects who received at least one dose of study drug. 
The Safety Set will be used for the analyses of safety variables.
9.2
Subject demographics and other baseline characteristics
Baseline value is defined as the last non-missing assessment prior to the first dose of study 
medication, unless specified otherwise in the protocol.
Summary statistics will be provided for demographics and baseline characteristics. 
Continuous variables will be summarized using n, mean, standard deviation, median, 25th and 
75th percentiles, interquartile range, minimum, and maximum. Geometric means will be used 
to summarize the NT-proBNP results.  Categorical variables will be summarized using 
frequency and percentage.
The Treatment Set and FAS will be the subject sets for the above analyses.
9.3
Treatments
The overall duration on the open-label study drug will be summarized by using mean, 
standard deviation, median, 25th and 75th percentiles, interquartile range, minimum, and 
maximum. Additionally, the number and percentage of subjects will be summarized for 
duration category.
Concomitant medications and significant non-drug therapies, prior to and after the start of the 
open-label treatment epoch will be summarized by therapeutic class, and preferred term.
The Safety Set will be used for the above analyses.
9.4
Analysis of the primary variable(s)
9.4.1
Variable(s)

Change in concentration of NT-proBNP from baseline to one year

Change in LVESVi, LVEDVi, LVEF, and LAVi from baseline to one year. 
9.4.2
Statistical model, hypothesis, and method of analysis
Pearson’s correlation coefficient and its two-sided 95% confidence interval (CI) to examine 
the association between change in log-transformed NT-proBNP and LVESVi, LVEDVi, 
LVEF, and LAVi from baseline to one year will be calculated.  
Similar correlation coefficients and CIs will be calculated for the following subgroups:  

Subjects with de novo HF (naïve to ACE inhibitor or ARB therapy) and those with 
previously established HF.

Subjects with NT-proBNP values <600 pg/mL (or 400 pg/mL if hospitalized for HF 
within 1 year) at the time of drug initiation, and those with higher values.


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
In those not receiving the target sacubitril/valsartan dose and those achieving target dose.

In those with an NT-proBNP concentration <1000 pg/mL at Month 12 and those with NT-
proBNP ≥1000 pg/mL at the same time point.

As a function of time from baseline to an NT-proBNP value of <1000 pg/mL for subjects 
with a baseline value >=1000 pg/mL (percentiles of response time).

As a function of time spent with NT-proBNP concentration <1000 pg/mL across study 
visits (percentiles of response time).
The primary analysis of the primary efficacy variables will be based on the Full Analysis Set.
9.4.3
Handling of missing values/censoring/discontinuations
Missing data will not be imputed.  
9.4.4
Sensitivity analyses
Pearson’s correlation coefficient and its 95% confidence interval (CI) to examine the 
association between change in log-transformed NT-proBNP and each structural cardiac 
measurement from baseline to one year will be calculated using the last observation carried 
forward (LOCF) method.
Spearman’s correlation coefficient and its 95% confidence interval (CI) to examine the 
association between change NT-proBNP and each structural cardiac measurement from 
baseline to one year will be calculated based on observed cases.
9.5
Analysis of secondary 
 variables
9.5.1
Secondary variables 
Analyses of the secondary variables will be based on the Full Analysis Set.
The secondary efficacy variables are:
1. Change in concentration of NT-proBNP from baseline to 6 months
2. Change in LVESVi, LVEDVi, LVEF, and LAVi from baseline to 6 months
3. Change in KCCQ-23 clinical summary score from baseline to 12 months
Pearson’s correlation coefficient and its two-sided 95% confidence interval (CI) to examine 
the association between change in log-transformed NT-proBNP and LVESVi, LVEDVi, 
LVEF, and LAVi from baseline to 6 months will be calculated.  Similar CIs will be calculated 
for the following subgroups:

Subjects with de novo HF (naïve to ACE inhibitor or ARB therapy) and those with 
previously established HF.

Subjects with NT-proBNP values <600 pg/mL (or 400 pg/mL if hospitalized for HF 
within 1 year) at the time of drug initiation, and those with higher values.

In those not receiving the target sacubitril/valsartan (LCZ696) dose and those achieving 
target dose.

In those with an NT-proBNP concentration <1000 pg/mL and those with NT-proBNP 
≥1000 pg/mL at the same time points.


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
As a function of time from baseline to an NT-proBNP value of <1000 pg/mL for subjects 
with a baseline value >=1000 pg/mL (percentiles of response time).

As a function of time spent with NT-proBNP concentration <1000 pg/mL across study 
visits (percentiles of response time.
An analysis of variance will be done to compare the mean change in the KCCQ-23 summary 
score between the groups of subjects with NT-proBNP<1000 pg/mL and NT-proBNP>=1000 
pg/mL at Month 12. Because the treatments in this study are not assigned randomly, the 
groups may consist of subjects that are systematically different from each other with respect 
to their baseline covariate information, therefore propensity score adjustment will be used in 
the comparison of treatment groups.


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9.5.3
Resource utilization 
Not applicable.
9.5.4
Pharmacokinetics 
Not applicable.
9.5.5
DNA 
Not applicable.
9.5.6
Biomarkers 
See Sections 9.4 and Section 9.5 for a description of the methods used to analyze the 
biomarkers.  Any other biomarkers collected but not specifically mentioned in Sections 9.4 or 
Section 9.5 will be analyzed in the same manner. 
9.5.7
PK/PD
Not applicable.
9.6
Other safety variables
The safety and tolerability assessments are listed below:

AEs and SAEs

Sitting systolic, diastolic BP, and pulse pressure

Heart rate

Laboratory values
The assessment of safety will be based primarily on the frequency of adverse events, SAEs, 
and laboratory abnormalities. Other safety data will be summarized as appropriate.
The incidence of treatment-emergent adverse events (new or worsened) will be summarized 
by primary system organ class, preferred term, severity, and relationship to study drug. In 
addition, the incidence of death, SAEs, and AEs leading to discontinuation will be 
summarized separately by primary system organ class and preferred term.
Laboratory data will be summarized by presenting shift tables using extended reference 
ranges (baseline to most extreme post-baseline value), by presenting summary statistics of 
raw data and change from baseline values (mean, median, standard deviation, 25th and 75th


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percentiles, interquartile range, minimum and maximum) and by the flagging of notable 
values in data listings.
Data from other tests (e.g., ECG) will be listed, notable values will be flagged, and any other 
information collected will be listed as appropriate.
Safety analyses will be performed based on the Safety Set. There will be no inferential 
analyses of the safety data.
9.7
Interim analyses
Not applicable
9.8
Sample size calculation
The objective of this study is to estimate the correlation coefficient between change in log 
NT-proBNP and each structural cardiac measurement overall and in each subgroup of interest. 
We would like to estimate the correlation coefficient with a precision (half-width of the 
confidence interval (CI)) of at least 0.15 for a 2-sided 95% CI in the intended subgroups of 
interest. The subgroups of interest are:  (1) subjects with HFrEF and “low” NT-proBNP (<600 
if not hospitalized or <400 if hospitalized) or “low” BNP (<150 if not hospitalized, <100 if 
hospitalized) at baseline (Ambrosy 2012), (2) subjects with new onset HF and/or RAAS naïve 
(Fonarow 2010), and (3) subjects who are not receiving the target sacubitril/valsartan dose 
(McMurray 2014). It is estimated that these subgroups will represent approximately 25%, 20% 
and 30% of the study population, respectively.  Assuming, the population correlation 
coefficient of -0.35 (Weiner 2013) for the overall study sample and within each subgroup, the 
smallest sample size that would yield a precision of at least 0.15 for the estimated correlation 
coefficient would be n=133. Accounting for assumed 20% drop-out rate, 166 patients would 
be required. If the n=166 was the smallest subgroup of interest (20% of the overall study 
population), an overall sample size of 830 would be required to enroll in this study. For any 
other subgroup with more than 166 patients will yield precision smaller than 0.15 for the 
estimated correlation coefficient. For the overall sample size of N=830 patients the precision 
of the estimate of correlation coefficient would be 0.07 (PASS 2008).
10
Ethical considerations 
10.1
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 
Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in 
the Declaration of Helsinki.
10.2
Informed consent procedures
Eligible subjects/subjects may only be included in the study after providing written (witnessed, 
where required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of 


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doing so, after such consent has been provided by a legally acceptable representative(s) of the 
subject. In cases where the subject’s representative gives consent, the subject must be 
informed about the study to the extent possible given his/her understanding. If the subject is 
capable of doing so, he/she must indicate assent by personally signing and dating the written 
informed consent document or a separate assent form. 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 subject
source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing 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 requirement for the 
duration of the study. If there is any question that the subject will not reliably comply, they 
must not be entered in the study.
10.3
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, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to 
patients/subjects. 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.
10.4
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report 
the results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results.
10.5
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.


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Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance (CQA), a group 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.
11
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 subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
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. 
11.1
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 intended to eliminate an apparent immediate 
hazard to subjects 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 subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed.


