A Multicenter, Randomized, Double-blind, Double-dummy, Parallel Group, Active-controlled, Forced-titration, 12-week Comparison of Combined Angiotensin-neprilysin Inhibition With Sacubitril and Valsartan Versus Enalapril on Changes in Central Aortic Stiffness in Patients With Heart Failure and Reduced Ejection Fraction (HFrEF)
Phase: PHASE4
Conditions: Heart Failure and Reduced Ejection Fraction
Sponsor: Novartis Pharmaceuticals

US Clinical Development and Medical Affairs - General Medicine 
LCZ696B 
sacubitril/valsartan 
Clinical Trial Protocol CLCZ696BUS08 / NCT02874794 
A multicenter, randomized, double-blind, double-dummy, 
parallel group, active-controlled, forced-titration, 12-week 
comparison of combined angiotensin-neprilysin inhibition 
with sacubitril/valsartan versus enalapril on changes in 
central aortic stiffness in patients with heart failure and 
reduced ejection fraction (HFrEF): EVALUATE-HF 
Document type: 
Amended Clinical Trial Protocol 
EUDRACT number: 
NA 
Version number: 
02 (Clean) 
Clinical trial phase: 
IV 
Release date: 
15-Mar-2019
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 03 (August 2015) 

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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures....................................................................................................................... 7 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ............................................................................................................... 10 
Protocol summary .............................................................................................................. 12 
1 
Introduction ....................................................................................................................... 17 
1.1 
Background ............................................................................................................ 17 
1.2 
Purpose .................................................................................................................. 19 
2 
Study objectives and endpoints ......................................................................................... 20 
2.1 
Primary objective(s) ............................................................................................... 20 
2.2 
Secondary objective(s) ........................................................................................... 20 
 
 20 
 
 21 
3 
Investigational plan ........................................................................................................... 22 
3.1 
Study design ........................................................................................................... 22 
3.2 
Rationale for study design ..................................................................................... 24 
3.3 
Rationale for dose/regimen, route of administration and duration of treatment .... 24 
3.4 
Rationale for choice of comparator ....................................................................... 25 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 25 
3.6 
Risks and benefits .................................................................................................. 25 
3.6.1 
Risks ...................................................................................................... 25 
3.6.2 
Benefits ................................................................................................. 26 
4 
Population .......................................................................................................................... 27 
4.1 
Inclusion criteria .................................................................................................... 27 
4.2 
Exclusion criteria ................................................................................................... 28 
5 
Treatment ........................................................................................................................... 30 
5.1 
Study treatment ...................................................................................................... 30 
5.1.1 
Investigational and control drugs .......................................................... 30 
5.1.2 
Additional treatment .............................................................................. 32 
5.2 
Treatment arms ...................................................................................................... 32 
5.3 
Treatment assignment and randomization ............................................................. 32 
5.4 
Treatment blinding ................................................................................................. 33 
5.5 
Treating the patient ................................................................................................ 33 
5.5.1 
Patient numbering ................................................................................. 33 

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5.5.2 
Dispensing the study drug ..................................................................... 33 
5.5.3 
Handling of study treatment .................................................................. 34 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 35 
5.5.5 
Permitted dose adjustments and interruptions of study treatment 
based on safety and tolerability ............................................................. 37 
5.5.6 
Rescue medication for worsening heart failure ..................................... 39 
5.5.7 
Concomitant medication ....................................................................... 40 
5.5.8 
Prohibited medication ........................................................................... 41 
5.5.9 
Emergency breaking of assigned treatment code .................................. 41 
5.6 
Study completion and discontinuation ................................................................... 42 
5.6.1 
Study completion and post-study treatment .......................................... 42 
5.6.2 
Discontinuation of study treatment ....................................................... 42 
5.6.3 
Withdrawal of informed consent ........................................................... 43 
5.6.4 
Loss to follow-up .................................................................................. 44 
5.6.5 
Early study termination by the sponsor ................................................. 44 
6 
Visit schedule and assessments ......................................................................................... 45 
6.1 
Information to be collected on screening failures .................................................. 51 
6.2 
Patient demographics/other baseline characteristics.............................................. 51 
6.3 
Treatment exposure and compliance ..................................................................... 51 
6.4 
Efficacy .................................................................................................................. 51 
6.4.1 
Hemodynamic Assessments using arterial tonometry .......................... 53 
6.4.2 
Echocardiography ................................................................................. 54 
6.4.3 
Biomarkers ............................................................................................ 55 
6.4.4 
Appropriateness of efficacy assessments .............................................. 56 
6.5 
Safety ..................................................................................................................... 56 
6.5.1 
Required sequence of cardiovascular data collection ........................... 56 
6.5.2 
Physical examination ............................................................................ 56 
6.5.3 
Heart failure signs and symptoms ......................................................... 57 
6.5.4 
Vital signs .............................................................................................. 57 
6.5.5 
Height and weight ................................................................................. 57 
6.5.6 
Angioedema .......................................................................................... 57 
6.5.7 
Laboratory evaluations .......................................................................... 58 
6.5.8 
Urinalysis .............................................................................................. 58 
6.5.9 
Electrocardiogram (ECG) ..................................................................... 59 
6.5.10 
Pregnancy and assessments of fertility.................................................. 59 
6.5.11 
Appropriateness of safety measurements .............................................. 59 

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7 
Safety monitoring .............................................................................................................. 60 
7.1 
Adverse events ....................................................................................................... 60 
7.2 
Serious adverse events ........................................................................................... 62 
7.2.1 
Definition of SAE ................................................................................. 62 
7.2.2 
SAE reporting........................................................................................ 63 
7.3 
Liver safety monitoring ......................................................................................... 64 
7.4 
Renal safety monitoring ......................................................................................... 64 
7.5 
Reporting of study treatment errors including misuse/abuse ................................. 64 
7.6 
Pregnancy reporting ............................................................................................... 65 
8 
Data review and database management ............................................................................. 65 
8.1 
Site monitoring ...................................................................................................... 65 
8.2 
Data collection ....................................................................................................... 66 
8.3 
Database management and quality control ............................................................ 66 
8.4 
Data monitoring committee ................................................................................... 66 
8.5 
Angioedema Adjudication Committee .................................................................. 67 
8.5.1 
Composition and purpose ...................................................................... 67 
8.5.2 
Overview of site responsibility ............................................................. 67 
9 
Data analysis ...................................................................................................................... 67 
9.1 
Analysis sets .......................................................................................................... 68 
9.2 
Patient demographics and other baseline characteristics ....................................... 68 
9.3 
Treatments ............................................................................................................. 68 
9.4 
Analysis of the primary variable(s) ....................................................................... 69 
9.4.1 
Variable(s) ............................................................................................. 69 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 69 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 69 
9.4.4 
Sensitivity analyses ............................................................................... 69 
9.5 
Analysis of secondary variables ............................................................................ 69 
9.5.1 
Efficacy variables .................................................................................. 69 
9.5.2 
Safety variables ..................................................................................... 70 
9.5.3 
Biomarkers ............................................................................................ 71 
 
 71 
9.7 
Interim analyses ..................................................................................................... 73 

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9.8 
Sample size calculation .......................................................................................... 73 
10 Ethical considerations ........................................................................................................ 73 
10.1 
Regulatory and ethical compliance ........................................................................ 73 
10.2 
Informed consent procedures ................................................................................. 73 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 74 
10.4 
Publication of study protocol and results ............................................................... 74 
10.5 
Quality Control and Quality Assurance ................................................................. 74 
11 Protocol adherence ............................................................................................................ 74 
11.1 
Protocol amendments ............................................................................................. 75 
12 References ......................................................................................................................... 76 
13 Appendix 1: Clinically notable laboratory values and vital signs ..................................... 78 
14 Appendix 2: Treatment guidelines for hyperkalemia (serum potassium greater than 
or equal to 5.5 mEq/L) ....................................................................................................... 79 
15 Appendix 3: Guidelines for the management of blood pressure ....................................... 81 
16 Appendix 4: Guidelines for the management of renal dysfunction ................................... 81 
17 Appendix 5: Specific Renal Alert Criteria and Actions .................................................... 82 
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List of tables 
Table 5-1 
Investigational and comparator treatment during the double-blind 
epoch ..................................................................................................... 30 
Table 5-2 
Treatment dose level during the double-blind epoch ............................ 30 
Table 5-3 
Investigational treatment during the open label epoch .......................... 31 
Table 5-4 
Treatment Dose Levels during the open-label epoch ............................ 31 
Table 5-5 
Study drug dispense during double-blind treatment epoch ................... 36 
Table 5-6 
Study drug dispense during open-label treatment epoch ...................... 37 
Table 5-7 
Safety and tolerability guidance for dose adjustments .......................... 38 
Table 5-8 
Concomitant medications to be used with caution ................................ 40 
Table 5-9 
Prohibited medication ........................................................................... 41 
Table 6-1 
Assessment schedule ............................................................................. 46 
Table 6-2 
Echocardiographic Assessment Obtained at Sites ................................ 54 
Table 17-1 
Specific Renal Alert Criteria and Actions ............................................. 82 

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List of figures 
Figure 3-1 
Study design .......................................................................................... 24 

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List of abbreviations 
 
ACE 
angiotensin converting enzyme 
ACEi 
angiotensin converting enzyme inhibitor 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANCOVA 
analysis of covariance model 
ARNi 
angiotensin receptor neprilysin inhibitor 
AST 
Aspartate Aminotransferase 
BID 
twice a day 
BNP 
B-type natriuretic peptide 
CFR 
US Code of Federal Regulations 
CDS 
Core Data Sheet (for marketed drugs) 
CRF/eCRF 
(electronic) Case Report/Record Form 
CPO 
Country Pharma Organization 
CRO 
Contract Research Organization 
CTC 
Common Terminology Criteria 
CTRD 
Clinical Trial Results Database 
CV 
Cardiovascular 
DBP 
diastolic blood pressure 
DMC 
Data Monitoring Committee 
DS&E 
Drug Safety & Epidemiology 
ECG 
Electrocardiogram 
Echo 
Echocardiogram 
ED 
Emergency Department 
EDC 
Electronic Data Capture 
eGFR 
estimated glomerular filtration rate 
EOS 
End of Study 
EOT 
End of Treatment 
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 
 
 
LFT 
Liver function test 
MAP 
Mean arterial pressure 
MedDRA 
Medical dictionary for regulatory activities 
 

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mm Hg 
millimeter mercury 
MoA 
Mechanism of action 
NEP 
Neutral endopeptidase 
NEPi 
Neutral endopeptidase inhibitor 
NPO 
Nothing by mouth 
NP 
Natriuretic peptide 
NT-proBNP 
N-terminal pro-brain natriuretic peptide
o.d.
once a day
p.o.
oral(ly)
RAAS
Renin angiotensin aldosterone system
SAE
Serious Adverse Event
SBP
Systolic blood pressure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TD
Study Treatment Discontinuation
UNL
Upper limit of normal
USPI
United States prescribing information/package insert
WHO
World Health Organization
WoC
Withdrawal of Consent
Zc
Characteristic impedance

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Glossary of terms 
Cohort 
A specific group of patients/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 patient in a time unit (e.g. 100 
mg once a day, 75 mg twice a day) 
Enrollment 
Point/time of patient 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 
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 
patients/subjects with established disease and in those with newly- 
diagnosed disease. 
Patient/subject ID 
A unique number assigned to each patient upon signing the informed 
consent 
Randomization number 
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
Study drug/ treatment 
Any single drug or combination of drugs administered to the patient 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 patient 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 patient 
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 material 

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Amendment 2 
Rationale for amendment 
The purpose for Amendment 2 is to add the echocardiographic parameters of Left Ventricular 
end systolic and diastolic volume indices, LVESVi and LVEDVi, to the secondary endpoints at 
12 weeks 
 in the Protocol summary, Sections: 2.2, 
 6.4, 9.5.1, 9.6, and a few other editorial changes. 

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Protocol summary 
Protocol number 
CLCZ696BUS08 
Title 
A multicenter, randomized, double-blind, double-dummy, parallel group, 
active-controlled, forced-titration, 12-week comparison of combined 
angiotensin-neprilysin inhibition with sacubitril/valsartan versus enalapril 
on changes in central aortic stiffness in patients with heart failure and 
reduced ejection fraction (HFrEF) 
Brief title 
A study of the effects of sacubitril/valsartan vs. enalapril, on aortic 
stiffness, in patients with mild to moderate heart failure and reduced 
pumping ability. 
Sponsor and Clinical 
Phase 
Novartis 
Phase IV 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
The purpose of this study is to determine the effect of sacubitril/valsartan 
compared to enalapril on reducing aortic stiffness in patients with mild to 
moderate heart failure with reduced ejection fraction 
Primary Objective(s) 
The primary objective is to determine whether treatment with 
sacubitril/valsartan provides a superior effect on aortic characteristic 
impedance compared to enalapril in patients with heart failure and 
reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤ 40%) 
after 12 weeks of treatment. The primary endpoint is the change in aortic 
characteristic impedance (Zc = dP/dQ in early systole) between baseline 
and Week 12. 
Secondary Objectives 
1. To evaluate the effect of sacubitril/valsartan vs. enalapril after 12 
weeks of treatment on change from baseline in NT-proBNP. 
2. To explore the effect of sacubitril/valsartan vs. enalapril after 12 
weeks of treatment on the changes from baseline in 
echocardiographic measures including: 
• Global longitudinal strain 
• Left atrial volume index 
• Mitral annular E’ velocity (Doppler Tissue Imaging) 
• Mitral E/E’ 
• Left ventricular ejection fraction 
• Ventricular-vascular coupling (Ea/Ees) 
• LV end systolic and diastolic volume indices 
3. To evaluate the effect of sacubitril/valsartan vs. enalapril after 4 
weeks of treatment on the relation between the change in aortic 
characteristic impedance and change in biomarker levels, including 
BNP, U-cGMP/U-creatinine, during both trough and 4 hours post- 
dose. 
Study design 
This study will use a multicenter, randomized, double-blind, double- 
dummy, parallel group, active-controlled, forced - titration, 12-week 
design in patients with heart failure and reduced ejection fraction (HFrEF) 
≤ 40%. The study duration is a maximum of 30 weeks with 8 scheduled 
outpatient visits. Patients will enter a screening epoch up to 6 weeks to 
assess eligibility requirements and to confirm patients are on stable 
treatment with guideline-directed therapy for HFrEF, other than ACEis 
and ARBs. Patients will then be randomized to either sacubitril/valsartan 