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12
References 
Ambrosy AP, Fonarow GC, Albert NM, Curtis AB, Heywood JT, Mehra MR, O'Connor CM, 
Reynolds D, Walsh MN, Yancy CW and Gheorghiade M. B-type natriuretic peptide 
assessment in ambulatory heart failure patients: insights from IMPROVE HF. J Cardiovasc 
Med (Hagerstown). 2012;13:360-7.
Fonarow GC, Albert NM, Curtis AB, Stough WG, Gheorghiade M, Heywood JT, McBride 
ML, Inge PJ, Mehra MR, O'Connor CM, Reynolds D, Walsh MN and Yancy CW. Improving 
evidence-based care for heart failure in outpatient cardiology practices: primary results of the 
Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient  
Setting (IMPROVE HF). Circulation. 2010;122:585-96
Gaggin HK, Truong QA, Rehman SU, Mohammed AA, Bhardwaj A, Parks KA, Sullivan DA, 
Chen-Tournoux A, Moore SA, Richards AM, Troughton RW, Lainchbury JG, Weiner RB, 
Baggish AL, Semigran MJ and Januzzi JL, Jr. Characterization and prediction of natriuretic 
peptide "nonresponse" during heart failure management: results from the ProBNP Outpatient  
Tailored Chronic Heart Failure (PROTECT) and the NT-proBNP-Assisted Treatment to 
Lessen Serial Cardiac Readmissions and Death (BATTLESCARRED) study. Congest Heart
Fail. 2013;19:135-42.
Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of 
the Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart failure.  
J AM Coll Cardiol. 2000 Apr;35(5):1245-55.
Januzzi JL, Jr., Rehman SU, Mohammed AA, Bhardwaj A, Barajas L, Barajas J, Kim HN, 
Baggish AL, Weiner RB, Chen-Tournoux A, Marshall JE, Moore SA, Carlson WD, Lewis 
GD, Shin J, Sullivan D, Parks K, Wang TJ, Gregory SA, Uthamalingam S and Semigran MJ. 
Use of amino-terminal pro-B-type natriuretic peptide to guide outpatient therapy of patients 
with chronic left ventricular systolic dysfunction. J Am Coll Cardiol. 2011;58:1881-9.
Konstam MA, Kramer DG, Patel AR, Maron MS and Udelson JE. Left ventricular remodeling 
in heart failure: current concepts in clinical significance and assessment. JACC Cardiovasc 
Imaging. 2011;4:98-108.
Masson S, Latini R, Anand IS, Vago T, Angelici L, Barlera S, Missov ED, Clerico A, 
Tognoni G, Cohn JN and Val-He FTI. Direct comparison of B-type natriuretic peptide (BNP) 
and amino-terminal proBNP in a large population of patients with chronic and symptomatic 
heart failure: the Valsartan Heart Failure (Val-HeFT) data. Clin Chem. 2006;52:1528-38.
McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, 
Solomon SD, Swedberg K, Zile MR, Investigators P-H and Committees. Angiotensin-
neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993-1004.
Packer M, McMurray JJ, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, 
Solomon SD, Swedberg K, Zile M, Andersen K, Arango JL, Arnold JM, Belohlavek J, Bohm 
M, Boytsov S, Burgess LJ, Cabrera W, Calvo C, Chen CH, Dukat A, Duarte YC, Erglis A, Fu 
M, Gomez E, Gonzalez-Medina A, Hagege AA, Huang J, Katova T, Kiatchoosakun S, Kim 
KS, Kozan O, Llamas EB, Martinez F, Merkely B, Mendoza I, Mosterd A, Negrusz-Kawecka 
M, Peuhkurinen K, Ramires FJ, Refsgaard J, Rosenthal A, Senni M, Sibulo AS, Jr., Silva-


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Cardoso J, Squire IB, Starling RC, Teerlink JR, Vanhaecke J, Vinereanu D, Wong RC, 
Investigators P-H and Coordinators. Angiotensin receptor neprilysin inhibition compared with 
enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation. 
2015;131:54-61.
Weiner RB, Baggish AL, Chen-Tournoux A, Marshall JE, Gaggin HK, Bhardwaj A, 
Mohammed AA, Rehman SU, Barajas L, Barajas J, Gregory SA, Moore SA, Semigran MJ 
and Januzzi JL, Jr. Improvement in structural and functional echocardiographic parameters 
during chronic heart failure therapy guided by natriuretic peptides: mechanistic insights from 
the ProBNP Outpatient Tailored Chronic Heart Failure (PROTECT) study. Eur J Heart Fail. 
2013;15:342-51.
Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Jr., Drazner MH, Fonarow GC, Geraci 
SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, 
McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, 
Wilkoff BL, American College of Cardiology F and American Heart Association Task Force 
on Practice G. 2013 ACCF/AHA guideline for the management of heart failure: a report of the 
American College of Cardiology Foundation/American Heart Association Task Force on 
Practice Guidelines. J Am Coll Cardiol. 2013;62:e147-239.


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13
Appendix 1: Clinically 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
Alkaline phosphatase >100% increase
Potassium
>20% increase, >20% decrease


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Appendix 2: Specific Renal Alert Criteria and Actions
Table 14-1
Specific Renal Alert Criteria and Actions
Serum Event
Serum creatinine increase
25 – 49% compared to baseline
Confirm 25% increase after 24-48h 
Follow up within 2-5 days
Acute Kidney Injury: Serum creatinine increase 
50% compared to baseline
Follow up within 24-48h if possible
Consider study treatment interruption 
Consider subject hospitalization /specialized treatment
Urine Event
New dipstick proteinuria ≥1+
Albumin- or Protein-creatinine ratio increase ≥2-fold
Albumin-creatinine ratio (ACR) ≥30 mg/g or ≥3 
mg/mmol;
Protein-creatinine ratio (PCR )≥150 mg/g or >15 
mg/mmol
Confirm value after 24-48h
Perform urine microscopy
Consider study treatment interruption / or discontinuation 
New dipstick glycosuria ≥1+ not due to diabetes
Blood glucose (fasting)
Perform serum creatinine, ACR 
New dipstick hematuria ≥1+ not due to trauma
Urine sediment microscopy
Perform serum creatinine, ACR 
For all renal events:
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and additional diagnostic 
procedures performed 
Monitor subject regularly (frequency at investigator’s discretion) until either: 
Event resolution: sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline, or
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio stabilization at a 
new level with ±50% variability over last 6 months.


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Appendix 3: 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.
Subjects with elevated potassium value will be managed according to the corrective actions 
outlined below and the investigator’s clinical judgment. 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)

Consider down-titration of study medication, according to investigator’s medical 
judgment.


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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 subject 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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Appendix 4: 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 5.4.5 should be adhered to as much as possible.


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Appendix 5: Guidelines for the management of renal 
dysfunction
General principles:
Glomerular filtration rate in HF subjects 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 subjects after study drug 
administration. These recommendations have been developed to guide the investigators in 
managing subjects with renal dysfunction after administration of study drug.
Two types of response to serum creatinine increase are described:
Surveillance situation 
If, at any time after study drug administration, 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 subject 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).
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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Appendix 6: Kansas City Cardiomyopathy Questionnaire


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SAP_001.pdf: 
Clinical Development 
LCZ696/Sacubitril/Valsartan/Entresto®
CLCZ696BUS13 / NCT02887183
A 52 week, open label evaluation of the effects of 
sacubitril/valsartan (LCZ696) therapy on biomarkers, 
myocardial remodeling and patient-reported outcomes in 
heart failure with reduced left ventricular ejection fraction: 
(PROVE-HF) 
Statistical Analysis Plan (SAP) 
Author: 
CRO Statistician, 
 
Statistician, Novartis, 
 
Document type: 
SAP Documentation 
Document status: 
Final 2.0, Amendment 1 
Release date: 
22-Feb-2019
Number of pages: 
40 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous final version of SAP 
 
 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title impacted 
(Current) 
09- 
May- 
2017 
Prior 
to 
DB 
Creation of 
Final 
Version 
NA – First Version 
NA 
  
Lock 
 
22-Feb- 
2019 
Prior 
to 
DB 
Lock 
Creation of 
Amendment 
1 
1. Updated to align with protocol 
version 03 (amended protocol) 
dated 27-Feb-2018: removal of 
interim analysis 
2. Updated list of abbreviations 
3. Clarified MedDRA version 
4. Clarified WHO Drug version 
5. Specified that geometric means 
and confidence intervals will 
be presented for biomarker 
data 
6. Updated baseline definitions 
for biomarkers and echo 
variables 
7. Added subgroups for the 
analysis of the primary 
objective 
8. Specified addional biomarkers 
for the summary of baseline 
characteristics 
9. Updated table of BB 
standardization factors 
10. Clarified LOCF method for 
supportive analysis of primary 
objective 
11. Added two supportive analyses 
of the primary objective based 
on alternative baseline 
definitions for 
echocardiographic variables 
12. Removed optional sensitivity 
analysis of KCCQ-23 clincial 
summary score change from 
baseline at one year using 
1. Section 1.1 Study design; 
Section 2.14 Interim analysis 
2. List of abbreviations table 
3. Section 2.3.3 
Demographics and other 
baseline characteristics; 
Section 2.8.1.1 Coding of 
AEs; Section 2.8.2 Deaths; 
Section 5.2 AE 
coding/grading 
4. Section 2.4.2 Prior, 
concomitant and post 
therapies 
5. Section 2.1 Data analysis 
general information 
6. Section 2.1.1 
7. Section 2.2.1 Subgroup of 
interest 
8. Section 2.3.3 
Demographics and other 
baseline characteristics 
9. Section 2.4.2 Prior, 
concomitant and post 
therapies 
10. Section 2.5.4 Supportive 
analyses 
11. Section 2.5.4 Supportive 
analyses 
12. Section 2.7.2 Statistical 
hypothesis, model, and 
method of analysis 
13. Section 2.8.1.3 AE 
summaries 
  
propensity score stratification 
 


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Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title impacted 
(Current) 
13. Added AE summaries: non- 
serious AEs ≥5%, SAEs 
≥0.5%, SAEs by seriousness 
criteria, AE overview 
14. Specified conversion factors 
for lab values indicated as <x 
or >x 
15. Specified repeated measures 
analysis of change from 
baseline for echocardiographic 
variables, biomarkers, and 
KCCQ-23 domains/scores 
16. Added summary of patients 
with hypotension based on 
SBP criteria 
17. Added summary of patients 
with hyperkalemia based on 
central lab data 
18. Added summary of patients 
with worsening renal function 
based on central lab data 
19. Added summary of positively 
adjudicated angioedema 
20. Added subgroup analyses of 
KCCQ-23 clinical summary 
score change from baseline at 
one year 
21. For biomarkers specified that 
values <LOD will be converted 
to (0.5)(LOD); and samples 
from patients who withdrew 
consent will not be analyzed by 
the central laboratory 
 
 
 
 
 
14. Section 2.8.3 Laboratory 
data 
15. Section 2.8.4 
Echocardiographic data; 
Section 2.11.1 Kansas City 
Cardiomyopathy 
Questionnaire; Section 2.12 
Biomarkers 
16. Section 2.8.5.1 Vital 
signs 
17. Section 2.8.5.3 
Hyperkalemia 
18. Section 2.8.5..4 
Creatinine 
19. Section 2.8.5.7 
Angioedema 
20. Section 2.11.1 Kansas 
City Cardiomyopathy 
Questionnaire 
21. Section 2.12 Biomarkers 
22. Section 2.12 Biomarkers 
 
 
 
 
27. Section 5.1.4 Heart 
failure diagnosis date 
imputation 
28. Section 5.6 Rule of 
exclusion criteria of analysis 
sets 
29. Section 2.4.2 Prior, 
concomitant and post 
therapies 
  
 
 


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Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title impacted 
(Current) 
 
 
 
 
 
 
 
 
 
 
 
27. Added imputation rules for 
partial HF diagnosis dates 
28. Updated tables 1 and 2 for 
rules of exclusion criteria of 
analysis sets 
29. Added separate summaries of 
prior and concomitant CV, HF, 
ACEi, and ARB medications 
30. Clarified that subgroup defined 
by NT-proBNP concentration 
≤1000 pg/mL at Month 12 is 
determined in patients with 
baseline NT-proBNP >1000 
pg/mL 
31. Added new subgroup defined 
by NT-proBNP concentration 
≤1000 pg/mL at Month 12 for 
patients with baseline NT- 
proBNP >1000 pg/mL, 
or >30% reduction from 
baseline in NT-proBNP at 
Month 12 
 
 
 
 
  
 


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Date 
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point 
Reason for 
update 
Outcome for update 
Section and title impacted 
(Current) 
 
 
 
 
 
  
 


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Table of contents 
Table of contents ................................................................................................................. 6 
List of abbreviations ............................................................................................................ 8 
1 
Introduction ....................................................................................................................... 10 
1.1 
Study design ........................................................................................................... 10 
1.2 
Study objectives and endpoints.............................................................................. 10 
2 
Statistical methods ............................................................................................................. 11 
2.1 
Data analysis general information ......................................................................... 11 
2.1.1 
General definitions ................................................................................ 12 
2.2 
Analysis sets .......................................................................................................... 13 
2.2.1 
Subgroup of interest .............................................................................. 13 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 14 
2.3.1 
Patient disposition ................................................................................. 14 
2.3.2 
Protocol deviations ................................................................................ 16 
2.3.3 
Demographics and other baseline characteristics.................................. 16 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 19 
2.4.1 
Study treatment / compliance ................................................................ 19 
2.4.2 
Prior, concomitant and post therapies ................................................... 20 
2.5 
Analysis of the primary objective .......................................................................... 21 
2.5.1 
Primary endpoint ................................................................................... 21 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 21 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 21 
2.5.4 
Supportive analyses ............................................................................... 21 
2.6 
Analysis of the key secondary objective ................................................................ 22 
2.7 
Analysis of secondary objectives ........................................................................... 22 
2.7.1 
Secondary endpoints ............................................................................. 22 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 22 
2.7.3 
Handling of missing values ................................................................... 22 
2.8 
Safety analyses ....................................................................................................... 22 
2.8.1 
Adverse events (AEs) ............................................................................ 23 
2.8.2 
Deaths .................................................................................................... 24 
2.8.3 
Laboratory data ..................................................................................... 24 
2.8.4 
Echocardiographic data ......................................................................... 25 
2.8.5 
Other safety data.................................................................................... 25 
2.9 
Pharmacokinetic endpoints .................................................................................... 29 
2.10 
PD and PK/PD analyses ......................................................................................... 29 


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2.11 
Patient-reported outcomes (PRO) .......................................................................... 29 
2.11.1 
Kansas City Cardiomyopathy Questionnaire ........................................ 29 
2.12 
Biomarkers ............................................................................................................. 30 
 
 31 
2.14 
Interim analysis ...................................................................................................... 32 
3 
Sample size calculation ..................................................................................................... 33 
4 
Change to protocol specified analyses ............................................................................... 33 
5 
Appendix ........................................................................................................................... 35 
5.1 
Imputation rules ..................................................................................................... 35 
5.1.1 
Study drug ............................................................................................. 35 
5.1.2 
AE date imputation ............................................................................... 35 
5.1.3 
Concomitant medication date imputation ............................................. 36 
5.1.4 
Heart failure diagnosis date imputation ................................................ 37 
5.2 
AEs coding/grading ............................................................................................... 37 
5.3 
Laboratory parameters derivations ........................................................................ 37 
5.3.1 
Laboratory grading ................................................................................ 37 
5.3.2 
Notable laboratory values...................................................................... 37 
5.4 
Vital signs .............................................................................................................. 38 
5.4.1 
Notable vital sign values ....................................................................... 38 
5.5 
Statistical models ................................................................................................... 38 
5.5.1 
Primary analysis .................................................................................... 38 
5.6 
Rule of exclusion criteria of analysis sets .............................................................. 39 
6 
Reference ........................................................................................................................... 39 


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List of abbreviations 
 
ACE 
angiotensin converting enzyme 
ACEI 
angiotensin converting enzyme inhibitor 
AE 
adverse event 
ALT 
Alanine Aminotransferase 
ARB 
Angiotensin receptor blocker 
ARNI 
Angiotensin receptor neprilysin inhibitor 
AST 
Aspartate Aminotransferase 
BB 
β-Blocker, β-Blocking agent 
BID 
bis in diem/twice a day 
BMI 
Body mass index 
BNP 
B-type natriuretic peptide 
 
 
BUN 
Blood urea nitrogen 
CABG 
Coronary artery bypass graft 
cGMP 
Cyclic guanosine monophosphate 
CHF 
Chronic heart failure 
CFR 
US Code of Federal Regulations 
CRF/eCRF 
(electronic) Case Report/Record Form 
CRO 
Contract Research Organization 
CRT-D 
Cardiac resynchronization therapy defibrillator 
CRT-P 
Cardiac resynchronization therapy pacemaker 
CSR 
Clinical study report 
CV 
Cardiovascular 
DBP 
Diastolic blood pressure 
DCT 
Data collection tool 
DM 
Diabetes mellitus 
DMC 
Data Monitoring Committee 
DS&E 
Drug Safety & Epidemiology 
Echo 
Echocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
eGFR 
Estimated glomerular filtration rate 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
HF 
Heart failure 
HFrEF 
Heart failure with reduced ejection fraction 
hs-Troponin 
High sensitivity troponin 
HTN 
Hypertension 
ICH 
International   Conference   on  Harmonization   of   Technical Requirements  for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
 


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KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LA 
Left atrial 
LAVi 
Left atrial volume index 
LVEF 
Left ventricular ejection fraction 
LVEDVi 
Left ventricular end diastolic volume index 
LVESVi 
Left ventricular end systolic volume index 
LV 
Left ventricular 
mmHg 
Millimeter mercury 
MOA 
Mechanism of action 
MRI 
Magnetic resonance imaging 
NEP 
Neutral endopeptidase 
NP 
Natriuretic peptide 
NT-proBNP 
N-terminal pro-brain natriuretic peptide 
NYHA 
New York Heart Association 
PCI 
Percutaneous coronary intervention 
pg/mL 
Picogram per milliliter 
RAAS 
Renin angiotensin aldosterone system 
SAE 
Serious Adverse Event 
SBP 
Systolic blood pressure 
SS 
Safety set 
sST2 
Soluble ST2 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TIA 
Transient ischemic attack 
TS 
Treatment set 
 
 
ULN 
Upper limit of normal 
USPI 
United States prescribing information/package insert 
VAD 
Ventricular assistance device 
 
 
WoC 
Withdrawal of Consent 
 


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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 
protocol version 03 (amended protocol) dated 27-Feb-2018 and the data collection tool (DCT) 
version 10.0 dated 27-Nov-2018. 
 