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or to enalapril starting doses (Dose Level 1), according to the product 
label(s).  Forced titration will occur every 2 weeks to reach the target 
dose of sacubitril valsartan or enalapril (Dose Level 3). Dose adjustments 
will only be allowed if indicated per protocol defined safety and tolerability 
criteria and investigator judgement, or if the investigator believes that 
adjustment/elimination of concomitant medications is not possible or does 
not alleviate the side effects of concern. After 12 weeks of double-blind 
treatment, patients will continue into the 12-week open-label extension 
epoch. 
Population 
The study population will consist of male and female patients, ≥ 50 years 
of age with a history of hypertension (HTN) and heart failure (NYHA 
Class I-III) with a reduced ejection fraction (HFrEF) ≤ 40%. The goal is to 
randomize a total of approximately 432 patients in a 1:1 ratio (216 per 
arm) to sacubitril/valsartan or enalapril in approximately 80 centers in the 
United States. It is estimated that approximately 575 patients will be 
screened because a screen failure rate of approximately 25% is 
anticipated based on previous experience. 
Key Inclusion criteria 
1. Men and women ≥ 50 years of age. 
2. History of HTN and one of the following at BOTH screening and pre- 
randomization: 
a. SBP ˃ 105 mm Hg on antihypertensive medication. 
b. SBP ≥ 140 mm Hg and NOT on antihypertensive medication. 
3. NYHA class I-III heart failure and with a reduced ejection fraction ≤ 
40%. 
4. On stable doses of treatment with guideline-directed therapy, other 
than ACEis and ARBs prior to randomization. 
5. On an optimal medical regimen of diuretics and background 
medications to effectively treat co-morbidities such as HTN, DM, and 
coronary artery disease 
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. Previous history of intolerance to sacubitril/valsartan, ACEi or ARB 
standard of care doses despite appropriate and gradual up-titration. 
3. History of angioedema, drug-related or otherwise. 
4. Requirement of treatment with both ACE inhibitor and ARB. 
5. Current or prior treatment with sacubitril/valsartan 
Study treatment 
All eligible patients will be randomized to receive either 
sacubitril/valsartan or enalapril. The following study treatment will be 
provided for the 12-week double blind double dummy treatment epoch: 
• 
sacubitril/valsartan tablets + matching placebo, or; 
• 
enalapril tablets + matching placebo. 
All patients will begin on Dose Level 1 and will be titrated every 2 weeks 
to target Dose Level 3. Safety and tolerability is monitored. Down-titration 
to temporary withdrawal of study treatment is permitted. Rescue option is 
available for worsening heart failure. 
Sacubitril/valsartan tablets will be provided for the 12-week open label 
extension. All dose levels are available. Target is Dose Level 3. 
Efficacy assessments 
Primary (Week 12) 

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•
Change in aortic characteristic impedance (Zc = dP/dQ) between
baseline and Week 12.
Secondary 
1.
Change from baseline in NT-proBNP at Week 12.
2.
Changes from baseline in echocardiographic measures at week 12
including:
•
Global longitudinal strain
•
Left atrial volume index
•
Mitral annular E’ velocity (Doppler Tissue Imaging)
•
Mitral E/E’
•
Left ventricular ejection fraction
•
Ventricular-vascular coupling (Ea/Ees)
•
LV end systolic and diastolic volume indices
3.
The change in aortic characteristic impedance and change in
biomarker levels, including BNP, U-cGMP/U-creatinine, during both
trough and 4 hours post-dose at Week 4.
Key safety 
assessments 
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. 
The safety and tolerability assessments are listed below: 
•
AEs and SAEs
•
Sitting systolic, diastolic BP, and pulse pressure
•
Heart rate
•
Laboratory values

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Data analysis 
Primary 
The primary efficacy variable will be analyzed by an analysis of 
covariance (ANCOVA) model with treatment and baseline as explanatory 
variables. The least squares means of the two treatment groups, least 
squares mean difference of the treatment groups, 95% confidence 
interval for the difference in the two treatment groups, and p-value based 
on the fitted linear model will be reported. If the p-value is < 0.05 and the 
least squares mean difference of the treatment groups favors 
sacubitril/valsartan, statistical significance in favor of sacubitril/valsartan 
is shown. The primary analysis of the primary efficacy variable will be 
based on the Full Analysis Set. 
Secondary 
For NT-proBNP, a proportional change from baseline in a logarithmic 
scale will be analyzed using an ANCOVA model with treatment and the 
logarithmic baseline (Day 1) biomarker value as explanatory variables. 
The estimated treatment effects in terms of ratios of geometric means, 
based on the least-squared means from the ANCOVA model, the 
corresponding two-sided 95% confidence intervals and p-values will be 
provided. 
The change from baseline in the echocardiographic measures will be 
analyzed using an ANCOVA model with treatment and baseline as 
explanatory variables. 
Correlation coefficients between changes from baseline in aortic 
characteristic impedance and biomarker levels (markers such as BNP, 
U- cGMP/U-creatinine) during both trough and 4 hours post-dose at 
Week 4 will be calculated by treatment and overall. 
Analyses of the secondary efficacy variables will be based on the Full 
Analysis Set. 
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. 

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In CHOIR, treatment with Omapatrilat was associated with an 
approximately ~10% reduction in characteristic impedance at 12 weeks, 
with little or no change seen amongst enalapril- treated patients. Based 
on a similar study design and population, and accounting for a dropout 
rate of 20% from first visit to subsequent follow up and a 10% rate of non- 
evaluable data, assuming a standard deviation of 80 for the primary 
efficacy variable and 90% power, a sample size of 432 subjects (216 per 
arm) will be necessary to detect a clinically important change of 30 dyne 
x sec/cm5 between the two treatment groups. 
Key words 
aortic characteristic impedance, heart failure, increased pulsatile load, 
reduced ejection fraction, hypertension, angiotensin receptor-neprilysin 
Inhibition, ventricular-vascular coupling (Ea/Ees) 

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1 
Introduction 
1.1 
Background 
Central Aortic Stiffening May be an Important Mediator of Heart Failure Progression 
Higher pulse pressure, an indirect measure of proximal aortic stiffness, is an independent 
predictor of cardiovascular events in the general population and in those with hypertension. 
Aortic stiffening enhances the amplitude of incident pressure waves leaving the heart, which 
increases load on the heart. Aortic stiffening also reduces the amount of protective wave 
reflection that normally occurs at the interface between a compliant aorta and stiff muscular 
arteries (Mitchell 2008). The resulting enhanced pulse wave transmission into the periphery 
due to stiffening of the proximal aorta and reduced wave reflection is associated with excessive 
energy transmission into the microcirculation. Excessive energy dissipation in the 
microcirculation is associated with microvascular damage and greater risk for end-organ 
damage, particularly in high flow organs like the brain (Mitchell 2011) and kidneys (Woodard 
2015). Increased pulsatile load has been associated with several deleterious consequences 
including accelerated vascular and ventricular hypertrophy and fibrosis, endothelial 
dysfunction, atherogenesis, cognitive impairment and kidney dysfunction, which may explain 
the association between pulse pressure and various clinical events including incident 
myocardial infarction and heart failure. In addition, because of direct mechanical coupling 
between LV and aorta, stiffening of the proximal aortic increases systolic longitudinal load on 
the left ventricle (LV) and reduces early diastolic filling (Bell 2015). These features suggest 
that proximal aortic stiffening may play an important role in mediating the development and 
progression of heart failure. 
While pulse pressure is an important cardiovascular disease risk factor and a rough surrogate 
for central arterial stiffening, it is an imprecise measure of load because it is flow-dependent 
and therefore highly variable. Thus, pulse pressure can be shown to predict risk in large 
observational studies, but in smaller, mechanistic studies, pulse pressure cannot be used as a 
robust measure of load. Some have argued that central pressure is a more precise measure of 
load on the LV and various devices have been developed that purport to measure central 
pressure. However, central pressure is confounded by the same dependency on flow as 
peripheral pressure. Furthermore, central pressure is not independently related to events in 
models that account for peripheral pressure. Thus central pressure alone, without concurrent 
assessment of flow, provides limited additional information as compared to peripheral pressure. 
Aortic characteristic impedance, Zc, is the ratio of the change in pressure (dP) produced by a 
given change in flow (dQ) in early systole, i.e., Zc = dP/dQ. Zc is related directly to aortic wall 
stiffness and inversely to lumen area and accurately summarizes the initial load that the heart 
encounters in early systole. The importance of forward wave amplitude, Zc and pulsatile load 
was highlighted in a recent paper from the Framingham Heart Study (FHS), which showed that 
higher forward wave amplitude and Zc were associated with increased risk for a first major 
cardiovascular disease event during 7 years of follow-up (Cooper 2015). These relations 
persisted in models that adjusted for standard cardiovascular disease risk factors, including 
systolic blood pressure and carotid-femoral pulse wave velocity. 
As the forward wave travels down the aorta, it encounters regions of impedance mismatch that 
give rise to wave reflection. Although often portrayed as unfavorable, wave reflection plays a 

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critical role in normal function of the arterial system because it limits the amount of pulsatile 
energy that is transmitted distally into the microvasculature. Wave reflection has been 
maligned because of the perceived increase in late systolic load on the heart that results from 
a premature reflected wave that produces pressure augmentation in late systole, as often 
assessed by measuring augmentation index (AI) on a central pressure waveform. However, 
recent studies have shown that much of the apparent increase in wave reflection with advancing 
age, as assessed by AI, is not attributable to an increase in wave reflection or early arrival of 
the reflected wave, but is rather a result of alterations in the ejection pattern of the LV (Fok 
2014, Torjesen 2014). Importantly, measures of wave reflection were not independently related 
to events in the FHS analysis of components of pulsatile load, where central aortic pressure 
and flow were measured in order to assess load comprehensively (Cooper 2015). In patients 
with heart failure and reduced LV function, Zc is elevated and measures of apparent wave 
reflection, such as AI, are actually reduced (Mitchell 2001). Thus, Zc is a major contributor  
to abnormal hemodynamic load in patients with heart failure. 
The LV must interact directly with Zc in order to deliver pulsatile flow. When LV function is 
preserved, an increase in hemodynamic demand leads to an increase in forward wave amplitude 
and pulse pressure. However, an impaired LV has a limited ability to increase pressure and 
hence higher Zc will limit flow in patients with reduced LV function. The load imposed by Zc 
is present throughout systole, including early systole when flow is high and LV geometry in 
unfavorable (large chamber volume and thin wall). As a result, Zc is the principal determinant 
of peak wall stress in the LV (Chirinos 2012). In contrast, wave reflection has a limited effect 
on wall stress because late systolic geometry (smaller chamber, thicker wall) protects the heart 
from external pressure load. It is likely, therefore, that changes in Zc, more than changes in 
wave reflection or central pressure, may adversely impact ventricular-vascular coupling and 
promote heart failure progression in patients with reduced ejection fraction. 
Composite Angiotensin Receptor-Neprilysin Inhibition may reduce Central Aortic 
Stiffness in Heart Failure and Improve Ventricular-Vascular Coupling 
Traditional afterload reduction with peripheral vasodilator drugs reduces peripheral resistance, 
MAP and wave reflection, but does not reduce Zc. If cardiac output increases because of the 
reduction in peripheral resistance, pulsatile overhead will paradoxically increase because the 
additional flow must be transferred through Zc, which remains high. In addition, even more 
pulsatile energy will be transmitted to the periphery because of the reduction in wave reflection. 
Thus, traditional vasodilator drugs reduce MAP, which is often already either normal or low  
in patients with heart failure, yet increase pulsatile stress on the LV and arterial system. 
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARB) 
may reduce aortic stiffness by opposing vasoconstrictive, hypertrophic, and profibrotic effects 
of angiotensin II on the vessel wall. Neprilysin or neutral endopeptidase (NEP) is an enzyme 
that inactivates several vasodilatory peptides including the natriuretic peptides that are thought 
to play a role in the body’s defense against hypertension. Data from experimental models 
suggests that natriuretic peptides may have favorable effects on the aorta. Combined 
ACE/NEP inhibition with omapatrilat 80 mg was associated with greater reductions in pulse 
pressure and Zc than enalapril 40 mg in the Conduit Hemodynamics of Omapatrilat 
International  Research  Study (CHOIR),  but  was  associated  with  an  unacceptable  risk of 

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angioedema. The novel Angiotensin Receptor-Neprilysin inhibitor sacubitril/valsartan is 
associated with similar hemodynamic and antihypertensive benefits to omapatrilat, but does 
not carry the same risks of angioedema. The PARAMOUNT study of sacubitril/valsartan 
versus valsartan in subjects with heart failure and preserved ejection fraction suggested 
significant reductions in natriuretic peptide levels and left atrial remodeling that may be 
mediated in part through impacts on pulsatile load. More recently the PARADIGM-HF study 
identified a 20% reduction in the primary composite outcome of cardiovascular death or heart 
failure hospitalization as well as a 20% reduction in cardiovascular death associated with 
sacubitril/valsartan treatment relative to enalapril in patients with heart failure and reduced 
ejection fraction (McMurray 2014). The mechanism of sacubitril/valsartan benefit in heart 
failure patients remains unclear. We propose a study to examine the effects of 
sacubitril/valsartan relative to enalapril on aortic stiffness and ventricular-vascular coupling in 
heart failure patients. 
We further propose to explore the effects of sacubitril/valsartan on carotid pressure-flow 
relations in order to gather preliminary support for the hypothesis that a reduction in Zc will 
reduce pressure and flow pulsatility transmitted into the cerebrovasculature. Data from the 
AGES-Reykjavik Study has demonstrated that higher aortic Zc is associated with reduced wave 
reflection at the interface with the common carotid arteries, resulting in greater transmission of 
pressure and flow pulsatility into the cerebral microcirculation, which is associated with 
cerebral small vessel disease and lower performance on cognitive testing (Mitchell 2011). 
Carotid flow pulsatility was strongly related to various magnetic resonance imaging measures 
of cerebral small vessel disease as well as performance in all 3 major cognitive domains 
(memory, processing speed and executive function). Some have expressed concern that NEP 
inhibition may reduce clearance of amyloid from the brain. However, recent evidence suggests 
that amyloid deposition may be increased or clearance decreased by exposure of the 
cerebrovasculature to excessive pulsatility (Hughes 2015). By measuring pressure and flow in 
the common carotids, we can examine the effective reflection coefficient, which should be 
increased, as well as the carotid flow pulsatility, which should be reduced, by a treatment- 
related reduction in Zc. If sacubitril/valsartan reduces Zc, and thereby reduces transmission of 
pressure and flow pulsatility into the cerebrovasculature, there may be a net beneficial effect of 
treatment on amyloid deposition and cognitive performance—a hypothesis that could be tested 
in an adequately powered follow-up study. 
Please refer to the Clinical Data Sheet for further information on sacubitril/valsartan. 
 
1.2 
Purpose 
The purpose of this study is to determine the effect of sacubitril/valsartan compared to enalapril 
on reducing aortic stiffness in patients with mild to moderate HFrEF. Results from this study 
may be used to support the mechanism of benefit for sacubitril/valsartan and to subsequently 
explore if heart failure progression may be slowed down or mitigated by treatment. 

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2 
Study objectives and endpoints 
2.1 
Primary objective(s) 
The primary objective is to determine whether treatment with sacubitril/valsartan provides a 
superior effect on aortic characteristic impedance compared to enalapril in patients with heart 
failure and reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤ 40%) after 12 
weeks of treatment. 
The primary endpoint is the change in aortic characteristic impedance (Zc = dP/dQ in early 
systole) between baseline and Week 12. 
 
2.2 
Secondary objective(s) 
1. To evaluate the effect of sacubitril/valsartan vs. enalapril after 12 weeks of treatment on 
change from baseline in NT-proBNP. 
2. To evaluate the effect of sacubitril/valsartan vs. enalapril after 12 weeks of treatment on 
the changes from baseline in echocardiographic measures including: 
• Global longitudinal strain 
• Left atrial volume index 
• Mitral annular E’ velocity (Doppler Tissue Imaging) 
• Mitral E/E’ 
• Left ventricular ejection fraction 
• Ventricular-vascular coupling (Ea/Ees) 
• LV end systolic and diastolic volume indices 
3. To evaluate the effect of sacubitril/valsartan vs. enalapril after 4 weeks of treatment on the 
relation between the change in aortic characteristic impedance and change in biomarker 
levels, including BNP, U-cGMP/U-creatinine, during both trough and 4 hours post-dose. 
 