1.1 
Study design 
This study will use a multicenter, open-label, single-arm design in a population of outpatients 
with heart failure and reduced ejection fraction (HFrEF) ≤40%. The study duration is a 
maximum of 52 weeks (365 days). A study cohort of approximately 830 patients will be 
enrolled in approximately 100 centers in the United States. At the time of enrollment, patients 
will be considered eligible if they are identified as clinically appropriate HFrEF patients and 
who are candidates to receive sacubitril/valsartan per the United States Prescribing Information 
(USPI) prescribing information. As this is a single-arm open-label design, all patients will be 
treated with sacubitril/valsartan and no randomization will be done. 
Patients will enter a 4-week screening epoch to confirm that they meet all study inclusion 
criteria and none of the exclusion criteria. Patients that have been treated with an angiotensin 
converting enzyme inhibitor (ACEi) before the study will require a 36-hour wash out period 
before starting sacubitril/valsartan treatment. 
Sacubitril/valsartan will be dispensed to eligible patients on Study Day 1. The initial dose will 
be determined by the investigator and per the approved indication described in the USPI. The 
three doses available are: 24/26 mg bis in diem/twice a day (BID) (Dose Level 1), 49/51 mg 
BID (Dose Level 2), and 97/103 mg BID (Dose Level 3). Open-label treatment will be provided 
through the duration of the trial. Adjustment of the sacubitril/valsartan dose levels may be 
increased on an every 2-4 week basis per USPI to the desired target maintenance dose of 97/103 
mg BID or increased within a 1-2 week time period based on clinical need and/or investigator 
judgment. 
The primary analysis time point will be 12 months. 
 
1.2 
Study objectives and endpoints 
The primary objective of this study is to examine the association between change in 
concentration of N-terminal pro b-type natriuretic peptide (NT-proBNP) and change in 
structural cardiac measurements (left ventricular end systolic and diastolic volume indices 
[LVESi, LVEDi], left ventricular ejection fraction [LVEF], and left atrial volume index [LAVi]) 
from baseline to one year. 
The secondary objectives are: 
1. To examine the association between change in concentration of NT-proBNP and 
change in structural cardiac measurements (LVESi, LVEDi, LVEF, and LAVi) from 
baseline to 6 months overall and in subgroups of interest. Subgroups for this analysis 
are listed in Section 2.2.1. 


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2. To examine the association between the change in NT-proBNP concentrations and 
patient-reported outcomes from the Kansas City Cardiomyopathy Questionnaire 
(KCCQ)-23 during a year of follow up. 
 
2 
Statistical methods 
2.1 
Data analysis general information 
 a Novartis-designated Contract Research Organization 
(CRO) will be performing all analyses outlined in this SAP. SAS® version 9.3 (or higher) will 
be used for all analyses. 
Data from all centers that participate in this protocol will be combined, so that an adequate 
number of patients will be available for analysis. 
Unless otherwise specified, for continuous data, the mean, standard deviation, median, first and 
third quartiles, interquartile range, and minimum and maximum values will be presented. 
Geometric means and 95% confidence intervals will also be presented for biomarker data. 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. 
All data will be provided in listings in addition to summaries described below. 


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2.1.1       General definitions 
Study treatment 
All eligible patients will receive open-label sacubitril/valsartan through the duration of the trial. 
Baseline 
For echocardiographic variables baseline is defined as the last non-missing assessment 
performed ≤1 week from the date of first administration of study treatment. 
For biomarkers baseline is defined as the last non-missing assessment collected ≤6 hours from 
the time of first administration of study treatment. If the assessment was collected on the date 
of first administration of study treatment, but the timing relative to first administration of study 
treatment cannot be determined, the assessment will be excluded from the determination of 
baseline. 
For all other assessments baseline is defined as the last non-missing assessment prior to or on 
the date of first administration of study treatment. 
Unscheduled assessments will be excluded from the determination of baseline. 
Date of first administration of study treatment 
The date of first administration of study treatment is defined as the first date a dose of  
sacubitril/valsartan is administered and recorded on the Dosage Administration Record - At 
Visit (Visit 2) electronic case report form (eCRF). 
Date of last administration of study treatment 
The date of last administration of study treatment is defined as the last date a dose of 
sacubitril/valsartan is administered and recorded on the Study Completion eCRF. In the event 
this date is not available from the Study Completion eCRF, it will be obtained from the Dosage 
Administration Record - Summary eCRF. 
Study day 
The study day describes the day of the assessment relative to the date of first administration of 
study treatment at Visit 2 (Day 1/Baseline). 
The study day will be calculated as the difference between the date of assessment and the date 
of first administration of study treatment, plus 1. If the date of assessment is prior to the date of 
first administration 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 first administration of study 
treatment. 
Last contact 
The date of last contact will be the last visit date for each patient and will be derived by 
examining all visit data collected in the eCRFs. 
Year, month and week 
For reporting purposes, the rules below will be followed to convert a year, month, and week to 
days. 


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1 year = 365.25 days 
1 month = 30.3475 days 
1 week = 7 days 
1 day = 24 hours 
 
2.2 
Analysis sets 
The following subject sets will be used for the statistical reporting and analyses: 
The Treatment Set (TS) will consist of all patients enrolled at Visit 2. 
The Full Analysis Set (FAS) will consist of all patients enrolled at Visit 2 with the exception 
for those patients who have not been qualified for study treatment and have not received study 
drug, but have been inadvertently entered into the study. Efficacy variables will be analyzed 
based on the FAS as the primary set. 
 
The Safety Set (SS) will consist of all patients who received at least one dose of study treatment. 
The SS will be used for the analyses of safety variables. 
 
2.2.1 
Subgroup of interest 
The following subgroups will be analyzed for the primary objective: 
1. New onset HF or naïve to ACEi/angiotensin receptor blocker (ARB) therapy (No, 
Yes) 
2. Baseline NT-proBNP (<600 pg/mL, or <400 pg/mL if hospitalized for HF within 1 
year) (No, Yes) 
3. Target dose of sacubitril/valsartan (dose level 3) achieved by Month 12 (No, Yes) 
4. NT-proBNP concentration ≤1000 pg/mL at Month 12 for patients with baseline NT- 
proBNP >1000 pg/mL (No, Yes) 
5. NT-proBNP concentration ≤1000 pg/mL at Month 12 for patients with baseline NT- 
proBNP >1000 pg/mL, or >30% reduction from baseline in NT-proBNP at Month 12 
(No, Yes) 
6. Groups defined by quintiles of response time (defined for patients with baseline NT- 
proBNP >1000 pg/mL as the time from baseline to date when NT-proBNP ≤1000 
pg/mL) through Month 12 
7. Groups defined by quintiles of time spent with NT-proBNP ≤1000 pg/mL across study 
visits through Month 12 
8. Age (<75 years, ≥75 years) 
9. Baseline New York Heart Association (NYHA) class (I and II, III and IV) 
10. Prior atrial fibrillation (AF) (No, Yes) 


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11. Baseline body mass index (BMI) (<30 kg/m2, ≥30 kg/m2) 
12. Baseline NT-proBNP <125 pg/mL (No, Yes) 
13. Groups defined by quartiles of baseline estimated glomerular filtration rate (eGFR) 
14. Prior diabetes (No, Yes) 
15. Prior ACEi/ARB (No [naïve], Yes) 
The following subgroups will be analyzed for the secondary objective of the calculation of 
Pearson correlation coefficients and the corresponding two-sided 95% confidence intervals and 
p-values: 
1. New onset HF or naïve to ACEi/ARB therapy (No, Yes) 
2. Baseline NT-proBNP (<600 pg/mL, or <400 pg/mL if hospitalized for HF within 1 
year) (No, Yes) 
3. Target dose of sacubitril/valsartan (dose level 3) achieved by Month 12 (No, Yes) 
4. NT-proBNP concentration ≤1000 pg/mL at Month 12 for patients with baseline NT- 
proBNP >1000 pg/mL (No, Yes) 
5. NT-proBNP concentration ≤1000 pg/mL at Month 12 for patients with baseline NT- 
proBNP >1000 pg/mL, or >30% reduction from baseline in NT-proBNP at Month 12 
(No, Yes) 
6. Groups defined by quintiles of response time (defined for patients with baseline NT- 
proBNP >1000 pg/mL as the time from baseline to date when NT-proBNP ≤1000 
pg/mL) through Month 12 
7. Groups defined by quintiles of time spent with NT-proBNP ≤1000 pg/mL across study 
visits though Month 12 
 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
All patients will be used for the summary of patient disposition. The following categories will 
be summarized: 
• Number of patients who were screened 
• Screening phase disposition 


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o Completed 
o Adverse event 
o Death 
o Pregnancy 
o Screen failure 
o Study terminated by sponsor 
o Technical problems 
o Lost to follow-up 
o Physician decision 
o Subject/Guardian decision 
• Number and percentage of patients who continued into the open-label treatment phase 
• Number and percentage of patients who were treated 
• Number and percentage of patients who completed study treatment 
• Number and percentage of patients who achieved dose level 3 
• Number and percentage of patients who did not achieve dose level 3 
o Reason for not achieving dose level 3 
i. Hyperkalemia 
ii. Symptomatic hypotension 
iii. Renal dysfunction 
iv. Angioedema 
v. Other adverse event 
vi. Unrelated to study treatment tolerability 
• Number and percentage of patients who prematurely discontinued study treatment 
• Patient status at study completion 
o Completed 
o Adverse event 
o Death 
o Pregnancy 
o Protocol deviation 
o Study terminated by sponsor 
o Technical problems 
o Lost to follow-up 


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o Physician decision 
o Subject/guardian decision 
• Study duration in months [(date of last contact/death – date of first administration of 
study treatment +1)/30.3475] 
Additionally, listings of inclusion/exclusion criteria, screening disposition, and study treatment 
disposition will be provided. 
 
2.3.2 
Protocol deviations 
The number and percentage of patients with protocol deviations by category will be summarized. 
Additionally, a listing of protocol deviations during the study will also be presented. The TS 
will be used. 
 
2.3.3 
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. 
The FAS 
 will be used. 
Demographics and baseline characteristics 
Demographic variables include: 
• Age (years) 
o Age group (<65 years, ≥65 years; <75 years, ≥75 years) 
• Sex (Male, Female) 
o Child bearing status (Able to bear children, Post-menopausal, Sterile - of child 
bearing age) 
• Race (Caucasian, Black, Asian, Native American, Pacific Islander, Other, Unknown) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown) 
• Source of patient referral: 
o Physician’s own practice 
o Physician referral 
o Television advertisement 
o Radio advertisement 
o Print advertisement 
o Internet 


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o Newsletter/Educational material 
o Advocacy group 
o ER or hospital 
o Friend/family member 
o Patient database 
o Unknown 
o Other 
General baseline characteristic variables include: 
• Height (cm) 
• Weight (kg) 
• BMI (kg/m2) [weight (kg)/height (m2)] 
o BMI categories (<20, 20 - <25, 25 - 30, >30 kg/m2) 
• eGFR (ml/min/1.73 m2) 
o eGFR categories (<45, 45 - <60, ≥60 mL/min/1.73 m2) 
Biomarker baseline characteristic variables include: 
• NT-proBNP (pg/mL) 
o NT-proBNP categories (<300, 300 - <1000, 1000 - <1600, 1600 - <3000, ≥3000 
pg/mL; <1000, ≥1000 pg/mL) 
 
 
  
 
 
• hs-Troponin T (ng/L) 
• sST2 (ng/mL) 
• UcGMP (nmol/L) 
• UcGMP to Urinary Creatinine ratio (nmol/mmol) 
• Mid-regional pro-adrenomedullin (nmol/L) 
Key structural cardiac baseline characteristic variables include: 
• Left ventricular end systolic volume index, LVESVi (mL/m2) 
• Left ventricular end diastolic volume index, LVEDVi (mL/m2) 
• Left ventricular ejection fraction, LVEF (%) 


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• Left atrial volume index, LAVi (mL/m2) 
• Diastolic function (E/E’) 
Disease history 
Disease history variables, as collected on the Heart Failure History eCRF at screening, include: 
• Time since diagnosis (months) 
• New onset heart failure (No, Yes) 
• NYHA classification [best value during the month prior to screening visit] (I, II, III, IV) 
• Primary heart failure etiology (Ischemic, Non-ischemic) 
o Non-ischemic etiology (Hypertensive [No, Yes], Diabetic [No, Yes], Alcoholic 
[No, Yes], Myocarditis [No, Yes], Peripartum [No, Yes], Drug induced [non- 
chemotherapy] [No, Yes], Chemotherapy [No, Yes], Idiopathic Other [No, Yes], 
Valvular heart disease [No, Yes], Other [No, Yes]) 
• Myocardial infarction (No, Yes) 
• Coronary revascularization (No, Yes) 
o Coronary revascularization type (Percutaneous coronary intervention [PCI], 
Coronary Artery Bypass Graft [CABG]) 
• Prior heart failure hospitalization (No, Yes) 
o Number of heart failure hospitalizations in the last 12 months 
• Most recent ejection fraction (%) 
o Ejection fraction categories (<25%, 25% - <35%, ≥35%) 
o Method used (Magnetic Resonance Imaging [MRI], Echocardiography, Nuclear 
[SPECT/PET/MUGA], Ventriculogram, Other) 
• Known history of diabetes mellitus (No, Yes) 
Cardiovascular history 
Cardiovascular history will be summarized. The following disease information will be collected: 
• Hypertension (No, Yes, Unknown) 
• Transient Ischemic Attack (TIA) (No, Yes, Unknown) 
• Stroke (No, Yes, Unknown) 
• Peripheral vascular disease (No, Yes, Unknown) 
• Chronic Kidney Disease (CKD) stage (CKD stage 1 [eGFR ≥90], CKD stage 2 [eGFR 
60 - 89], CKD stage 3 [eGFR 30 - 59], CKD stage 4 [eGFR 15 - 29], CKD stage 5 
[eGFR <15 or dialysis], No CKD) 
• Arrhythmia (No, Yes, Unknown) 


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o Arrhythmia type (Atrial fibrillation, Atrial flutter, Supraventricular tachycardia, 
Ventricular tachycardia) 
• Pacemaker/Implantable Cardioverter Defibrillator (ICD) (No, Yes, Unknown) 
o Device type (Pacemaker, Cardiac resynchronization therapy - no ICD [CRT-P], 
Cardiac resynchronization therapy - with ICD [CRT-D], ICD only [single/dual 
chamber], Unknown) 
• Moderate to severe valvular heart disease (No, Yes, Unknown) 
o Valvular heart disease type (Mitral regurgitation, Aortic regurgitation, Aortic 
stenosis, Tricuspid regurgitation, Other) 
• Prior valvular surgery (No, Yes, Unknown) 
o Valvular surgery type (Mitral, Aortic, Tricuspid, Pulmonic) 
Non-cardiovascular medical history 
Non-cardiovascular medical history will be summarized and listed. The summary will be 
presented by primary system organ class (SOC) and preferred term (PT). Non-cardiovascular 
medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
terminology (v21.0 or higher). 
Surgeries and Medical Procedures 
Surgeries and medical procedures will be listed. Surgeries and medical procedures will be coded 
using MedDRA terminology (v21.0 or higher). 
 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
The SS 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 dates of first and last study treatment are defined in Section 2.1.1. 
Summary statistics will be displayed for the duration of study treatment. 
The duration of study treatment will also be categorized into 90-day time intervals (<90, 90   - 
<180, 180 - <270, ≥270 days.). The number and percentage of patients in each category will be 
presented. 
Total patient-days of exposure will also be summarized. 
In addition, the number and percentage of patients at each dose level dispensed by visit will be 
summarized. The number and percentage of the maximum dose level dispensed will also be 
presented. Similarly, the up-titrated doses, down-titrated doses and unchanged doses will be 
summarized by visit. 


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All information on dose administration will be listed. 
 
2.4.2 
Prior, concomitant and post therapies 
Prior and concomitant medications will be coded according to the World Health Organization 
(WHO) Drug Reference List (v2017 Mar or later). Prior and concomitant medications are 
mutually exclusive, as defined below: 
• A prior medication is defined as any medication with an end date prior to the first dose 
of study treatment. 
• A concomitant medication is defined as any medication taken on or after the start of 
study treatment. A prior medication that is ‘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 patients with prior medications will be summarized by 
Anatomical Therapeutic Chemical (ATC) class and preferred term (PT). Separate summaries 
of prior CV, HF, ACEi, and ARB medications will also be produced. Concomitant medications 
will be summarized in a similar fashion. All medications will be listed. 
The number and percentage of patients will be summarized by ACEi/ARB status (ACEi/ARB 
naïve [never exposed], previously on ACEi/ARB but not currently taking [previously exposed], 
and currently taking) at screening. 
In addition, among patients with concomitant use of beta-blocking agents (based on ATC 
class C07) the total daily dose achieved at one year will be calculated. The total daily beta 
blocker (BB) dose will be converted to an equivalent total daily dose of metoprolol succinate 
extended release (Gaggin 2014) as described below. The total daily dose in equivalent mg of 
metoprolol succinate extended release will be calculated for each BB by multiplying the BB 
total daily dose (mg) by the standardization factor in the table below. For patients without 
concomitant use of beta-blocking agents at one year, the total daily dose in equivalent mg of 
metoprolol succinate extended release will be set to 0 for purposes of analysis. 
 