 

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3 
Investigational plan 
3.1 
Study design 
This study will use a multicenter, randomized, double-blind, double-dummy, parallel group, 
active-controlled, forced titration, 12-week design in patients with heart failure and reduced left 
ventricular ejection fraction (LVEF) ≤ 40%. The study duration is a maximum of 30 weeks, 
including the screening epoch, with 8 scheduled outpatient visits. 
Screening epoch 
Patients will enter a screening epoch up to 6 weeks, beginning with Baseline (Visit 1) at - 42 to 
-1 day(s) prior to randomization to assess eligibility requirements and to confirm patients are 
on stable treatment with guideline-directed therapy for HFrEF, other than ACEis and ARBs. 
• Screening/Baseline echocardiography (echo), ECG and safety labs will be obtained. 
• Non-invasive arterial hemodynamics assessments will be obtained specifically within the 
window of study day -7 to -2 prior to randomization on Day 1 (Visit 2) to ensure quality 
control and to allow for a repeat study on day -1, if necessary. 
• Biomarkers 
 will be obtained on Day 1 (Visit 
2), pre-randomization. 
• If the patient is currently taking an ACEi, a 36-hour washout is required prior to 
randomization (Visit 2). 
• If the patient is currently taking an ARB, they must discontinue the ARB before initiation 
of study treatment however, washout is not required. 
Note: Baseline for this study includes assessments performed during Screening and through 
Day 1 (Visit 2) pre-randomization. 
Patients can be randomized as soon as screening criteria are met. 
 
Double-blind, randomized treatment epoch 
• On Day 1 (Visit 2), patients will be randomized to either sacubitril/valsartan 24/26 mg 
BID or enalapril 2.5 mg BID (Dose Level 1), according to the product label(s) and will 
return for a safety assessment at Week 1 (Visit 3). 
• Study treatment will be force-titrated every 2 weeks to reach the target dose of 
sacubitril/valsartan 97/103 mg BID and enalapril 10 mg BID (Dose Level 3). 
Deviation from the titration schedule or dose adjustments will only be allowed if indicated per 
protocol defined safety and tolerability criteria (See Section 5.5.5, Table 5-7) and investigator 
judgement, if the investigator believes that adjustment/elimination of concomitant medications 
is not possible or does not alleviate the side effects of concern. 
At any time during the 12 week randomized, double-blind treatment epoch, investigators have 
the option to withdraw patients from study treatment if they develop signs and symptoms of 
worsening heart failure for which the investigator would like to administer appropriate therapy. 
(See Section 5.5.5 and Section 5.5.6) 

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Open-label extension epoch 
The purpose of this open-label period is to observe the additional vascular effects of 
sacubitril/valsartan that occur beyond 12 weeks of treatment. 
After 12 weeks of successful double-blind, active treatment, patients will continue into the 12 
week open-label extension epoch. Patients will have received the final dose of double-blind 
treatment medication in the clinic at Week 12 (Visit 6). 
• ALL patients will need to have a 36-hour washout from study treatment prior to starting 
the open-label extension to ensure that the blinding of the core study is maintained and to 
reduce the risk of angioedema. 
• To facilitate this washout, patients will be instructed NOT to start their open-label 
treatment until the evening of the following day. 
• All patients will start open-label treatment on sacubitril/valsartan 49/51 mg BID (Dose 
level 2), unless they completed the double-blind treatment epoch on Dose Level 1. 
Instead, these patients will enter the open-label epoch on sacubitril/valsartan 24/26 mg 
BID dose (Dose level 1). 
• Study treatment will be force-titrated every 2 weeks to reach the target dose of 
sacubitril/valsartan 97/103 mg BID (Dose Level 3). 
Deviation from the titration schedule or dose adjustments will only be allowed if indicated per 
protocol defined safety and tolerability criteria (See Section 5.5.5, Table 5-7), and investigator 
judgement, if the investigator believes that adjustment/elimination of concomitant medications 
is not possible or does not alleviate the side effects of concern. 
Follow-up safety visits will occur throughout the study at Weeks 1, 2, 4, 12, 14 and 24 (Visits 
3, 4, 5, 6, 7, and 8). 
Primary efficacy assessments will be conducted at Screening/Baseline, Day 1 (Visit 2) pre- 
randomization, and Week 12 (Visit 6). 
 
 
 
 
Patients will be contacted by phone at approximately 30 days following the last administration 
of study treatment at Week 24 (Visit 8), or early withdrawal, in order to determine if any SAE(s) 
occurred during this time period. These SAEs will be recorded in the source document only and 
must be reported to Novartis. Attempts to contact the patient should also be recorded in the 
source document. 
Every SAE occurring after the patient has provided informed consent and until 30 days 
following the last administration of study treatment must be reported directly to the Novartis 
Drug Safety and Epidemiology Department within 24 hours of learning of its occurrence. 
No interim analysis is planned. If it is deemed necessary for internal decision making, due to 
patient safety, an interim analysis will be conducted by an independent statistical group. 

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Figure 3-1 
Study design 
 
3.2 
Rationale for study design 
The Evaluate-HF study is designed to provide a definitive assessment of the hemodynamic 
mechanism of action of sacubitril/valsartan in HFrEF. 
In the CHOIR study, ACE/NEP inhibition with omapatrilat was associated with greater 
reductions in pulse pressure and Zc than enalapril after 12 weeks of treatment. Based on this, 
the double-blind treatment epoch of this study was designed to be 12 weeks. Additionally, 
given the superior results obtained with sacubitril/valsartan in the PARADIGM-HF trial, the 
duration of the double-blind period also limits the patients’ exposure to the current standard of 
care, enalapril. 
Prior to the double-blind treatment epoch, we wanted to ensure that patients had the opportunity 
to be optimized on treatment with guideline-directed therapy for HFrEF, other than ACEi and 
ARBs. As many patients are able to be up-titrated on medications in a 4 to 6 week period, we 
have allowed up to 6 weeks for the screening epoch. 
We wanted the ability to assess the vascular effects of patients who switch from enalapril to 
sacubitril/valsartan as well as to understand if there are additional vascular effects in patients 
who have extended treatment with sacubitril/valsartan. We believe that 12 weeks of open-label 
treatment was enough time to evaluate both of these measures. 
 
3.3 
Rationale for dose/regimen, route of administration and duration 
of treatment 
Sacubitril/valsartan 97/103 mg BID was selected as the target dose because it was the dose used 
in the PARADIGM-HF study where it was shown to have superior results versus enalapril in 
reducing CV death and heart failure hospitalizations. This is also the USPI approved target dose. 

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In addition, this dose delivers similar exposures of valsartan as Diovan 160 mg BID, the 
maximal approved Diovan dose for heart failure and the dose recommended in international 
guidelines for the treatment of heart failure and biomarker analysis (increase in ANP and cGMP) 
indicates that this sacubitril dose delivers approximately 90% of its maximal neutral 
endopeptidase (NEP) inhibition. Dosing with 97/103 mg twice daily ensures sustained NEP 
inhibition over 24 hours, which is thought to be critical for patients with heart failure. 
 
3.4 
Rationale for choice of comparator 
Treatment with ACEi has been well established as the standard of care for RAAS blockade and 
is recommended by treatment guidelines as a 1A recommendation for all patients with CHF and 
reduced LVEF, unless ACEi-intolerant. Additionally, ACEi may reduce aortic stiffness by 
opposing vasoconstrictive, hypertrophic, and profibrotic effects of angiotensin II on the vessel 
wall. 
As a well-studied ACEi in heart failure, enalapril has been selected as the comparator for this 
study with a target dose of 10 mg BID. The 10 mg BID dose was the same target dosage studied 
in the SOLVD study and is the dose that was chosen in the PARADIGM-HF trial. The same 
dose will be used in this study so that we can appropriately assess the hemodynamic benefits of 
the drug and whether it supports the clinical outcomes that were seen in both trials. 
 
3.5 
Purpose and timing of interim analyses/design adaptations 
Not Applicable 
 
3.6 
Risks and benefits 
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria 
and study procedures, close clinical monitoring, and the provision of rescue options. 
 
3.6.1 
Risks 
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, [426 (10.14%) in 4203 patients in the double-blind 
treatment period], hyperkalemia, [488 (11.61%) in 4203 patients in the double-blind treatment 
period], and hypotension [740 (17.61%) in 4203 patients in the double-blind treatment period]. 
In PARADIGM-HF, patients treated with enalapril experienced these events at a similar rate 
with the exception of hypotension; renal dysfunction, [487 (11.52%) in 4229 patients in the 
double-blind treatment period]; hyperkalemia, [592 (14%) in 4229 patients in the double-blind 
treatment period]; and hypotension, [506 (11.97%) in 4229 patients in the double-blind 
treatment period]. Results from the TITRATION study indicated that patients whom 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. The risks are further 
mitigated by appropriate inclusion and exclusion criteria. Patients entering into the study must 
have an SBP of at least 140 mmHg if not treated for hypertension or a SBP of >105 mmHg  if 

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they are currently on treatment. Additionally, patients are excluded if they have an eGFR < 30 
ml/min/1.73 m2 or a potassium > 5.2 mEq/L at screening. 
Drug to drug interactions are known to occur with concomitant use of ACE/ARB/NEP and 
renin inhibitors. See Section 5.5.8 for prohibited medications. Patient will be provided with 
study treatment instructions and their medication histories will be reviewed at Screening and 
all subsequent visits. 
Sacubitril/valsartan, [19 (0.5%) in 4203 patients in the double-blind treatment period of 
PARADIGM-HF] and enalapril 10 (0.2%) in 4229 patients in the double-blind treatment period 
of PARADIGM-HF] may also cause angioedema. The risk of developing angioedema is 
increased if patients take both an ACEi and sacubitril/valsartan. To decrease this risk, patients 
will be required to undergo a 36-hour washout prior to randomization as well as the open-label 
treatment epoch to minimize the interaction between an ACEi and sacubitril/valsartan in 
potentiating the development of angioedema. 
In the PARADIGM-HF study, sacubitril/valsartan reduced the risk of CV death and HF 
hospitalization versus enalapril. In the US, sacubitril/valsartan is approved and indicated to 
reduce these risks in patients with chronic heart failure (NYHA class II-IV) and reduced ejection 
fraction. Due to this, the double-blind treatment epoch is limited to 12 weeks to minimize the 
chance of exposure to standard treatment with enalapril. Thereafter, all patients will have the 
opportunity to receive 12 weeks of open-label sacubitril/valsartan. It should be noted that the 
population of patients studied in PARADIGM-HF included NYHA class II-IV patients that 
were all on either ACEi or ARBs prior to study enrollment. The population of patients included 
in this study is different than that of PARADIGM-HF. 
There is a chance a patient may develop signs and symptoms of worsening heart failure for 
which the investigator would like to administer appropriate therapy. Appropriate adjustments, 
intensifications, or additions to concomitant medications should be considered. If needed, the 
investigator can choose to withdraw the patient from the study to initiate treatment with 
sacubitril/valsartan, ACEi, or ARBs if the investigator believes this to be appropriate treatment. 
Rescue options are provided in Section 5.5.6. 
In addition to investigational treatment, all patients will be allowed to continue receiving the 
rest of their background cardiovascular (CV) medications throughout the study. Patients will be 
randomized to study treatment only after the investigator has confirmed the patient is on stable 
treatment with guideline-directed therapy for HFrEF, other than ACEis and ARBs, which will 
ensure that patients are receiving appropriate treatment for their heart failure. 
The study procedures and assessments for this study are either non-invasive or minimally 
invasive (venipuncture for blood draws) and are considered low risk. 
 
3.6.2 
Benefits 
All patients will receive active treatment for heart failure that reduces the risk of mortality and 
hospitalizations. After completion of the double-blind treatment epoch, all patients will have 
the opportunity to receive 12 weeks of open-label sacubitril/valsartan, a drug which has been 
proven to reduce the risks of CV death and HF hospitalization versus enalapril. 

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This study is the first clinical trial to treat NYHA Class I asymptomatic heart failure patients 
with sacubitril/valsartan. Data collected may determine if heart failure progression can be 
prevented. Additionally, patients with NYHA Class I heart failure wouldn’t otherwise have 
access to sacubitril/valsartan as the drug is not approved for use in these patients. 
Study assessments and frequent visits will provide close monitoring of patients’ conditions and 
may provide information that may benefit heart failure patients in the future. 
 
4 
Population 
The study population will consist of out-patient male and female patients, ≥ 50 years of age 
with HFrEF ≤ 40% who have a history of hypertension. The goal is to randomize a total of 
approximately 432 patients to sacubitril/valsartan or enalapril in a 1:1 ratio at approximately 
80 centers in the United States. The estimated screen failure rate is 25%. Approximately 575 
patients will be screened. 
At the time of randomization, patients will have been on stable treatment with guideline- 
directed therapy for HFrEF, other than ACEis and ARBs, and on an optimal medical regimen 
to effectively treat co-morbidities such as HTN, DM and coronary artery disease. Patients will 
have met all other inclusion and none of the exclusion criteria. 
 
4.1 
Inclusion criteria 
Patients/subjects eligible for inclusion in this study must fulfill all of the following criteria at 
screening and randomization: 
1. Written informed consent must be obtained before any assessment is performed. 
2. Men and women ≥ 50 years of age. 
3. History of HTN and one of the following at BOTH screening and pre-randomization: 
a. SBP ˃ 105 mm Hg on antihypertensive medication. 
b. SBP ≥ 140 mm Hg and NOT on antihypertensive medication. 
4. Patients diagnosed with heart failure NYHA class I-III and reduced ejection fraction ≤ 
40% as determined by any local measurement made within the past 12 months using 
echocardiography, MUGA, CT scanning, MRI, ventricular angiography or single-photon 
emission computed tomography (SPECT), provided no subsequent measurement above 
40%. Patients who have had an intervening medical event (e.g. myocardial infarction) or 
procedure (e.g. revascularization, cardiac resynchronization), must have a reassessment of 
EF ≥ 3 months following the event to ensure that eligibility criteria are still met. 
5. On stable doses of treatment with guideline-directed therapy, other than ACEis and ARBs, 
prior to randomization. 
a. If the patient is currently taking an ACEi, a 36-hour washout is required prior to 
randomization (Visit 2). 
b. If the patient is currently taking an ARB, they must discontinue the ARB before 
initiation of study treatment however, washout is not required. 
6. On an optimal medical regimen to effectively treat co-morbidities such as HTN, DM, and 
coronary artery disease. Investigators should make every effort to control a patient’s BP in 
accordance with local treatment guidelines and investigator judgment. 

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4.2 
Exclusion criteria 
Patients fulfilling any of the following criteria, at screening and prior to randomization, are not 
eligible for inclusion in this study for purposes of safety measures. No additional exclusions 
may be applied by the investigator, in order to ensure that the study population will be 
representative of all eligible patients/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. Previous history of intolerance to sacubitril/valsartan, ACEi or ARB standard of care 
doses despite appropriate and gradual up-titration. 
3. History of angioedema, drug-related or otherwise. 
4. Requirement of treatment with both ACE inhibitor and ARB. 
5. Current or prior treatment with sacubitril/valsartan. 
Patients/subjects taking medications prohibited by the protocol (see Section 5.5.8, Table 5-9). 
6. 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. 
7. Currently enrolled in any other clinical trial involving any investigational agent or 
investigational device. 
8. DBP ˃ 100 mm Hg at screening or at randomization. 
9. eGFR < 30 ml/min/1.73 m2 (calculated by the Modification of Diet in Renal Disease 
formula) at screening. 
10. Potassium > 5.2 mEq/L at screening. 
11. Documented or untreated ventricular arrhythmia with syncopal episodes within the 3 
months prior to Screening/Baseline (Visit 1). 
12. Persistent or permanent atrial fibrillation at Screening/Baseline (Visit 1). 
13. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other major 
CV surgery, percutaneous coronary intervention (PCI) or carotid angioplasty within the 3 
months prior to first Screening/Baseline (Visit 1). 
14. Implantation of a cardiac resynchronization therapy pacemaker (CRT-P) or a cardiac 
resynchronization therapy defibrillator (CRT-D) or upgrading of an existing conventional 
pacemaker or an implantable cardioverter defibrillator (ICD) to CRT device within 3 
months prior to first visit or intent to implant such a device. 
15. Heart transplant or ventricular assistance device (VAD) or intent to transplant (on 
transplant list) or implant a VAD. 
16. Coronary or carotid artery disease likely to require surgical or percutaneous intervention 
within the 6 months after Visit 1. 
17. Hemodynamically significant aortic stenosis/regurgitation or mitral valve disease other 
than mitral valve regurgitation related to LV dilation. 
18. Presence of other hemodynamically significant obstructive lesions of left ventricular 
outflow tract, including aortic and sub-aortic stenosis. 
19. Isolated right HF due to severe pulmonary disease. 

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20. Diagnosis of peripartum or chemotherapy induced cardiomyopathy within the 12 months 
prior to Screening/Baseline (Visit 1). 
21. Treatment with Vaughn Williams Type Ic anti-arrhythmic agents (e.g., Flecainide, 
propafenone, moricizine). 
22. Symptomatic bradycardia or second or third degree heart block without a pacemaker. 
23. History of familial long QT syndrome or known family history of Torsades de Pointes 
24. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin), treated or untreated, within the past year with a life expectancy of less than 1 
year. 
25. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or extraction of study drug, including but not limited to any of 
the following: 
a. History of active inflammatory bowel disease during the 12 months prior to 
Screening/Baseline (Visit 1) 
b. History of peptic ulcer disease without successful eradication of H. pylori. 
c. Gastrointestinal/rectal bleeding during the 3 months prior to Screening/Baseline (Visit 
1). 
d. Current treatment with cholestyramine of colestipol resins. 
26. Known hepatic impairment (as evidenced by total bilirubin > 3 mg/dL, or increased 
ammonia levels, if performed), or history of cirrhosis with evidence of portal hypertension 
such as varices. 
27. Bilateral renal artery stenosis. 
28. Inability to secure technically adequate baseline tonometry study. 
29. 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. 
30. Women of childbearing 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 

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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. 
31. Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she considered 
not of child-bearing potential. 
32. 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 and control drugs 
All eligible patients will be randomized to receive either sacubitril/valsartan or enalapril. The 
following study treatment will be provided: 
 
Table 5-1 
Investigational and comparator treatment during the double-blind 
epoch 
 
Treatment Arm 
Number of 
Patients 
Minimum 
dose 
Maximum 
dose 
Frequency Formulation 
Administration 
Route 
sacubitril/valsarta 
n* 
216 
24/26 mg 
97/103 mg 
BID 
tablet 
oral 
sacubitril/valsarta 
n matching 
placebo 
oral 
enalapril 
216 
2.5 mg 
10 mg 
BID 
tablet 
oral 
enalapril 
matching placebo 
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. 
 
 
Table 5-2 
Treatment dose level during the double-blind epoch 
 
Dose Level 
Sacubitril/valsartan* 
Enalapril 
1 
24/26 mg or matching placebo BID 
2.5 mg or matching placebo BID 
2 
49/51 mg or matching placebo BID 
5 mg or matching placebo BID 
3 
97/103 mg or matching placebo BID 
10 mg or matching placebo 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. 
 

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Both sacubitril/valsartan and enalapril and their matching placebos will be packaged and 
labeled by the sponsor in accordance with the US Code of Federal Regulations governing 
handling of investigational treatments, and will be dispensed by the study physician. 
Sacubitril/valsartan and enalapril will be packaged separately to limit the number of pack types, 
which will allow more flexibility in the drug supply process to cover all the different treatment 
possibilities (treatment arm and medication dose level), see Table 5-2 and Table 5-4. Packaging 
type is described below: 
• sacubitril/valsartan and its matching placebo will be provided in HDPE bottles. 
• enalapril 2.5 mg and its matching placebo will be provided in HDPE bottles. 
• enalapril 5 mg and 10 mg and its matching placebo will be provided in blister packs. 
Each participating site will be provided with an investigational drug supply containing Dose 
Levels 1, 2, and 3 and their matching placebos. Bottles and blister packs will be numbered and 
assigned via an interactive voice response system (IRT). Treatment for the day of randomization 
and all visits forward will be assigned via IRT. All patients will begin the study on Dose Level 
1. Then: 
• Sacubitril/valsartan or enalapril dose levels will be force-titrated to achieve the targeted 
desired dose of 97/103 mg BID or 10 mg BID (Dose Level 3). 
• Patients not tolerating the target dose of sacubitril/valsartan 97/103 mg BID or enalapril 
10 mg BID (Dose Level 3) can be titrated down to Dose Level 2 (including active 
medication and matching placebos), if, in the investigator’s judgement, the 
adjustment/elimination of concomitant medications is not possible or does not alleviate the 
side effects of concern. See Section 5.5.5. 
This study is designed as a double-blind, double-dummy trial to ensure the blinding during the 
entire course of the study. To maintain the blinding, patients will be required to take their 
assigned active treatment tablet along with placebo matching the opposite treatment twice daily. 
 
Table 5-3 
Investigational treatment during the open label epoch 
 
Treatment 
Number of 
patients 
Minimum 
dose* 
Maximum 
dose 
Frequency 
Formulation 
Route 
Open-label 
sacubitril/vals 
~346 
49/51 mg 
97/103 mg 
BID 
tablet 
oral 
  artan** 
 
*sacubitril/valsartan 24/26 mg BID (Dose Level 1) will be given to patients who completed the double-blind treatment 
epoch on Dose Level 1 and is available if down-titration is required. 
**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. 
 
 
Table 5-4 
Treatment Dose Levels during the open-label epoch 
Dose Level* 
Sacubitril/valsartan** 
2 
49/51 mg BID 
3 
97/103 mg BID 
*Sacubitril/valsartan 24/26 mg BID (Dose Level 1) will be given to patients who completed the 
double-blind treatment epoch on Dose Level 1. It is also available if down-titration is required. 
**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  

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Dose Level* 
Sacubitril/valsartan** 
 
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 for 12-weeks. 
• Patients entering the open label-treatment epoch will be given sacubitril/valsartan 49/51 
mg BID (Dose Level 2) unless they completed the double-blind treatment epoch on Dose 
Level 1. Instead, these patients will enter the open-label epoch on sacubitril/valsartan 
24/26 mg BID dose (Dose Level 1). 
• Study treatment will be force-titrated every 2 weeks to reach the target dose of 
sacubitril/valsartan 97/103 mg BID (Dose Level 3). 
Schedule and dose adjustments will only be allowed if, in the investigator’s judgement, the 
adjustment/elimination of concomitant medications is not possible or does not alleviate the side 
effects of concern. See Section 5.5.5. 
 
5.1.2 
Additional treatment 
The protocol requires patients to be on stable treatment with guideline-directed therapy for 
HFrEF, other than ACEis and ARBs, and on an optimal medical regimen to effectively treat co- 
morbidities such as HTN, DM and coronary artery disease. 
 
5.2 
Treatment arms 
Patients/subjects will be assigned at Visit 2 to one of the following two treatment arms in a 1:1 
ratio: 
• sacubitril/valsartan; or, 
• enalapril 
5.3 
Treatment assignment and randomization 
At Visit 2, all eligible patients/subjects will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The investigator or his/her delegate will contact 
the IRT after confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT 
will assign a randomization number to the patient, which will be used to link the patient to a 
treatment arm and will specify a unique medication number for the first package of study drug 
to be dispensed to the patient. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients/subjects and investigator staff. A 
patient randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis Drug Supply Management using a validated system that automates the random 
assignment of medication numbers to packs containing the investigational drug(s). 

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The randomization scheme for patients/subjects will be reviewed and approved by a member 
of the Novartis Biostatistics Group. 
 
5.4 
Treatment blinding 
Patients, investigator staff, persons performing the assessments, data analysts and the Clinical 
Trial Team (CTT) will remain blind to the identity of the treatment from the time of 
randomization until database lock, using the following methods: (1) Randomization data are 
kept strictly confidential until the time of unblinding, and will not be accessible by anyone else 
involved in the study with the exception of the IRT provider generating the randomization code. 
(2) The identity of the treatments will be concealed by the use of investigational treatments that 
are identical in packaging, labeling, and schedule of administration, appearance, taste and odor. 
A double-dummy design is used because the identity of the study drug cannot be disguised, as 
the drug products are visibly different. To maintain the blinding, patients will be required to 
take their assigned active treatment tablet along with placebo matching the opposite treatment 
twice daily. 
Unblinding will only occur in the case of patient emergencies see Section 5.6 and at the 
conclusion of the study. 
 
5.5 
Treating the patient 
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
 
5.5.1 
Patient numbering 
Each patient 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 patient identification number, 
e.g., 0501-001. Once assigned to a patient, the Subject Number will not be reused. 
Upon signing the informed consent form, the patient is assigned the next sequential number by 
the investigator. The investigator or his/her staff will contact the IRT and provide the assigned 
patient study identification number along with the requested identifying information for the 
patient to register them into the IRT. The site will enter this number on the electronic case report 
form (eCRF) in the electronic data capture system (EDC). 
 
5.5.2 
Dispensing the study drug 
Each study site will be supplied by Novartis with investigational and comparator treatment in 
packaging of identical appearance. 
The investigational and control treatment packaging will have a 2-part label. A unique 
randomization number is printed on each part of this label, which corresponds to one of the 2 
treatment arms and a dose level. Investigator staff will identify the investigational treatment 
package(s) to dispense to the patient by contacting the IRT and obtaining the medication 
number(s). Immediately before dispensing the package to the patient, investigator staff will 

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detach the outer part of the label from the packaging and affix it to the source document (Drug 
Label Form) for that patient’s unique subject number. 
 
5.5.3 
Handling of study treatment 
 
5.5.3.1 
Handling of investigational and comparator treatment 
Investigational and comparator 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. Medication labels will include storage 
conditions but no information about the patient except for the medication number. Clinical 
supplies are to be dispensed only in accordance with the protocol. Technical complaints are to 
be reported to the respective Novartis CPO Quality Assurance. 
The investigator must maintain an accurate record of the shipment and dispensing of 
investigational and comparator treatment in a drug accountability log. Monitoring of drug 
accountability will be performed by field monitors during site visits or remotely and at the 
completion of the trial. Patients will be asked to return all unused investigational or comparator 
treatment and packaging at the end of the study or at the time of discontinuation of treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused investigational and comparator treatment, packaging, drug labels, and a 
copy of the completed drug accountability log according to the instructions provided by 
Novartis or its agents. 
Medication labels will be in the local language and comply with the legal requirements of the 
country. They will include storage conditions for the study treatment but no information about 
the patient 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. Patients/subjects will 
be asked to return all unused study treatment and packaging 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. 
 
5.5.3.2 
Handling of other study treatment 
Each study site will be supplied, by Novartis, with open-label sacubitril/valsartan for the 12- 
week open-label treatment epoch. The IRT will need to be called to receive drug shipments 
prior to dispensing. 
The open-label sacubitril/valsartan packaging will have a 2-part label. Investigator staff will 
identify the treatment package(s) to dispense to the patient by contacting the IRT and obtaining 
the  medication  number(s).  Immediately  before  dispensing  the  package  to  the       patient, 

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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 patient’s unique subject number. 
Open-label sacubitril/valsartan 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 open-label sacubitril/valsartan 
treatment should 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 patient except for the medication number. The 
investigator must maintain an accurate record of the shipment and dispensing of open-label 
sacubitril/valsartan treatment in a drug accountability log. Monitoring of drug accountability 
will be performed by field monitors during site visits or remotely and at the completion of the 
study. Patients will be asked to return all unused open-label treatment and packaging at the end 
of the study or at the time of discontinuation of treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused open-label treatment, packaging, drug labels, and a copy of the completed 
drug accountability log according to the instructions provided by Novartis or its agents. 
 
5.5.3.3 
Handling of non-study treatment 
The following non-study treatment has to be monitored specifically and recorded in the CRF: 
• ACEi/ARB treatment prior to randomization and/or after early discontinuation of study 
treatment. 
• All protocol required background therapy. 
• Rescue treatment. 
5.5.4 
Instructions for prescribing and taking study treatment 
Novartis will supply the investigators with all medications sufficient for the course of the study. 
Patients will be provided with medication packs containing study drug corresponding to their 
assigned treatment arm and dose level, sufficient to last until the next scheduled visit. Patients 
will be instructed to hold their morning study medication dose on the day of study visits. Study 
drug will be administered at the site after pre-dose vital signs, blood samples and assessments 
are performed. Vital signs 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 seated position after 5 minutes of rest, with back supported and both 
feet placed flat on the floor. Every effort should be made to use the same arm for the patient for 
all vital signs assessments and where possible, the same person doing the assessment. 
In order to adequately blind the study, patients will be required to take their assigned active 
treatment tablet along with placebo matching the opposite treatment twice daily. Patients will 
be instructed to take a total of two tablets by mouth twice a day for the duration of the double- 
blind treatment epoch, as follows: 
• one tablet from the sacubitril/valsartan/sacubitril/valsartan matching placebo pack, and; 
• one tablet from the enalapril/enalapril matching placebo pack 

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Table 5-5 summarizes the study drug that will be taken during the double-blind treatment epoch 
by visit and Table 5-6 summarizes the study drug that will be taken during the open-label 
treatment epoch. 
Forced-titration will proceed according to the following table: 
 
Table 5-5 
Study drug dispense during double-blind treatment epoch 
Visit 
 Dose 
Level 
Sacubitril/valsartan** 
Enalapril 
Route 
Timing 
Rando/Visit 2 
1a,b 
24/26 mg or 
matching placebo BID 
Week 2/Visit 4 
2ce 
49/51 mg or 
matching placebo BID 
Week 4/Visit 5 
3d 
97/103 mg or 
matching placebo BID 
2.5 mg or 
matching placebo BID 
5 mg or 
matching placebo BID 
10 mg or 
matching placebo BID 
Oral 
AM & PM 
 
Oral 
AM & PM 
 
Oral 
AM & PM 
**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. 
a. Initial starting dose (Level 1) Eligible patients will be randomized via IRT to either sacubitril/valsartan or enalapril, Dose 
Level 1. 
b. Available after Rando/Visit 2 to end of double-blind treatment epoch only if Dose Levels 2 and 3 are not tolerated despite 
modification of other non-disease-modifying HF medications and re-challenge. 
c. Only if Dose Level 3 is not tolerated despite modification of other non-disease-modifying HF medications and re-challenge. 
d. This target Dose Level must be maintained for as long a duration as possible. If down-titration is necessary due to side 
effects, the patient should be re-challenged as soon as medically possible per the investigator’s judgment. 
e. The evening dose of study medication prior to Week 4/Visit 5 must be taken no less than 12 hours before the 
hemodynamic assessment time scheduled for Week 4/Visit 5. See Section 6.4.1. 
• At Randomization on Day 1 (Visit 2), eligible patients will be randomized via IRT to 
either sacubitril/valsartan or enalapril. All patients will start at Dose Level 1 (2.5 mg 
enalapril or 24/26 mg sacubitril/valsartan, BID). 
• At Week 1 (Visit 3), patients will return to the study center for a safety assessment only. 
Study medication will not be up-titrated. 
• At Week 2 (Visit 4), patients will be force-titrated to Dose Level 2 (5 mg enalapril or 
49/51 mg sacubitril/valsartan. 
• At Week 4 (Visit 5), patients will be force-titrated to the target dose, Dose Level 3 (10 mg 
enalapril or 97/100 mg sacubitril/valsartan and remain on this target dose for 8 weeks 
through the evening dose prior to Week 12 (Visit 6). 
• At Week 12 (Visit 6), patients will have the final dose of double-blind treatment 
medication administered in the clinic after pre-dose assessments have been completed. 
Drug accountability will be performed and all double-bind treatment medication will be 
returned to the site. 
• All patients that complete the 12 week (Visit 6) double-blind treatment epoch will proceed 
into the 12-week open-label epoch on sacubitril/valsartan. 
• Open-label sacubitril/valsartan will be dispensed at Week 12 (Visit 6) with patient 
instructions NOT to start their open label-treatment until the evening after completing a 
36-hour wash out. All patients will have the wash out in order to maintain the blinding of 
the core study. 