 
Beta Blocker 
Standardization Factor 
atenolol 
2 
bisoprolol, bisopropol fumarate 
20 
carvedilol, carvedilol phosphate hemihydrate 
4 
labetalol 
0.25 
metoprolol tartrate immediate release, metoprolol 
tartrate, metoprolol, metoprolol succinate 
1.0 
nadolol 
0.833 
propranolol 
0.833 
sotalol 
0.833 
nebivolol hydrochloride 
10 


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The resulting standardized BB dose (metoprolol succinate extended release equivalent dose) 
will be summarized with descriptive statistics and categorized into dose groups in two ways: 
• As five discrete dose groups (Fiuzat, 2016) having total daily dose = 0, 1 to 13, 14 to 
25, 26 to 50, and 51 to 200 mg 
• As three discrete dose groups, having total daily dose = 0, 1 to 24, and ≥25 mg. 
The number and percentage of patients in each category will be presented. 
2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint 
The primary endpoints are the change in concentration of NT-proBNP from baseline to one 
year, and the changes in structural cardiac measurements LVESVi, LVEDVi, LVEF, LAVi, 
and diastolic function (E/E’) from baseline to one year. The analysis of the primary endpoints 
will be based on the FAS. 
 
2.5.2 
Statistical hypothesis, model, and method of analysis 
Pearson correlation coefficients and the corresponding two-sided 95% confidence intervals and 
p-values will be calculated to examine the association between change in log-transformed NT- 
proBNP and each structural cardiac measurement (LVESVi, LVEDVi, LVEF, LAVi, and E/E’) 
from baseline to one year. 
 
2.5.3 
Handling of missing values/censoring/discontinuations 
Missing data will not be imputed. 
 
2.5.4 
Supportive analyses 
Pearson correlation coefficients and the corresponding two-sided 95% confidence intervals and 
p-values will be calculated to examine the association between change in log-transformed NT- 
proBNP and each structural cardiac measurement from baseline to one year using the last 
observation carried forward (LOCF) method used to impute missing data at one year. In 
particular, if the NT-proBNP value or the structural cardiac measurement value is missing at 
one year, then the NT-proBNP and structural cardiac measurement values at 6 months, if both 
available, will be carried forward. 
Spearman correlation coefficients and the corresponding two-sided 95% confidence intervals 
and p-values will be calculated to examine the association between change in log-transformed 
NT-proBNP and each structural cardiac measurement from baseline to one year. 
Pearson correlation coefficients and the corresponding two-sided 95% confidence intervals and 
p-values will be calculated to examine the association between change in log-transformed NT- 
proBNP and each structural cardiac measurement from baseline to one year where baseline for 
the structural cardiac measurements will be defined as: 
• The last non-missing assessment prior to or on the date of first administration of study 
treatment. 


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• The nominal Visit 2 (Baseline) assessment, regardless of when it occurred relative to 
the date of first administration of study treatment. 
 
2.6 
Analysis of the key secondary objective 
There is no key secondary objective. 
 
2.7 
Analysis of secondary objectives 
2.7.1 
Secondary endpoints 
Secondary endpoints include the following: 
1. Change in concentration of NT-proBNP from baseline to 6 months 
2. Change in LVESVi, LVEDVi, LVEF, LAVi, and E/E’ from baseline to 6 months 
3. Change in KCCQ-23 clinical summary score from baseline to 12 months 
 
2.7.2 
Statistical hypothesis, model, and method of analysis 
Pearson correlation coefficients and the corresponding two-sided 95% confidence intervals and 
p-values will be calculated to examine the association between change in log-transformed NT- 
proBNP and LVESVi, LVEDVi, LVEF, LAVi, and E/E’ from baseline to 6 months. 
An analysis of variance will be performed to compare the mean change in the KCCQ-23 clinical 
summary score between the groups of patients with NT-proBNP<1000 pg/mL and ≥1000 
pg/mL at one year (i.e., NT-proBNP status). It is likely that groups defined in this way will be 
different with respect to characteristics that are also associated with the KCCQ-23 clinical 
summary score. 
In order to assess the relative imbalance between NT-proBNP status groups with respect to 
characteristics that may be associated with the KCCQ-23 clinical summary score, key 
characteristics of interest will be summarized descriptively. These characteristics include 
baseline KCCQ-23 clinical summary score, age (<75, ≥75 years), baseline LVEF (≤median, 
>median) from echo, baseline eGFR (≤median, >median), primary HF etiology (ischemic, non- 
ischemic), prior AF, and standardized BB dose achieved at one year (0, 1 to 24, ≥25 mg). 
Multivariable regression will be used to compare the mean change in KCCQ-23 clinical 
summary score between the NT-proBNP status group, accounting for these characteristics by 
including them as covariates in the model. 
 
2.7.3 
Handling of missing values 
For the analysis of secondary endpoints, if a patient has no post-baseline value at the given time 
point (6 months or one year), the missing value will not be imputed and the patient will be 
removed from the analysis. 
 
2.8 
Safety analyses 
Safety analyses will be performed based on the Safety Set. There will be no inferential analyses 
of the safety data. 


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2.8.1 
Adverse events (AEs) 
 
2.8.1.1 
Coding of AEs 
Adverse events (AEs) will be coded using MedDRA terminology (v21.0 or later). 
 
2.8.1.2 
General rules for AE reporting 
AE summaries will include all treatment-emergent AEs (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. 
TEAEs will be summarized by presenting the number and percentage of patients having at least 
one TEAE, having at least one TEAE in each primary SOC, and for each PT using MedDRA 
terminology. A patient 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 patient with multiple 
severities for an AE will be summarized under the worse severity recorded for the event. 
Any information collected will be listed as appropriate. 
 
2.8.1.3 
AE summaries 
The following summary tables will be provided: 
• AEs, regardless of study treatment relationship, by primary SOC, PT, and worst severity 
• Most frequent (≥5%) AEs, regardless of study treatment relationship, by PT 
• Most frequent (≥5%) non-serious AEs, regardless of study treatment relationship, by PT 
• AEs, suspected to be related to study treatment, by primary SOC and PT 
• Serious adverse events (SAEs), regardless of study treatment relationship, by primary 
SOC and PT 
• SAEs, suspected to be related to study treatment, 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 
• 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 


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• Death resulting from AEs, regardless of study treatment relationship, by primary SOC 
and PT 
In addition, an overview of TEAEs presenting the number and percentage of patients having at 
least one TEAE for each of the above categories will be provided. 
 
2.8.2 
Deaths 
Patient deaths will be summarized by primary SOC and PT, as well as by primary cause of 
death, type of cardiovascular death, type of non-cardiovascular death, and whether an autopsy 
was performed. A patient listing of all deaths with primary and contributing reasons for death 
will be provided. All patients in FAS will be included for the above analysis. Deaths will be 
coded using MedDRA terminology (v21.0 or later). 
In addition, occurrences of resuscitated sudden death will be summarized based on the SS. The 
number and percentage of patients actively resuscitated will be presented. 
 
2.8.3 
Laboratory data 
Laboratory values will be summarized using shift tables (from baseline to most extreme post- 
baseline value) for each laboratory parameter. The number and percentage of patients will be 
presented by baseline and worst post-baseline lab value, with lab values classified as low, 
normal, high, and low/high using the upper and lower limit of normal values to define categories. 
Unscheduled assessments will be considered. 
In addition, laboratory values and the change from baseline for each parameter by visit will be 
summarized. In the event there are multiple laboratory values within a visit, the worst value will 
be summarized. 
A separate summary table will be presented with the number and percentage of patients having 
notable lab abnormalities based on percent change from baseline (see Section 5.3 for a list of 
notable laboratory abnormalities). Unscheduled assessments will be considered. 
Listings of all laboratory values will be provided. A separate listing for pregnancy tests will be 
provided. Any notable laboratory abnormalities will be flagged in the listings. 
Laboratory values indicated as <x will be converted to (0.5)(x) for purposes of analysis. 
Laboratory values indicated as >x will be converted to the values specified in the below table 
for purposes of analysis. 
 
 
Laboratory Test 
Unconverted Value 
Converted Value for Analysis 
Erythrocytes 
>7.00 
7.1 
HDL Cholesterol 
>135 
135.1 
Hemoglobin A1C 
>15.5 
15.51 
Potassium 
>7.0 
7.1 
Urine Erythrocytes 
>182 
182.1 
Urine Leukocytes 
>182 
182.1 


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2.8.4 
Echocardiographic data 
Echocardiographic parameters (LVESVi, LVEDVi, LVEF, LAVi, and E/E’) will be 
summarized by visit. Values and the change from baseline for each parameter by visit will be 
summarized. Change from baseline at visits will be analyzed using a repeated measures 
ANCOVA model with visit as a fixed-effect factor and the baseline value as a covariate. An 
unstructured covariance structure will be initially considered. The change from baseline 
estimates, corresponding two-sided 95% confidence intervals, and p-values will be provided at 
each post-baseline visit. 
 
2.8.5 
Other safety data 
 
2.8.5.1 
Vital signs 
All vital signs (systolic and diastolic blood pressure [mmHg], pulse rate [beats per minute], 
respiration rate [breaths per minute], weight [kg], height [cm], and BMI [kg/m2]) will be 
descriptively summarized at each visit. Change from baseline will also be presented. Note that 
height is only collected at Visit 1. 
A separate summary table will be presented with the number and percentage of patients having 
notable vital signs based on changes relative to baseline values (see Section 5.4 for a list of 
notable vital signs). In addition, the number and percentage of patients with hypotension (SBP 
<90 mmHg) will be presented. Unscheduled assessments will be considered. 
 