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All dose levels will be available throughout the study. Dose adjustments to lower dose levels 
may be made at any time at both scheduled and unscheduled visits only if indicated for blood 
pressure control/tolerability reasons. 
All study treatment assigned by the IRT will be recorded/databased in the IRT. 
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded in the IRT and on the Dosage Administration Record eCRF. 
Study medication should be taken twice daily with a glass of water with or without food. Prior 
to scheduled study visit days, instruct the patient to have nothing by mouth after midnight and 
to take study medication after vital signs and study assessments are taken by the study 
coordinator at the investigator site. 
If the patient misses taking any study drug dose, he/she should take it as soon as possible and 
within 4 hours of the scheduled dose time. If the patient is unable to take the missed dose within 
4 hours of the scheduled dose time, he/she should skip the missed dose and return to his/her 
regular study drug administration schedule. 
The investigator must promote compliance by instructing the patient to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and the 
validity of the study. The patient must also be instructed to contact the investigator if he/she is 
unable for any reason to take the study treatment as prescribed. 
 
Table 5-6 
Study drug dispense during open-label treatment epoch 
 
Dose Level 
Visit 
Sacubitril/valsartan** 
Route 
Timing 
2a 
Week 12/Visit 6 
49/51 mg 
Oral 
AM & PM 
3 
Week 14/Visit 7 
97/103 mg 
Oral 
AM & PM 
**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. 
• All patients entering the open-label treatment epoch will start open-label treatment on 
sacubitril/valsartan 49/51 mg BID (Dose Level 2) unless they completed the double-blind 
treatment epoch on Dose Level 1. Instead, these patients will enter the open-label epoch 
on sacubitril/valsartan 24/26 mg BID dose (Dose Level 1). 
• Study treatment will be force-titrated every 2 weeks to reach the target dose of 
sacubitril/valsartan 97/103 mg BID (Dose Level 3). 
Schedule and dose adjustments will only be allowed if, in the investigator’s judgement, the 
adjustment/elimination of concomitant medications is not possible or does not alleviate the side 
effects of concern. See Section 5.5.5. 
 
5.5.5 
Permitted dose adjustments and interruptions of study treatment 
based on safety and tolerability 
Study drug dose level adjustments should be mainly based on overall safety and tolerability and 
investigator judgement, with a special focus on: 

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• hyperkalemia; 
• clinically significant decreases in eGFR/increase in serum creatinine; and, 
• symptomatic hypotension 
Table 5-7 
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 of ≥0.5mg/dl with at least a 25% decrease in 
eGFR 
Blood pressure 
• 
No symptomatic hypotension or SBP ˂ 90 mmHg 
Adverse events (AEs) or conditions 
• 
No postural symptoms or any conditions that preclude 
continuation according to the investigator’s judgment 
 
Every attempt should be made to maintain patients on target study drug Dose Level 3 for as 
long a duration as possible throughout the study. If, however, in the opinion of the investigator, 
a patient is unable to tolerate the protocol-specified target dose, the investigator will manage 
the patient’s treatment according to the below guidelines: 
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 to the previous dose level. The patient may continue 
receiving the lower dose level for a recommended period of 1 to a maximum of 4 
weeks. 
• A re-challenge to titrate back up to the target dose level should be attempted at 2 
weeks, or when patient is deemed stable. THEN: 
3. Further Adjust Study Treatment Dose Level 
• If tolerability issues are not alleviated despite down-titration by one dose level, the 
investigator may down-titrate further to the next lower study treatment dose level. The 
patient may continue receiving the lower dose level for a recommended period of one 
to a maximum of 4 weeks, up to a temporary withdrawal of study treatment. See Step 
5. 
• Again, once stable, the patient should be re-challenged with up-titration to the next 
higher dose level in an attempt to gradually bring the patient back to the target study 
treatment dose level (Dose Level 3). 
• The investigator may choose the next dose level for down- or up-titration according to 
his or her clinical judgment. 
4. Stopping Study Treatment 
If needed, the study treatment may be stopped completely, however, the patient should continue 
to attend all study visits and be followed until the completion of the study. See Section 5.5.6. 

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5. Study drug restart after temporary treatment interruption 
• Once the investigator considers the patient’s condition appropriate for receiving the 
study drug, the investigator should re-start the patient on study treatment at the most 
appropriate and allowable dose level per his/her medical judgment. 
• If tolerated, the patient should be titrated up to the next dose level every 1 to 4 weeks, 
as per the investigator’s judgment. 
• In some instances, Dose Level 1 or 2 could be maintained if the investigator considers 
that the patient’s condition would not allow any further up-titration to the target dose 
of study medication (Dose Level 3). In this case, it would be acceptable to maintain 
the patient at Dose Level 1 or 2, whichever is the higher and tolerated dose level by 
the patient, but reasons for not getting to Dose Level 3 need to be captured in the 
eCRF. 
• Should the patient not tolerate the re-start study drug dose level, he/she may be down- 
titrated again (if appropriate) or discontinued from study treatment. 
Patients re-started on the study drug will retain their original randomization and study 
identification numbers. 
The IRT must be contacted to register any changes in the patient’s study treatment dose level, 
including in cases of temporary and permanent withdrawal or re-start of the study drug, and to 
obtain the medication numbers of the study drug supplies required for the new study treatment 
dose level. All dose changes and interruptions must also be recorded on the Dosage 
Administration Record eCRF. 
Study visits should occur as close as possible to the pre-defined visit and time schedule 
described in Table 6-1. The timeframe between the regular visits should be maintained as 
scheduled, irrespective of the number of unscheduled visits that may be performed in between, 
or dose interruptions that may occur. 
In case of pregnancy discovered during the study, the patient should be instructed to stop taking 
the study drug immediately. (See Section 6.5.6 and Section 7.6) 
 
5.5.6 
Rescue medication for worsening heart failure 
At any time during the 12 week randomized, double-blind treatment epoch, investigators have 
the option to withdraw patients from study treatment if they develop signs and symptoms of 
worsening heart failure for which the investigator would like to administer appropriate therapy. 
• Appropriate adjustments, intensifications, or additions to concomitant medications should 
be considered before deciding to withdraw the patient from study treatment. 
• Other than their study treatment, patients CANNOT receive ACEis, ARBs, or 
sacubitril/valsartan during the study. These medications can ONLY be administered 
if the investigator believes that the patient needs to be withdrawn from study 
treatment so that they may be treated with these therapies due to signs and 
symptoms of worsening heart failure. 
• A 36 hour wash-out period is required if the investigator chooses to withdraw the 
patient from double-blind treatment and switch to sacubitril/valsartan or ACEi due 
to symptoms of worsening heart failure. 

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• Use of rescue medication must be recorded on the Concomitant medications eCRF. 
Investigators will use clinical judgement to determine if patient condition requires closer 
monitoring. Unscheduled visits are permitted as needed. 
Guidance on handling hyperkalemia, hypotension, and renal dysfunction are provided to 
investigators in the appendices. 
 
5.5.7 
Concomitant medication 
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All new medications, administered 
after the patient signs the study informed consent, must be recorded on the concomitant 
medications eCRF. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started. 
ACEis and ARBs: 
Patients taking an ACEi at screening must undergo a 36-hour washout prior to randomization 
(Visit 2). Patients taking an ARB must discontinue the ARB prior to initiating treatment with 
study medication however, a washout is not necessary. 
The concomitant use of ACEis or ARBs is strictly prohibited while the patient is receiving study 
medication. Adjustment, intensification, or addition of concomitant medications should be 
considered first before the decision is made to treat the patient with an ACEi or ARB. If the 
investigator believes that the patient needs to be withdrawn from the study medication so 
that they may be treated with either an ACEi or ARB, the study medication must first be 
stopped and a 36-hour washout period will be required for patients being switched to an 
ACEi. 
Other heart failure and cardiovascular medication 
If a patient’s condition warrants any change in concomitant heart failure or cardiovascular 
medications, changes may be made at the investigator’s discretion. 
Oral diuretics may be used and may be adjusted throughout the study duration at the 
discretion of the investigator. 
 
Table 5-8 
Concomitant medications to be used with caution 
Classification 
Caution 
Action 
 
1. Potassium sparing diuretics; 
2. Potassium supplements; 
3. Aldosterone antagonists; and, 
4. Any other medication known 
to raise potassium levels. 
Phosphodiesterase-5 (PDE-5) 
inhibitors 
Increased possibility of 
hyperkalemia. 
 
 
 
Increased possibility of 
occurrence of hypotension. 
Monitor potassium levels 
regularly, especially after dose 
initiation and up-titration. 
 
 
 
Monitor for symptomatic 
hypotension. 
 

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5.5.8 
Prohibited medication 
Use of the treatments displayed in Table 5-9 is NOT allowed after the screening epoch. 
 
Table 5-9 
Prohibited medication 
Medication 
Prohibition period 
Action taken 
ACEis/ARBs/NEPs 
ACEi 36 hour prior to study 
treatment, ACEi, ARB, NEP 
during study treatment, 
ACEi and NEP within 36 
hours post double-blind 
randomization. 
If the investigator believes that addition of an 
ACEi ARB or sacubitril/valsartan is necessary, 
then study drug must be discontinued, while 
monitoring renal function. ACEi or 
sacubitril/valsartan must not be started until 36 
hours after discontinuing study drug to reduce 
the risk of angioedema. 
Renin inhibitors 
(Aliskerin) 
Bile acid 
sequestering 
agents (such as 
cholestyramine or 
colestipol) 
Nesiritide and 
intravenous 
nitrates 
During study treatment. 
Do not randomize, or, use alternate treatment. 
 
During study treatment. 
Switch to alternate agent to avoid interference 
with study drug absorption. If use of alternate 
agent is not allowed, do not randomize or 
discontinue study drug treatment. 
 
During study treatment. 
Do not randomize.  If hospitalized, either 
interrupt or discontinue study treatment. 
Nesiritide and intravenous nitrates have not 
been studied. Oral, topical and sublingual 
nitrates are permissible. 
 
 
5.5.9 
Emergency breaking of assigned treatment code 
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
patient safely and efficaciously. Most often, study treatment discontinuation and knowledge of 
the possible treatment assignments are sufficient to treat a study patient who presents with an 
emergency condition. Emergency treatment code breaks are performed using the IRT. When 
the investigator contacts the system to break a treatment code for a patient, he/she must provide 
the requested patient identifying information and confirm the necessity to break the treatment 
code for the patient. The investigator will then receive details of the investigational drug 
treatment for the specified patient and a fax or email confirming this information. The system 
will automatically inform the Novartis monitor for the site and the Clinical Trial Lead (CTL) 
that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a procedure in place in case of an 
emergency. The investigator will inform the patient how to contact his/her backup in cases of 
emergency when he/she is unavailable. The investigator will provide protocol number, study 
treatment name if available, patient number, and instructions for contacting Novartis Country 
Pharma Organization CPO (or any entity to which it has delegated responsibility for emergency 
code breaks) to the patient in case an emergency treatment code break is required at a time when 
the investigator and backup are unavailable. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide: 
• protocol number 

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• study drug name (if available) 
• patient number 
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
 
5.6 
Study completion and discontinuation 
5.6.1 
Study completion and post-study treatment 
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol, Week 24 (Visit 8). 
• Week 12 (Visit 6), completes the end of double-blind treatment epoch 
• Week 24 (Visit 8) completes the end of open-label treatment epoch and the end of study 
At the end of study visit, investigational product will be returned and reconciled. Concomitant 
medications and adverse events will be reconciled. Continuing care should be provided by 
investigator and/or referring physician based on patient availability for follow-up. The 
following recommendations for initiating other treatment outside the study include: 
• Continue on commercially available sacubitril/valsartan 
• Return to treatment regimen prior to study 
Patients will be contacted by phone at approximately 30 days following the last administration 
of study treatment (Week 24), or early withdrawal, in order to determine if any SAE(s) occurred 
during this time period. These SAEs will be recorded in the source document only and must be 
reported to Novartis. Attempts to contact the patient should also be recorded in the source 
document. 
Every SAE occurring after the patient has provided informed consent and until 30 days 
following the last administration of study treatment must be reported directly to the Novartis 
Drug Safety and Epidemiology Department within 24 hours of learning of its occurrence. 
 
5.6.2 
Discontinuation of study treatment 
Discontinuation of study treatment for a patient occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by either the patient or the investigator. 
The investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation. 
Patients may voluntarily discontinue the study drug for any reason at any time. 
Study treatment must be discontinued under the following circumstances: 
• Patient wish 
• Withdrawal of consent 
• Pregnancy (see Section 6.5.8 and Section 7.6) 
• Use of prohibited treatment as per recommendations in Table 5-9 
• Any protocol deviation that constitutes a risk to the patient 

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• Any situation in which study participation might result in a safety risk to the patient 
• Unresolved worsening HF 
Study medication may be discontinued at the investigator’s discretion if any of the following 
serious suspected drug-related AEs occur: 
• Symptomatic hypotension 
• Suspected occurrence of angioedema. A patient with any signs or symptoms of clinically 
significant angioedema should be thoroughly evaluated by the investigator to determine if 
it constitutes a reason for discontinuation of study medication. 
• Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the subject’s overall status, prevents the subject from continuing 
participation in the study. 
Depending on the serum potassium, blood pressure, or eGFR, patients 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 patient should NOT be considered withdrawn 
from the study. The investigator must determine the primary reason for the patient’s premature 
discontinuation of study treatment and record this information on End of Study Treatment eCRF. 
After study treatment discontinuation, the patient should attend the regularly scheduled visits 
and have all study assessments performed. 
Investigator judgement will determine if the patient should return to the clinic for an earlier 
unscheduled visit. If discontinuation of study treatment occurred due to a significant adverse 
event, an unscheduled visit should occur to assess the patient and obtain laboratories as needed. 
See Table 6-1 for Unscheduled Visit assessments. At a minimum, in abbreviated visits, the 
following data should to be collected at clinic visits or via telephone visits: 
• new / concomitant treatments 
• adverse events/Serious Adverse Events 
If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient. This telephone 
contact should preferably be done according to the study visit schedule. 
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment. 
If study drug discontinuation occurs because treatment code has been broken, please refer to 
Section 5.5.9. 
 
5.6.3 
Withdrawal of informed consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent from the study is defined as when a patient: 
• Does not want to participate in the study anymore 
And 

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• 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 
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’s decision to withdraw his/her consent and record 
this information in the eCRF. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in Table 6- 
1, End of Treatment Visit 6 assessments or End of Study Visit 8 assessments, based on the 
treatment epoch from which the patient discontinues. 
 
5.6.4 
Loss to follow-up 
For patients whose status is unclear, because they fail to appear for study visits without stating 
an intention to withdraw, the investigator should show "due diligence" by contacting the patient, 
family or family physician as agreed in the informed consent and by documenting, in the source 
documents, steps taken to contact the patient, e.g. dates of telephone calls, registered letters, etc. 
A patient should not be formally considered lost to follow-up until his/her scheduled end of 
study visit would have occurred. 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should 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 patient cannot be considered as lost to follow-up until the time 
point of his/her scheduled end of study visit has passed. 
 
5.6.5 
Early study termination by the sponsor 
The study can be terminated at any time, for any reason, by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated as a prematurely withdrawn patient. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient’s interests. The investigator 
will be responsible for informing the Institutional Review Board/Independent Ethics Committee 
(IRBs/IECs) of the early termination of the trial. 
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 enrollment). Should this be necessary, the patient 
must  be  seen  as  soon  as  possible  and  treated  as  a  prematurely  withdrawn  patient.  The 

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investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator 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 
Table 6-1 lists all of the assessments and indicates with an “X” when the visits are performed. 
Assessments that will only be reported in the source documentation are marked with an ‘S’. 
Patients must be seen for all visits on the designated day, or as close to it as possible, including 
those on dose interruptions or discontinued treatment. A visit window of +/- 3 days is allowed. 
Every effort should be made to respect the time frame for the primary efficacy endpoint at Week 
12 (Visit 6) visit. 
Missed or rescheduled visits should not lead to automatic discontinuation. Patients who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for Visit 6 (End of Treatment) or Visit 8 
(End of Study) will be performed, depending on the epoch from which the patient prematurely 
discontinues from the study. See Section 5.6.3. At this final visit, all dispensed investigational 
product should be reconciled and the adverse event and concomitant medications reconciled on 
the eCRF. 
Patients will be contacted by phone at approximately 30 days following the last administration 
of study treatment, Week 24 (Visit 8), or early study discontinuation, in order to determine if 
any SAE(s) occurred during this time period. These SAE(s) will be recorded in the source 
document only and must be reported to Novartis. Attempts to contact the patient should be 
recorded within the source document. 
Every SAE occurring after the patient has provided informed consent and until 30 days 
following the last administration of study treatment must be reported directly to the Novartis 
Drug Safety and Epidemiology Department within 24 hours of learning of its occurrence. 
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 
 
 
Epoch 
Screening/ 
Baseline** 
Double-Blind Treatment 
Open Label Treatment 
Unsched. 
Visit◊ 
Visit number 
D/S* 
1 
2 
3 
4 
5 
6/EOT* 
7 
8/EOS** 
Week 
-6 to -1 
1† 
2 
4 
12 
14 
24 
Day 
-42 to – 1 
1 
7 
14 
28 
84 
98 
168 
Obtain informed consent1 
S 
X 
Inclusion/Exclusion 
S 
X 
X 
Demography/ medical history 
D 
X 
HF and CV disease history 
D 
X 
ECG2 
S 
X 
Full Physical Exam 
S 
X 
X 
X 
X 
Cardiac Exam3 
S 
X 
X 
X 
X 
X 
X 
Height 
D 
X 
Weight 
D 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs4 
D 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NYHA Classification (HF signs and 
symptoms) 
D 
X 
X 
X 
X 
X 
X 
X 
HF and CV medications 
D 
X* 
X 
X 
X 
X 
X 
X 
X 
X 

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Epoch 
Screening/ 
Baseline** 
Double-Blind Treatment 
Open Label Treatment 
Unsched. 
Visit◊ 
Visit number 
D/S* 
1 
2 
3 
4 
5 
6/EOT* 
7 
8/EOS** 
Week 
-6 to -1 
1† 
2 
4 
12 
14 
24 
Day 
-42 to – 1 
1 
7 
14 
28 
84 
98 
168 
Concomitant medication 
D 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events/SAEs 
D 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Angioedema assessment 
D 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy5 
D 
X 
X 
X 
X 
Dipstick urinalysis6 
D 
X 
X 
X 
X 
X 
X 
Hematology 
D 
X 
X 
X 
X 
Full chemistry profile7 
D 
X 
X 
X 
X 
X 
X 
Abbreviated chemistry panel7 
D 
X 
X 
X 
X 
Cardiac Biomarkers: NT-proBNP, BNP, 
 
 (pre-dose)8 
D 
X 
X 
X 
X 
X 
Additional Cardiac plasma/serum biomarkers 
for bio-banking (pre-dose)8,9 
D 
X 
X 
X 
X 
X 
Spot urine biomarkers (pre-dose)8,10 
D 
X 
X 
X 
X 
X 
BNP and spot urine biomarkers @ 4 hours 
post-dose8,10,19 
D 
X 
Echocardiography11 
D 
X12 
X 
X 
X 
Hemodynamic assessment trough study with 
limited echo13 
D 
X14 
X 
X 
X 

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Epoch 
Screening/ 
Baseline** 
Double-Blind Treatment 
Open Label Treatment 
Unsched. 
Visit◊ 
Visit number 
D/S* 
1 
2 
3 
4 
5 
6/EOT* 
7 
8/EOS** 
Week 
-6 to -1 
1† 
2 
4 
12 
14 
24 
Day 
-42 to – 1 
1 
7 
14 
28 
84 
98 
168 
Hemodynamic assessment 4 hours post-dose 
with limited echo15,19 
D 
X 
X 
X 
Contact IRT 
D 
X 
X 
X 
X 
X 
X 
X 
Randomize 
D 
X 
Dispense treatment 
D 
X 
X 
X 
X 
X 
X 
Dosage Administration Record16 
D 
X 
X 
X 
X 
X 
X 
X 
Drug accountability 
S 
X 
X 
X 
X 
X 
X 
X 
X 
Titration 
D 
X 
X 
X 
X 
Screening Disposition 
D 
X 
Study phase completion – randomized 
double-blind treatment 
D 
X 
36 hour study drug wash-out17 
D 
X 
X 
Study completion - open-label treatment and 
end of study18 
D 
X18 
* D: to be documented in the clinical database; S: in the source data. 
** Baseline is defined as assessments occurring any time prior to randomization. In this study, some of the baseline assessments are performed 
during the Screening period and some are performed on Day 1 prior to Randomization. 
ӿ End of Treatment Visit: Visit 6 (Week 12) assessments must be performed for subjects who discontinue from the study prematurely during the 
double-blind treatment period, as well as all subjects who complete the double-blind treatment period. 
ӿ ӿ End of Study Visit: Visit 8 (Week 24) assessments must be performed for subjects who discontinue the study prematurely during the open label 
phase, as well as all study completers. 
◇ Unscheduled Visit Assessments marked with (X) are optional procedures that may be performed at the investigator’s discretion. 
†. Safety visit post-dose initiation. No titration. Perform Drug Accountability, administer dose in clinic and return study medication to patient. 

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Epoch 
Screening/ 
Baseline** 
Double-Blind Treatment 
Open Label Treatment 
Unsched. 
Visit◊ 
Visit number 
D/S* 
1 
2 
3 
4 
5 
6/EOT* 
7 
8/EOS** 
Week 
-6 to -1 
1† 
2 
4 
12 
14 
24 
Day 
-42 to – 1 
1 
7 
14 
28 
84 
98 
168 
1. ICF includes 24 week study and hemodynamic assessments using arterial tonometry (trough and 4-hrs post-dose) 
2. ECG to be performed locally. 
3. Cardiac exam to be completed on Day 1 pre-randomization (Visit 2) and at Weeks 1 2, 4, and 14 (Visits 3, 4, 5 and 7). Document in Source. 
4. Vital signs include blood pressure, pulse and respiratory rate 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, with back supported and both feet placed flat on the 
floor. Every effort should be made to use the same arm for the patient for all vital signs assessments and where possible, the same person doing the 
assessment. 
5. 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. 
6. Urine dipstick. If positive, send full urinalysis to central laboratory. 
7. Clinical Chemistry: Repeat Full Chemistry Profile if Randomization (Visit 2) occurs greater than 2 weeks from Screening (Visit 1). Abbreviated 
Chemistry Panel (electrolytes and creatinine) is measured for safety at visits not requiring full chemistry profile. Hemoglobin A1c is measured at 
Screening and at Weeks 12 and 24 (Visits 6 and 8). 
8. Must be strictly processed and stored according lab manual instructions and timelines. 
9. Includes cardiac, renal, and drug mechanism of action biomarkers. 
10. Includes urinary biomarkers such as U-cGMP/U-creatinine. 
11. Echocardiography is completed simultaneously with hemodynamic assessments. 
12. Screening echocardiography can be performed any time during the Screening/Baseline epoch, but should be performed before the hemodynamic 
assessment to ensure inclusion criterion is met first. 
13. Fasting required after midnight prior to hemodynamics trough studies. Instruct and remind patient to take study medication the evening before the 
actual visit and no less than 12-hrs prior to the scheduled assessment time. 
14. Screening hemodynamic assessment can be done within the window of day -7 to day -2 to allow sufficient time for a repeat test, if quality is not 
good. 
15. Patient to remain at clinic for 4-hr post-dose hemodynamic assessment. 
16. Instruct patient to take morning dose of study treatment in the clinic on the day of visit, after all pre-dose assessments have been completed. 

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Epoch 
Screening/ 
Baseline** 
Double-Blind Treatment 
Open Label Treatment 
Unsched. 
Visit◊ 
Visit number 
D/S* 
1 
2 
3 
4 
5 
6/EOT* 
7 
8/EOS** 
Week 
-6 to -1 
1† 
2 
4 
12 
14 
24 
Day 
-42 to – 1 
1 
7 
14 
28 
84 
98 
168 
17. 36-hr washout required post-dose at Week 12 to avoid drug-drug interaction between ACEis and NEPi. Also, post-dose at Week 24 after open- 
label epoch is completed, if ACEi is to be initiated post-study. 
18. Patients will be contacted by phone approximately 30 days following the last administration of study treatment (Week 24), or early study 
discontinuation, in order to determine if any SAE(s) occurred during this time period. Document in source. Every SAE occurring after the patient has 
provided informed consent and until 30 days following the last administration of study treatment must be reported to the Novartis Drug Safety and 
Epidemiology Department within 24 hours of learning of its occurrence. 
19. Window for 4 hrs. post-dose assessments is ± 0.5 hrs. 

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6.1 
Information to be collected on screening failures 
All patients/subjects who have signed informed consent but not entered into the next epoch will 
have screening disposition, 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 
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristic data to be collected on all patients include: date 
of birth, age, sex, race, and ethnicity. Relevant medical history/current medical condition data 
includes data until the subject provides written informed consent for the study. Where possible, 
diagnoses and not symptoms will be recorded. HF medications and other CV medications will 
also be recorded in Concomitant Medications eCRF. Detailed HF history and other relevant 
CV medical history will be recorded on eCRFs separately from other medical history. 
 
6.3 
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 patient. This information should be captured in the 
source document at each visit. All study treatment dispensed and returned must be recorded in 
the Drug Accountability Record. 
Patient compliance should be at least 80% during the double- blind treatment period. The 
investigator and/or study personnel will counsel the patient if compliance is below 80%. Study 
drug accountability will also be determined by the site monitor while performing routine site 
visits and at the completion of the study. 
Duration of double-blind study drug exposure will be calculated based upon the start and end 
dates recorded in the Dosage Administration Record eCRF. 
 
6.4 
Efficacy 
The efficacy variables are: 
Primary: 
• Change in aortic characteristic impedance (Zc = dP/dQ) between baseline and Week 12 
Secondary variables are: 
1. Change from baseline NT-proBNP after 12 weeks of treatment 
2. Changes from baseline in echocardiographic measures at week 12 including: 
• Global longitudinal strain 
• Left atrial volume index 
• Mitral annular E’ velocity (Doppler Tissue Imaging) 
• Mitral E/E’ 
• Left ventricular ejection fraction 
• Ventricular-vascular coupling (Ea/Ees) 

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• LV end systolic and diastolic volume indices 
 
3. The change in aortic characteristic impedance and change in biomarker levels such as, 
BNP , U-cGMP/U-creatinine during both trough and 4 hours post-dose at Week 4 
 

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6.4.1 
Hemodynamic Assessments using arterial tonometry 
Hemodynamic assessment of arterial parameters during trough and 4 hours post-dose will be 
obtained using the methods, custom instrumentation and software reported by (Mitchell, et al. 
2008, 2010, and 2011). Auscultatory brachial blood pressure will be assessed by using the 
computer-controlled NIHem device, which is capable of digitizing the cuff pressure, 
electrocardiogram (1000 Hz) and a cuff microphone channel (12 kHz) throughout the inflation 
and deflation sequence in order to allow for over-read of all blood pressure acquisitions by the 
Hemodynamic Core Lab. A detailed manual with instructions on performing hemodynamic 
assessments using arterial tonometry will be provided to all sites. 
Hemodynamic trough assessments will be performed at approximately 08:00 hrs., prior to 
administration of study drug. A time window between 07:00 and 11:00 hrs. Is permitted to 
accommodate patient schedules while still allowing for the 4-hr post-dose assessment to be 
completed the same day. The Screening/Baseline assessment will be obtained between day -7 
to day -2 window to allow for a repeat test for quality assurance, if necessary, prior to 
Randomization on Day 1 (Visit 2). 
During treatment with study medication, hemodynamic trough and 4-hr.,, post-dose 
assessments will be performed at Weeks 4, 12 and 24 (Visits, 5, 6 and 8). The patient will be 
provided with the following instructions: 
• Take study medication the evening before the actual visit and no less than 12 hrs. prior to 
the scheduled assessment time. 
• No cigarettes or caffeinated beverages within 6 hrs. before (or between) studies. 
• Remain NPO after 12MN until after the 0:8:00 hemodynamic trough. 
Note: Patients may eat a light snack or breakfast after the 08:00 hemodynamic trough 
assessment. This would include a low glycemic energy bar or something that most people, 
including diabetic, would be able to tolerate. The meal time will be recorded in the source 
document. 
• Patients will then remain in or near the clinic until the hemodynamic assessment at 4-hrs 
post-dose (± 0.5 hrs.) is performed at 12:00. 
• Dress in comfortable clothing, preferably shorts, to allow access to anatomical pulse 
recording sites.  A patient gown may also be provided. 
• Arrive at the clinic one-half hour before the hemodynamic assessment, which will take 
approximately 1 hour. 
• Rest in a comfortably supported supine posture for 15–20 minutes. 
A qualified echocardiographer and a trained site professional will obtain the following 
hemodynamic measurements using arterial tonometry with electrocardiogram, using a custom 
transducer from the Cardiovascular Engineering, Inc. core lab. 
1. brachial, radial, femoral and carotid pulsatile pressures 
2. body surface measurements from suprasternal notch to pulse recording sites, using a 
fiberglass tape measure for carotid, brachial and radial sites and a caliper for the femoral 
site. 