2.8.5.2 
Symptomatic Hypotension 
The number and percentage of patients experiencing significant and/or non-resolving symptoms 
of lightheadedness, dizziness, feeling faint, blurred vision, auditory disturbances, emesis, or 
syncope will be presented by visit. The following characteristics will be summarized for patients 
experiencing one or more of these symptoms: 
• Whether symptoms occur only with standing 
• Treatment or medication change as a result of episode 
• Lowest documented systolic blood pressure with this episode 
• Systolic blood pressure position (Supine, Seated, Standing) 
• Lowest documented diastolic blood pressure with this episode 
• Diastolic blood pressure position (Supine, Seated, Standing) 
2.8.5.3 
Hyperkalemia 
The number and percentage of patients reporting a hyperkalemia episode as an AE or SAE will 
be presented by visit. The highest potassium value for each event will be summarized. This will 
be based on data collected from the Hyperkalemia Labs eCRF. 
The number and percentage of patients with hyperkalemia during the study will be determined 
from the central laboratory data as potassium >5.3 mEq/L. Unscheduled assessments will be 
considered. 


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2.8.5.4 
Creatinine 
The number and percentage of patients reporting an elevated creatinine event as an AE or 
SAE will be presented by visit. The highest creatinine recorded for each event will be 
summarized. This will be based on data collected from the Creatinine Labs eCRF. 
The number and percentage of patients with worsening renal function during the study will be 
determined from the central laboratory data as a worsening (decrease) in eGFR of ≥35% from 
baseline, or an increase in creatinine of ≥0.5 mg/dL from baseline and a worsening (decrease) 
in eGFR of ≥25% from baseline. Unscheduled assessments will be considered. 
 
2.8.5.5 
Pregnancy 
Among patients able to bear children, the number and percentage of patients assessed with a 
urine pregnancy test will be presented. Pregnancy test results (Negative, Positive, Unknown) 
will be summarized. 
 
2.8.5.6 
Heart Failure (HF) Signs and Symptoms 
The number and percentage of patients in the following heart failure signs and symptoms 
categories will be summarized by visit: 
• NYHA classification (Class I, Class II, Class III, Class IV) 
• Paroxysmal nocturnal dyspnea (Absent, Present) 
• Dyspnea at rest (Absent, Present) 
• Dyspnea  upon effort (Absent, Present) 
o Dyspnea category (Mild, Moderate, Severe) 
• Fatigue (Absent, Present) 
• Orthopnea (Absent, Present) 
o Orthopnea category (1 pillow [10 cm elevation], 2 pillows [20 cm elevation], >2 
pillows [>20 cm elevation]) 
• Jugular venous distention (Absent, Present, Not Available) 
o Jugular venous distension category (<6 , 6 to 10, >10 cm) 
• Edema (Absent, Trace, Feet and Ankles, Lower Legs or Thighs, Sacrum) 
o Edema category (Trace, 1+, 2+, 3+) 
o Feet and ankles (No, Yes) 
o Lower legs or thighs (No, Yes) 
o Sacrum (No, Yes) 
• Rales (Absent, Present) 
o Rales category (<1/3, 1/3 to 2/3,  >2/3) 
• Presence of a third heart sound (Absent, Present, Not Available) 


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2.8.5.7 
Angioedema 
Data collected from the angioedema assessment and questionnaire will be summarized. 
Separate summaries will be produced for suspected angioedema and positively adjudicated 
angioedema. The number and percentage of patients for categorical variables and summary 
statistics for continuous variables for the following angioedema assessment data will be 
presented. 
• Outcome (Not recovered/Not resolved, Recovered/Resolved, Recovering/Resolving, 
Recovered/Resolved with Sequelae, Fatal, Unknown) 
o Duration of angioedema in days [end date – start date + 1] 
• Timing of event (After first dose, after multiple doses, dose not given) [not asked for 
events that occurred during Screening study phase] 
o Study medication discontinued due to event (No, Yes) 
o 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) 
o If yes, medications taken at time of previous event: 
 ACE inhibitor 
 ARB 
 Renin inhibitor 
 Other medications 
• 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 
o Shortness of breath/dyspnea 
o Difficulty swallowing/dysphagia 
o Difficulty speaking/dysarthria 
o Pain on swallowing/odynophagia 
o Stridor 
o Abdominal pain 
o Other 
• Edema present (No, Yes) 
o Periorbital edema 
o Head edema 


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o Neck edema 
o Lip edema 
o Tongue edema 
o Throat edema 
o Submandibular edema 
o Genitalia edema 
o Extremities edema 
o Other 
• Previous edematous episodes (No, Yes, Unknown) 
o Number of previous edematous episodes 
• ACEi taken in the past (before screening) (No, Yes, Unknown) 
• ACEi taken (other than study medication) during trial participation after screening (No, 
Yes, Unknown) 
o Dose changed within 2 days of event (No, Yes, Unknown) 
• ARB taken in the past (before screening) (No, Yes, Unknown) 
• ARB taken (other than study medication) during trial participation after screening (No, 
Yes, Unknown) 
o Dose changed within 2 days of event (No, Yes, Unknown) 
• Patient 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 
o Food 
o Insect bite 
o Animal exposure 
o Medication 
o Dental work 
o Pollen 
o Dust 
o Concomitant disease 
o Idiopathic 


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o Other 
• Medical intervention (No, Yes) 
o Administration of H-1 blocker 
o Administration of H-2 blocker 
o Administration of steroids 
o Administration of epinephrine 
o Admission to hospital 
o Admission to ER 
o Endotracheal intubation 
o Tracheostomy 
o Discontinuation of ACE inhibitor (other than study medication) 
o Discontinuation of ARB (other than study medication) 
o Other 
All angioedema assessment data will be listed. Additionally, the adjudicated assessment of the 
event will be listed separately. 
 
2.9 
Pharmacokinetic endpoints 
Not applicable 
 
2.10 
PD and PK/PD analyses 
Not applicable 
 
2.11 
Patient-reported outcomes (PRO) 
All analyses will be performed on the FAS. 
 
2.11.1 
Kansas City Cardiomyopathy Questionnaire 
 
The KCCQ-23 is a self-administered questionnaire consisting of 23 items (Green et al 2000), 
each with different Likert scaling, that quantifies disease-specific health status for patients with 
congestive heart failure. The KCCQ-23 is scored within the domains of physical limitation, 
symptom frequency, symptom severity, symptom stability, self-efficacy and knowledge, social 
limitation, and quality of life (QoL). Scores from each domain are transformed to a 0-100 scale. 
The clinical summary score is calculated by combining the physical limitation, symptom 
frequency, symptom severity, social limitation, and QoL domains. 
Missing values within each domain will be imputed using the average of the answered items 
within the same domain. Scale scores will be transformed into values of 0 to 100 by subtracting 
the lowest possible scale score, dividing by the range of the scale, and multiplying by 100. 
Further details on calculation of the transformed scores are available in the programming 


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specifications section of the SAP Tables, Figures, and Listings (TFL) Shells document. All 
analysis will be based on the transformed score. 
Values and the change from baseline in the composite score for each domain, clinical summary 
score, and an overall summary score will be summarized by visit. Change from baseline at visits 
will be analyzed using a repeated measures ANCOVA model with visit as a fixed-effect factor 
and the baseline value as a covariate. An unstructured covariance structure will be initially 
considered. The change from baseline estimates, corresponding two-sided 95% confidence 
intervals, and p-values will be provided at each post-baseline visit. 
The above analysis will be performed for the clinical summary score within the subgroups 
defined for the secondary objective in Section 2.2.1. 
For patients who die, a worst score (score of 0) will be imputed for the domain scores and 
clinical and overall summary scores at all subsequent scheduled visits after the date of death 
where these scores would have been assessed. 
Additional KCCQ-23 analyses are described in Section 2.7. 
 
2.12 
Biomarkers 
The standard or more stable MOA biomarkers, assessed in the full patient population, include 
NT-proBNP, hs-Troponin T, sST2, UcGMP, and UcGMP to Urinary Creatinine ratio. Values 
and the change from baseline for each biomarker will be summarized by visit. Analyses will 
be based on the FAS. 
 
 
 
Change from baseline in biomarkers at visits will be analyzed using a repeated measures 
ANCOVA model with visit as a fixed-effect factor and the baseline value as a covariate. An 
unstructured covariance structure will be initially considered. The change from baseline 
estimates, corresponding two-sided 95% confidence intervals, and p-values will be provided 
at each post-baseline visit. 
Biomarker values will be based on clinical laboratory samples processed and assessed by the 
central laboratory. Values below the limit of detection (LOD) (i.e., indicated as <LOD) will 
be converted to (0.5)(LOD) for purposes of analysis. 
Biomarker samples from patients who withdrew consent will not be analyzed by the central 
laboratory. 
Any other biomarkers collected but not specifically mentioned in these sections will be analyzed 
in the same manner. 
 


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: 


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2.14 
Interim analysis 
Not applicable. 