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All blood pressure acquisitions and tonometry waveforms will be transmitted to the 
Hemodynamic Core Lab at Cardiovascular Engineering, Inc. for overreads. Tonometry 
waveforms will be signal-averaged using the electrocardiogram R-wave as a fiducial point. 
Carotid-femoral pulse wave velocity (CFPWV) will be calculated from ECG-gated carotid and 
femoral arterial waveforms and body surface measurements. Doppler audio signals recorded  
in the left ventricular outflow tract will be analyzed and signal averaged using custom software. 
The resulting high resolution flow waveform will be extracted and paired with the calibrated 
pressure waveform in order to perform central pressure-flow analysis. Characteristic 
impedance will be computed as the ratio of change in pressure divided by change in flow as 
assessed from the foot of the respective waveforms to the time when flow reaches 95% of peak 
flow. Joint analysis of pressure and flow waveforms will be used to separate forward, reflected 
waves, and measure their amplitudes. Augmentation index will be assessed from the carotid 
pressure waveform. 
Carotid artery flows will be analyzed from digitized Doppler audio data using a semi-automated 
signal-averaging approach as detailed previously by (Mitchell, et al. 2004, 2011). Flow spectra 
are signal-averaged (1000 Hz resolution) using the electrocardiogram as a fiducial point. Flow 
velocities are multiplied by carotid artery cross-sectional area to obtain volume flows. Carotid 
volume flows will be paired with the carotid pressure waveform to perform carotid artery 
pressure-flow analysis and to model transmission of pulsatility into the carotid circulation 
(Mitchell 2011). Carotid pulsatility index will be computed for each carotid by dividing the 
flow pulse amplitude (peak flow minus flow at the onset of the systolic upstroke) by mean flow. 
Values for the right and left carotid will be averaged. 
 
6.4.2 
Echocardiography 
Echocardiograms will be performed at the sites by qualified echocardiographic personnel 
(technicians or physicians) in accordance with standard echocardiographic clinical practice. 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 
Echocardiographic Assessment Obtained at Sites 
 
Echocardiographic view 
Images obtained 
• Parasternal long axis view 
• 2-D image for septal and posterior wall 
thickness 
• M-Mode Images 
• Color flow Doppler 

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• 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 and RV function 
• Color flow Doppler for assessment of mitral 
regurgitation 
• Doppler Tissue Imaging of Mitral annular 
velocities 
• Mitral Inflow Pulsed Doppler 
• Apical 5-chamber View 
• Apical 5 chamber view with LVOT PW Doppler 
and AV CW Doppler 
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 
, 
 
 
Ventricular-vascular coupling will be assessed noninvasively as the ratio (Ea/Ees) using the 
single-beat estimation formula proposed by Chen, et al. This method requires the measurement 
of systolic and diastolic BPs, ejection fraction (EF), and SV, pre-ejection period, and total 
systolic ejection period on Doppler echocardiography. This single-beat elastance approach has 
been validated against invasively measured ELV with a correlation coefficient of 0.81 (P < 0.001) 
[single-beat ELV = 0.78 × ELV(invasive) + 0.55, SE of estimate = 0.6]. 
The echo data obtained during Baseline/Screening (Visit 1), pre-dose at Weeks 4, 12 and 24 
(Visits 5, 6 and 8) and the limited echo data obtained post-dose at Weeks 4, 12 and 24 will be 
sent to a core laboratory for evaluations and analysis. A detailed manual of all echo procedures 
will be provided to all sites. 
 
6.4.3 
Biomarkers 
Blood samples for biomarkers related to heart failure or mechanism of action such as NT- 
proBNP, BNP, 
 and spot urine samples for urinary biomarkers U-cGMP/U- 
creatinine, will be obtained pre-dose in all patients on Day 1 pre-randomization (Visit 2) and at 
Weeks 2, 4 12 and 24 (Visits 4, 5, 6 and 8). BNP, U-cGMP/U-creatinine will also be collected 
in all patients at 4 hours post-dose (± 0.5 hrs.) at Week 4 (Visit 5). Specimens will be processed 
at a central laboratory. Details on sample collection, handling and shipment of biomarker 
samples will be provided to investigators in a laboratory manual. 
These and other selected biomarkers to be studied will be those believed to be relevant to the 
pathophysiology of heart failure, including those related to cardio-renal or vascular function, 
injury and/or fibrosis/remodeling. Biomarkers may include ones assessing cardio-renal or 
vascular benefit or ones related to the study drug mechanism of action. The list of blood and/or 
urine biomarkers may change during the course of the study, as new or more relevant 
biomarkers are determined. Biomarker analysis may also occur retrospectively after study close 
with biomarker decisions dependent on study outcome and/or new biomarkers relevant to this 
heart failure patient population. 

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6.4.4 
Appropriateness of efficacy assessments 
An assessment of aortic input impedance fully characterizes load on the left ventricle. Zc 
represents the contribution of proximal aortic properties to the aortic input impedance spectrum. 
Prior work has demonstrated that pulsatile hemodynamic load, as assessed by Zc, is increased 
in patients with heart failure (Mitchell 2001). Zc represents pulsatile load at the point of 
coupling between heart and arterial system. As a result, Zc represents a noncircumventable load 
on the left ventricle. Standard approaches to afterload reduction in heart failure, by using 
peripheral vasodilating drugs, will paradoxically increase pulsatile load on the heart in patients 
with elevated Zc, potentially attenuating favorable effects of vasodilation. Zc is the main 
hemodynamic determinant of peak left ventricular wall stress, which is particularly important 
in the presence of reduced left ventricular systolic function and enhanced load sensitivity. Zc 
has been shown to predict incident major CVD events in the Framingham Offspring cohort. 
Thus, Zc represents a critical component of pulsatile hemodynamic load that is abnormal in 
patients with heart failure and is associated with adverse outcomes. It stands to reason that 
therapy that specifically reduces Zc would be expected to have a favorable effect on left 
ventricular function and outcomes in patients with HFrEF. 
 
6.5 
Safety 
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. 
 
6.5.1 
Required sequence of cardiovascular data collection 
The sequential order of cardiovascular data collection during study visits is: 
1. ECG 
2. Physical exam/cardiac exam 
3. Vital signs 
4. Hemodynamic assessments 
5. Echo 
6. Blood sampling 
This sequence is important to minimize the impact of ECHO or blood sampling on 
hemodynamic assessments. 
 
6.5.2 
Physical examination 
A complete physical exam will be performed at Screening/Baseline and, Weeks 12 and 24 
(Visits 1, 6, and 8). 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. 
A cardiac exam will be performed at all visits starting at Visit 3, except where a complete 
physical examination is required (see above), and will include the examination of vital signs 

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(systolic and diastolic blood pressure, pulse and respiration rate), heart and lung sounds, jugular 
venous distension, and extremities. 
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. 
 
6.5.3 
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. 
 
6.5.4 
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, with back 
supported and both feet placed flat on the floor. Every effort should be made to use the same 
arm for the patient for all vital signs assessments and where possible, the same person doing the 
assessment. 
Clinically notable vital signs are defined in Appendix 1. 
 
6.5.5 
Height and weight 
Height in centimeters (cm) will be measured once at Screening/Baseline (Visit 1). Body weight 
(to the nearest 0.1 kilogram (kg) in indoor clothing, but without shoes) will be measured at 
every visit. 
 
6.5.6 
Angioedema 
Angioedema is a type of abrupt swelling that occurs under the skin and/or mucous membranes 
and is often localized to the head, neck, throat, and/or tongue, but may occur elsewhere, 
including the genitalia and intestines. Severe cases may be associated with airway compromise. 
Although, the mechanism is not fully understood, bradykinin has been implicated as the putative 
mediator. Therefore, medications that raise the levels of endogenous bradykinin by inhibiting 
the enzymes responsible for its breakdown, such as ACE, aminopeptidase P, and NEP, may 
result in this potentially dangerous side effect. All suspected cases of angioedema, regardless 
of suspected causality, must be reported. The Adverse Event and angioedema eCRFs 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. 

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6.5.7 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the laboratory manual. 
Clinically notable laboratory findings are defined in Appendix 1. Clinically significant 
abnormalities must be recorded on the AE e(CRF) page as appropriate. 
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 AE 
eCRF. If the laboratory abnormality is the primary reason for an unforeseen hospitalization or 
otherwise fulfills the seriousness criteria of an SAE, then the procedure for rapid notification of 
SAEs must be followed. Likewise, if the laboratory abnormality leads to discontinuation from 
the study drug (temporarily or permanently), the patient must be followed until the abnormality 
resolves or until it is judged 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, or designee. 
 
6.5.7.1 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential counts, 
and platelet count will be measured at Screening/Baseline, Weeks 12 and Week 24 (Visits 1, 6, 
and 8). 
 
6.5.7.2 
Clinical chemistry 
Blood urea nitrogen (BUN), creatinine, total bilirubin, AST (SGOT), ALT (SGPT), gamma- 
glutamyltransferase (GGT), alkaline phosphatase (ALT), sodium, potassium, chloride, calcium, 
magnesium, phosphorous, total protein, albumin, uric acid and glucose will be measured at 
Screening/Baseline (Visit 1) and at Weeks 1, 2, 12 and Week 24 (Visits 3, 4, 6, and 8). 
If Randomization occurs greater than 2 weeks from Screening (Visit 1), clinical chemistries 
will be repeated at pre-randomization (Visit 2). 
Hemoglobin A1c will be measured at Screening/Baseline (Visit 1) and at Weeks 12 and 24 
(Visits 6 and 8). 
 
6.5.7.3 
Abbreviated chemistry panel 
Electrolytes and creatinine will be measured pre-dose on Day 1 pre-randomization (Visit 2) and 
at Weeks 4, and 14 (Visits 2, 5 and 7) 
 
6.5.8 
Urinalysis 
Dipstick urine measurements Screening/Baseline (Visit 1) and at Weeks 0, 2, 4, and 12 (Visits 
2, 4, 5 and 6) for specific gravity, pH, albumin, total protein, bilirubin, glucose ketones, blood 
and leukocytes will be performed. Microscopy and WBC and RBC sediments will also be 
assessed in case of an abnormal dipstick test.  If dipstick is positive, a qualitative microscopic 

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determination, including white blood cells high power field (WBCs/HPF) and red blood cells 
high power field (RBCs/HPF) will be performed. 
 
6.5.9 
Electrocardiogram (ECG) 
In the event that a clinically significant ECG abnormality is identified at the site (e.g. severe 
arrhythmia, conduction abnormality of QTcF > 500 ms), a copy of the assessment is sent to the 
study medical monitor for expedited review and reported to Novartis Drug Safety and 
Epidemiology, if applicable, and the ECG is repeated to confirm the diagnosis. If the patient is 
hemodynamically compromised, the investigator or a medically qualified person must initiate 
appropriate safety procedures without delay (for example cardioversion). 
For this study, a Screening/Baseline ECG will be performed only. ECGs must be recorded after 
10 minutes rest in the supine position to ensure a stable baseline. The Fridericia QT correction 
formula (QTcF) should be used for clinical decisions. 
Single  12  lead  ECGs  are  collected.  The  original  ECGs  on  non-heat-sensitive  paper 
appropriately, signed by the investigator, must be collected and archived at the study site. 
Each ECG tracing must be labeled with study number, subject initials, subject number, date and 
time, and filed in the study site source documents. For any ECGs with subject safety concerns, 
two additional ECGs must be performed to confirm the safety finding. Clinically significant 
ECG findings at baseline must be discussed with the sponsor or designee before administration 
of study treatment. 
Clinically significant abnormalities must be recorded on the AE eCRF page as appropriate. Any 
SAE will be reported to Novartis Drug Safety and Epidemiology. 
 
6.5.10 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have pregnancy testing. A serum 
pregnancy test (hCG) will be performed by the central lab at Screening/Baseline, Weeks 12 and 
24 (Visits 1, 6, 8) and early withdrawal. If any of these tests are positive, the patient must be 
discontinued from the study. 
 
6.5.11 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population. They include 
the 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. 
 

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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 patient at 
each visit during the study. Adverse events also may be detected when the patient volunteers 
them 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 patient with 

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underlying disease. Investigators have the responsibility for managing the safety of individual 
patient 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: 
1. the severity grade [mild, moderate, severe] 
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
2. its relationship to the study drug(s) (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final exam) 
4. whether it constitutes a serious adverse event (SAE) 
CTCAE Grade 5 (death) is not used, but is collected in other CRFs (Study Completion). 
There may be cases where a CTCAE with a grade of 4 (life-threatening) may not necessarily 
be an SAE (e.g. certain laboratory abnormalities in the absence of meeting other serious criteria). 
• Its relationship to the study treatment and other investigational treatment 
• “No Relationship to study treatment or other investigational treatment” or 
• “Relationship to study treatment” or 
• “Relationship to other investigational treatment” or 
• “Relationship to both study treatment and other investigational treatment or 
indistinguishable“ 
• Its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported. 
• Whether it constitutes a serious adverse event (SAE - See Section 7.2 for definition of 
SAE) and which seriousness criteria have been met. 
• action taken regarding [investigational] treatment 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• no action taken (e.g. further observation only) 
• study treatment dosage increased/reduced 
• study  treatment dosage interrupted/withdrawn 
• concomitant medication given 
• non-drug therapy given 
• patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition of 
SAE) 
• 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 

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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 patient 
informed consent and should be discussed with the patient 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 patient. 
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’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 patient’s 
general condition 
• is medically significant, e.g. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention. 
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 patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (see Annex IV, ICH-E2D Guideline). 

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Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. 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 (see 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 patient safety, every SAE, regardless of causality, occurring after the patient 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] (please select as appropriate, see comment below) 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 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 patient continued or withdrew from study participation. 
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 

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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 
Liver safety monitoring 
Not applicable. 
 
7.4 
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 alert or renal event, as defined in Table 17-1 in Appendix 5, should be 
followed up by the investigator or designated personnel, at the trial site, as summarized in 
Appendix 5. 
 
7.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be 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. 
 
 
 
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 
 

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7.6 
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
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. 
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the female partner. 
 
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 CRO 
representative will review the protocol and 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 patient 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. The investigator must maintain source 
documents for each patient in the study, consisting of case and visit notes (hospital or clinic 
medical records) containing demographic and medical information, laboratory data, 
electrocardiograms, and the results of any other tests or assessments. All information on CRFs 
must be traceable to these source documents in the patient's file. The investigator must also 
keep the original informed consent form signed by the patient (a signed copy is given to the 
patient). 
 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the 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 CRFs are performed according to the study-specific 
monitoring plan. No information in source documents about the identity of the patients/subjects 
will be disclosed. 

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8.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms 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 before 
transfer of the data to the CRO working on behalf of Novartis. 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 patient data for archiving at the 
investigational site. 
 
8.3 
Database management and quality control 
CRO working on behalf of Novartis review the data entered into the eCRFs by investigational 
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. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to a 
designated CRO. 
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The IRT database will be sent 
electronically to a designated CRO. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared complete and accurate, it will be locked and 
the treatment codes will be unblinded and made available for data analysis. Any changes to the 
database after that time can only be made after written agreement by Novartis Medical Affairs 
management. 
 
8.4 
Data monitoring committee 
Not applicable. 

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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. 
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 
patients. 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 patients that may resemble an angioedema-like event. The 
investigator or his/her delegated staff must complete the required report forms and supply the 
required medical 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 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 
The analysis will be conducted on all patient data at the time the trial ends, defined as when the 
last patient enrolled completes the Week 24 visit. Any data analysis carried out independently 
by the investigator should be submitted to Novartis before publication or presentation. 
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. 