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3 
Sample size calculation 
The objective of this study is to estimate the correlation coefficient between change in log NT- 
proBNP and each structural cardiac measurement overall and in each subgroup of interest. We 
would like to estimate the correlation coefficient with a precision (half-width of the confidence 
interval (CI)) of at least 0.15 for a 2-sided 95% CI in the intended subgroups of interest. The 
subgroups of interest are: (1) patients with HFrEF and “low” NT-proBNP (<600 if not 
hospitalized or <400 if hospitalized) or “low” BNP (<150 if not hospitalized, <100 if 
hospitalized) at baseline (Ambrosy, 2012), (2) patients with new onset HF and/or RAAS naïve 
(Fonarow, 2010), and (3) patients who are not receiving the target sacubitril/valsartan dose 
(McMurray, 2014). It is estimated that these subgroups will represent approximately 25%, 20% 
and 30% of the study population, respectively. Assuming, the population correlation coefficient 
of -0.35 (Weiner, 2013) for the overall study sample and within each subgroup, the smallest 
sample size that would yield a precision of at least 0.15 for the estimated correlation coefficient 
would be n=133. Accounting for assumed 20% drop-out rate, 166 patients would be required. 
If the n=166 was the smallest subgroup of interest (20% of the overall study population), an 
overall sample size of 830 would be required to enroll in this study. For any other subgroup 
with more than 166 patients will yield precision smaller than 0.15 for the estimated correlation 
coefficient. For the overall sample size of N=830 patients the precision of the estimate of 
correlation coefficient would be 0.07 (PASS 2008). 
 
4 
Change to protocol specified analyses 
As of finalization of initial version of SAP dated 09-May-2017 
The following changes to protocol specified analyses (relative to protocol version 01 [amended 
protocol] dated 23-Sep-2016) were made: 
• Diastolic function, E/E’, is included in the primary endpoint for analyses, in addition to 
the other echocardiographic measures specified in the protocol. 
• The analysis of CV events and echocardiographic parameters is not included in the 
analyses specified in the protocol. 
• The following subgroups for the primary analysis were not included in the protocol. 
o Age group (<75 years,  ≥75 years) 
o NYHA class at baseline (I and II, III and IV) 
o AF at baseline (No, Yes) 
o Baseline BMI (<30 kg/m2, ≥30 kg/m2) 
 
 
 
 
 
 
As of finalization of SAP amendment 1 dated 22-Feb-2019 


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The following changes to protocol specified analyses (relative to protocol version 03 [amended 
protocol] dated 27-Feb-2018) were made: 
• Modified baseline definitions for biomarkers and echocardiographic variables to 
account for assessments performed post first dose of study treatment 
• Added the following subgroups for the analysis of the primary objective: 
o Baseline NT-proBNP <125 pg/mL (No, Yes) 
o Groups defined by quartiles of baseline estimated glomerular filtration rate 
(eGFR) 
o Prior diabetes (No, Yes) 
o Prior ACEi/ARB (No [naïve], Yes) 
• Added two supportive analyses of the primary objective based on the following 
alternative baseline definitions for echocardiographic variables: 
o The last non-missing assessment prior to or on the date of first administration 
of study treatment 
o The nominal Visit 2 (Baseline) assessment, regardless of when it occurred 
relative to the date of first administration of study treatment 
• Removed optional sensitivity analysis of KCCQ-23 clincial summary score change 
from baseline at one year using propensity score stratification 
• Specified repeated measures analysis of change from baseline for echocardiographic 
variables, biomarkers, and KCCQ-23 domains/scores 
• Added descriptive summary of patients with hypotension 
• Added separate descriptive summaries of patients with hyperkalemia or worsening 
renal function, based on central laboratory data 
• Added subgroup analyses of KCCQ-23 clinical summary score change from baseline 
at one year 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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• Added summary of positively adjudicated angioedema 
• Clarified that subgroup defined by NT-proBNP concentration ≤1000 pg/mL at Month 
12 is determined in patients with baseline NT-proBNP >1000 pg/mL 
• Added new subgroup defined by NT-proBNP concentration ≤1000 pg/mL at Month 12 
for patients with baseline NT-proBNP >1000 pg/mL, or >30% reduction from baseline 
in NT-proBNP at Month 12 
 
 
 
 
 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
Full dates for study treatment collected on the eCRF are required; therefore, no imputations will 
be made. 
 
5.1.2 
AE date imputation 
The following algorithm should be used to estimate start dates for which only partial 
information is known: 
Missing day and month 
- 
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. 
- 
If the year is prior to the year of first study treatment, then December 31 will be assigned 
to the missing fields. 
- 
If the year is after the year of first study treatment, then January 1 will be assigned to 
the missing fields. 
Missing month only 
- 
Treat day as missing and replace both month and day according to the above procedure. 
Missing day only 
- 
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. 
- 
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. 
- 
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. 


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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 
- 
Date left missing. 
Missing month 
- 
Impute ‘December’. 
Missing day 
- 
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 
- 
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. 
- 
If the year is prior to the year of first study treatment, then December 31 will be assigned 
to the missing fields. 
- 
If the year is after the year of first study treatment, then January 1 will be assigned to 
the missing fields. 
Missing month only 
- 
Treat day as missing and replace both month and day according to the above procedure. 
Missing day only 
- 
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. 
- 
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. 
- 
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 


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- 
Date left missing. Consider the medication to have been received at all periods after that 
period determined by the start date. 
Missing month 
- 
Impute ‘December’. 
Missing day 
- 
Impute ‘last date of that month’. 
 
5.1.4 
Heart failure diagnosis date imputation 
The following algorithm should be used to estimate the heart failure diagnosis date for which 
only partial information is known: 
Missing day and month 
- 
January 1 will be assigned to the missing fields. 
Missing month only 
- 
Treat day as missing and replace both month and day according to the above procedure. 
Missing day only 
- 
Assign first of the month to the missing day. 
 
5.2 
AEs coding/grading 
The 
 coding team will code the AE terms using MedDRA v21.0 or later. If any terms are 
not coded, the data management team will issue queries to sites to update the AE term 
appropriately. 
 
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 (CTCAE) grades. 
 
5.3.2 
Notable laboratory values 
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 


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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 
 
5.4 
Vital signs 
5.4.1 
Notable vital sign values 
Systolic blood pressure 
<90 mmHg and decrease of >20 mmHg from baseline 
>180 mmHg and increase of >20 mmHg from baseline 
Diastolic blood pressure 
<50 mmHg and decrease of >15 mmHg from baseline 
>105 mmHg and increase of >15 mmHg from baseline 
Pulse 
<50 bpm and decrease of > 15 bpm from baseline 
>120 bpm and increase of >15 bpm from baseline 
Weight 
>7% decrease; >7% increase 
 
 
5.5 
Statistical models 
5.5.1 
Primary analysis 
The Pearson product-moment correlation, ρxy, between variables X and Y for a population is 
defined by 
The sample correlation is expressed in terms of the sample means of x and y as 
 
The Spearman rank-order correlation is expressed in terms of the ranks, Ri and Si (and their 
respective means) of xi  and yi , as 


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The SAS CORR procedure will be used to estimate Pearson and Spearman correlation 
coefficients, and their two-sided 95% CIs (refer to the TFL Shells document for additional 
details). 
 
5.6 
Rule of exclusion criteria of analysis sets 
Table 1 
Protocol deviations that cause patients to be excluded 
Deviation 
ID 
Description of Deviation 
Exclusion in Analyses 
NA 
NA 
NA 
 
 
 
 
Table 2 
Patient Classification 
Analysis Set  Protocol Deviation ID that 
cause patients to be 
 
 
Non-PD criteria that cause patients to be 
excluded 
  
excluded 
 
 
TS 
NA 
Not enrolled at Visit 2 
FAS 
NA 
Not in TS 
SS 
NA 
No study treatment received 
 
 
6 
Reference 
Ambrosy AP, Fonarow GC, Albert NM, Curtis AB, Heywood JT, Mehra MR, O'Connor CM, 
Reynolds D, Walsh MN, Yancy CW and Gheorghiade M. B-type natriuretic peptide assessment 
in ambulatory heart failure patients: insights from IMPROVE HF. J Cardiovasc Med 
(Hagerstown). 2012;13:360-7. 
Fiuzat M, et al, Beta-blocker dose and outcomes from the HF-ACTION trial.. JACC Heart Fail. 
2012 July;4(2):208-15. 
Fonarow GC, Albert NM, Curtis AB, Stough WG, Gheorghiade M, Heywood JT, McBride ML, 
Inge PJ, Mehra MR, O'Connor CM, Reynolds D, Walsh MN and Yancy CW. Improving 
evidence-based care for heart failure in outpatient cardiology practices: primary results of the 
Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient 
Setting (IMPROVE HF). Circulation. 2010;122:585-96 
Gaggin HK, Motiwala S, Bhardwaj A, Parks KA, Januzzi JL. Soluble concentrations of the 
interleukin receptor family member ST2 and β-blocker therapy in chronic heart failure. Circ 
Heart Fail. 2013;6:1206-1213. 
Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the Kansas 
City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J AM Coll 
Cardiol. 2000 Apr;35(5):1245-55. 


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