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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 patient sets will be used for the statistical reporting and analyses: 
The Randomized Set will consist of all randomized patients. 
The Full Analysis Set (FAS) will consist of all patients with the exception for those patients 
who have not been qualified for randomization and have not received study drug, but have been 
inadvertently randomized into the study. Following the intent-to-treat principle, patients will be 
analyzed according to the treatment to which they were assigned at randomization. Efficacy 
variables will be analyzed based on the FAS as the primary set. 
The Safety Set (SAF) will consist of all randomized patients who received at least one dose of 
study drug. Patients will be included in the analysis according to the treatment actually received. 
The Safety Set will be used for the analyses of safety variables. 
The Per-Protocol (PP) set will be a subset of the FAS, which will consist of the patients who do 
not have major deviations from the protocol procedures in the double-blind study stage. Major 
protocol deviations will be pre-specified prior to unblinding treatment codes for analyses. This 
supplemental efficacy set will be used to support the primary analysis results. 
 
9.2 
Patient demographics and other baseline characteristics 
Baseline value is defined as the last non-missing assessment prior to the first dose of 
randomized study medication, unless specified otherwise in the protocol. 
Summary statistics will be provided, by treatment group, for demographics and baseline 
characteristics. Geometric means will be used to summarize the cardiac biomarkers results 
including NT-proBNP. Categorical variables will be summarized using frequency and 
percentage. 
The Randomized Set and FAS will be the patient sets for the above analyses. 
 
9.3 
Treatments 
The overall duration on the double-blind study drug will be summarized by treatment group 
using mean, standard deviation, median, 25th and 75th percentiles, interquartile range, 
minimum, and maximum. Additionally, the number and percentage of patients will be 
summarized by treatment group for duration category. 
Concomitant medications and significant non-drug therapies, prior to and after the 
randomization date will be summarized (frequency and percent) by therapeutic class, preferred 
term, and treatment group. 

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9.4 
Analysis of the primary variable(s) 
9.4.1 
Variable(s) 
Change in aortic characteristic impedance (Zc = dP/dQ) between baseline and Week 12. 
 
9.4.2 
Statistical model, hypothesis, and method of analysis 
Let µj denote the population mean of change from baseline in the aortic characteristic 
impedance at Week 12 for treatment group j, j = 0, 1, where 0 corresponds to enalapril and 1 
corresponds to sacubitril/valsartan. 
The following null hypothesis (H0) will be tested against the alternative hypothesis (HA): 
H0: µ1 – µ0 = 0 
HA: µ1 – µ0 ≠ 0 
The primary efficacy variable will be analyzed by an analysis of covariance (ANCOVA) model 
with treatment and Zc baseline as explanatory variables (Mitchell 2002). The least squares 
means of the two treatment groups, least squares mean difference of the treatment groups, 95% 
confidence interval for the difference in the two treatment groups, and p-value based on the 
fitted linear model will be reported. If the p-value is < 0.05 and the least squares mean 
difference of the treatment groups favors sacubitril/valsartan, statistical significance in favor of 
sacubitril/valsartan is shown. 
The primary analysis of the primary efficacy variable will be based on the Full Analysis Set. 
 
9.4.3 
Handling of missing values/censoring/discontinuations 
If a subject has no post-baseline value, the missing value will not be imputed and the subject 
will be removed from the analysis. 
 
9.4.4 
Sensitivity analyses 
A supportive nonparametric analysis will be performed to examine the consistency of results if 
the assumption of normality for the distribution of the primary efficacy variable  is  not 
tenable. For this supportive analysis, the primary efficacy variable will be analyzed using the 
Wilcoxon rank-sum test. The probability of one treatment being the same or better than the 
other treatment will be estimated (based on the Wilcoxon rank-sum test) and the associated 95% 
confidence interval will be reported (Chen and Kianifard, 2000). 
 
9.5 
Analysis of secondary variables 
9.5.1 
Efficacy variables 
1. Change from baseline in NT-proBNP at Week 12 
2. Changes from baseline in echocardiographic measures at week 12 including: 
• Global longitudinal strain 
• Left atrial volume index 
• Mitral annular E’ velocity (Doppler Tissue Imaging) 

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• Mitral E/E’ 
• Left ventricular ejection fraction 
• Ventricular-vascular coupling (Ea/Ees) 
• LV end systolic and diastolic volume indices 
 
3. The change in aortic characteristic impedance and change in biomarker levels such as 
BNP, U-cGMP/U-creatinine, during both trough and 4 hours post-dose at Week 4 
For NT-proBNP, a proportional change from baseline in a logarithmic scale will be analyzed 
using an ANCOVA model with treatment and the logarithmic baseline biomarker value as a 
covariate and baseline (Day 1) as explanatory variables. The estimated treatment effects in 
terms of ratios of geometric means, based on the least-squared means from the ANCOVA model, 
the corresponding two-sided 95% confidence intervals and p-values will be provided. 
The change from baseline in the echocardiographic measures will be analyzed using an 
ANCOVA model with treatment and baseline as explanatory variables. 
Correlation coefficients between changes from baseline in aortic characteristic impedance and 
biomarker levels (BNP, U-cGMP/U-creatinine) during both trough and 4 hours post-dose at 
Week 4 will be calculated by treatment and overall. 
For the analysis of secondary efficacy variables, if a subject has no post-baseline value, the 
missing value will not be imputed and the subject will be removed from the analysis. 
Analyses of the secondary efficacy variables will be based on the Full Analysis Set. 
 
9.5.2 
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 percentiles, 
interquartile range, minimum and maximum) and by the flagging of notable values in data 
listings. 

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Data from other tests (e.g., vital signs) 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. See Section 9.5.1. 
 
9.5.3 
Biomarkers 
See Section 9.5.1. 
 

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9.7 
Interim analyses 
No interim analysis is planned. 
 
9.8 
Sample size calculation 
In CHOIR (Mitchell 2002), treatment with Omapatrilat was associated with an approximately 
~10% reduction in characteristic impedance at 12 weeks, with little or no change seen amongst 
enalapril- treated patients. Based on a similar study design and population, and accounting for 
a dropout rate of 20% from first visit to subsequent follow up and a 10% rate of non-evaluable 
data, assuming a standard deviation of 80 for the primary efficacy variable and 90% power, a 
sample size of 432 subjects (216 per arm) will be necessary to detect a clinically important 
change of 30 dyne x sec/cm5 between the two treatment groups. 
Assuming a significance level of 0.05, a sample size 432 patients would provide 88% power to 
detect a 25% reduction in the geometric mean of the proportional change from baseline to Week 
12 in NT-proBNP for the sacubitril/valsartan treatment group assuming a value of 0.95 for the 
enalapril group, a value of 0.7125 for the sacubitril/valsartan group (25% reduction), a common 
standard deviation of 0.85 and a 20% drop-out rate. The difference between the logs for the two 
treatment groups is therefore assumed to be 0.288. 
 
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 patients/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 
doing so, after such consent has been provided by a legally acceptable representative(s) of the 
patient. In cases where the patient’s representative gives consent, the patient must be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, he/she must indicate 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 patient 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 

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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 patient 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. 
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 patients/subjects should 
be administered as deemed necessary on a case-by-case basis. Under no circumstances is an 

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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 patients/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 patient 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 
References are available upon request. 
Bell V, Sigurdsson S, Westenberg JJ, Gotal JD, Torjesen AA, Aspelund T, Launer LJ, Harris 
TB, Gudnason V, de RA, Mitchell GF (2015) Relations between aortic stiffness and left 
ventricular structure and function in older participants in the age, gene/environment 
susceptibility--Reykjavik Study. Circ Cardiovasc Imaging; 8:e003039. 
Chen M, Kianifard F (2000) A nonparametric procedure associated with a clinically 
meaningful efficacy measure. Biostatistics; 1:293-298. 
Chirinos JA, Segers P, Gillebert TC, Gupta AK, De Buyzere ML, De BD, St John-Sutton M, 
Rietzschel ER (2012) Arterial properties as determinants of time-varying myocardial stress in 
humans. Hypertension; 60:64-70. 
Cooper LL, Rong J, Benjamin EJ, Larson MG, Levy D, Vita JA, Hamburg NM, Vasan RS, 
Mitchell GF (2015) Components of hemodynamic load and cardiovascular events: the 
Framingham Heart Study. Circulation; 131:354-361. 
Fok H, Guilcher A, Li Y, Brett S, Shah A, Clapp B, Chowienczyk P ( 2014) Augmentation 
Pressure Is Influenced by Ventricular Contractility/Relaxation Dynamics: Novel Mechanism 
of Reduction of Pulse Pressure by Nitrates. Hypertension; 63:1050-1055. 
Hughes TM, Craft, S and Lopez, OL (2015) Review of ‘the potential role of arterial stiffness 
in the pathogenesis of Alzheimer’s disease’. Neurodegen Dis Manag; 5(2): 121–135. 
McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau J, Shi VC, 
Solomon SD, Swedberg K and Zile MR (2014) Angiotensin–Neprilysin Inhibition versus 
Enalapril in Heart Failure.  N Engl J Med 2014 Sep 11; 371(11): 993-1004. 
McMurray JJ, Packer M, Desai AS, et al. Dual angiotensin receptor and neprilysin inhibition 
as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic 
heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to 
Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM- 
HF). Eur J Heart Fail 2013; 15:1062-73. 
McMurray JJV, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WHW, 
Tsai EJ and Wilkoff BL (2013) 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. Circulation; 128: e240-e327. 
Mitchell GF, Tardif JC, Arnold JM, Marchiori G, O'Brien TX, Dunlap ME, Pfeffer MA 
(2001) Pulsatile hemodynamics in congestive heart failure. Hypertension; 38:1433-1439. 
Mitchell GF, Izzo JL, Jr., Lacourciere Y, Ouellet JP, Neutel J, Qian C, Kerwin LJ, Block AJ, 
Pfeffer MA (2002) Omapatrilat reduces pulse pressure and proximal aortic stiffness in 
patients with systolic hypertension: results of the conduit hemodynamics of omapatrilat 
international research study. Circulation; 105:2955-2961. 
Mitchell GF, Parise H, Benjamin EJ, Larson MG, Keyes MJ, Vita JA, Vasan RS, Levy D 
(2004) Changes in arterial stiffness and wave reflection with advancing age in healthy men 
and women: the Framingham Heart Study. Hypertension; 43:1239-1245. 

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Mitchell GF (2008) Effects of central arterial aging on the structure and function of the 
peripheral vasculature: implications for end-organ damage. J Appl Physiol; 105:1652-1660. 
Mitchell GF, Wang N, Palmisano JN, Larson MG, Hamburg NM, Vita JA, Levy D, Benjamin 
EJ, Vasan RS (2010) Hemodynamic correlates of blood pressure across the adult age 
spectrum: noninvasive evaluation in the Framingham Heart Study. Circulation; 122:1379- 
1386. 
Mitchell GF, Hwang SJ, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, Vita JA, Levy D, 
Benjamin EJ (2010) Arterial stiffness and cardiovascular events: the Framingham Heart 
Study. Circulation; 121:505-511. 
Mitchell GF, van Buchem MA, Sigurdsson S, Gotal JD, Jonsdottir MK, Kjartansson O, 
Garcia M, Aspelund T, Harris TB, Gudnason V, Launer LJ (2011) Arterial stiffness, pressure 
and flow pulsatility and brain structure and function: the Age, Gene/Environment 
Susceptibility--Reykjavik study. Brain; 134:3398-3407. 
Senni1, M, Gogia, H, Martinez Selles, M, Fischer, S, Zilahi, Z, Cosmi, F, Gelev, V, Galve 
Basilio, E, Reimund, B, Charney, A (2015) Effect of baseline ACEI/ARB use on the safety 
and tolerability of up titrating LCZ696 over 3 vs. 6 weeks: results from the TITRATION 
study. Heart Failure 2015 / 2nd World Congress on Acute Heart Failure 2015. 
Solomon, SD, Zile, M, Pieske, B, Voors, A, Shah, A, Kraigher-Krainer, E, Shi, V, Bransford, 
T, Takeuchi, M, Gong, J, Lefkowitz, M, Packer, M, McMurray, JJV for the Prospective 
comparison of ARNI with ARB on Management Of heart failure with preserved ejection 
fraction (PARAMOUNT) Investigators (2012) The angiotensin receptor neprilysin inhibitor 
LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised 
controlled trial. Lancet; 380:1387–95. 
Torjesen AA, Wang N, Larson MG, Hamburg NM, Vita JA, Levy D, Benjamin EJ, Vasan RS, 
Mitchell GF (2014) Forward and Backward Wave Morphology and Central Pressure 
Augmentation in Men and Women in the Framingham Heart Study. Hypertension; 64:259- 
265. 
Woodard T, Sigurdsson S, Gotal JD, Torjesen AA, Inker LA, Aspelund T, Eiriksdottir G, 
Gudnason V, Harris TB, Launer LJ, Levey AS, Mitchell GF (2015) Mediation analysis of 
aortic stiffness and renal microvascular function. J Am Soc Nephrol; 26:1181-1187. 
Yancy C, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, Fonarow GC, Geraci SA, 
Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, 
Zamani P, Jacobs DR, Jr., Segers P, Duprez DA, Brumback L, Kronmal RA, Lilly SM, 
Townsend RR, Budoff M, Lima JA, Hannan P, Chirinos JA (2014) Reflection magnitude as a 
predictor of mortality: the Multi-Ethnic Study of Atherosclerosis. Hypertension; 64:958-964. 

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13 
Appendix 1: Clinically notable laboratory values and vital 
signs 
Clinically notable vital signs will be defined in this study as a SBP ˂ 90 mmHg. The study 
treatment shall be interrupted or stopped based on investigator judgement. 
Clinically notable laboratory abnormalities for selected tests based on a percent change from 
baseline: 
Hematology 
RBC count 
>50% increase, >20% decrease 
Hemoglobin 
>50% increase, >20% decrease 
Hematocrit 
>50% increase, >20% decrease 
WBC count 
>50% increase, >50% decrease 
Platelet count 
>75% increase, >50% decrease 
Blood Chemistry 
ALT (SGPT) 
>150% increase 
AST (SGOT) 
>150% increase 
BUN 
>50% increase 
Creatinine 
>50% increase 
Total bilirubin 
>100% increase 
CPK 
>300% increase 
Alkaline phosphatase >100% increase 
Potassium 
>20% increase, >20% decrease 
Chloride 
>10% increase, >10% decrease 
Calcium 
>10% increase, >10% decrease 
Uric acid 
>50% increase 

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14 
Appendix 2: Treatment guidelines for hyperkalemia (serum 
potassium greater than or equal to 5.5 mEq/L) 
General principles 
Elevation of potassium levels above the predefined values should be repeated and confirmed 
before any action is taken. 
Any patient who experiences a potassium level ≥ 5.5 mEq/L confirmed by repeated testing after 
randomization requires regular, repeated checks of potassium concentration (beyond that 
prescribed in the protocol) until it is clear that the potassium concentration is stable and not 
rising into the range of concern (≥ 5.5 mEq/L). 
Patients with elevated potassium value will be managed according to the corrective actions 
outlined below and the investigator’s clinical judgement. Hyperkalemia should be followed 
until resolution. 
Recommended corrective action for management of hyperkalemia 
Serum potassium > 5.3 and less than or equal to 5.5 mEq/L 
• Confirm potassium concentration in a non-hemolyzed sample 
• Reinforce low potassium diet and restriction of food/drinks with high potassium content 
(e.g. orange juice, melon, bananas, low-salt substitutes etc.) 
• Review medical regimen (including dietary supplements and over-the-counter 
medications) for agents known to cause hyperkalemia. Consider reduction in dose or 
discontinuation of these agents: 
• Aldosterone antagonists (if they are believed to be the most likely cause of hyperkalemia) 
• Potassium-sparing diuretics (e.g. amiloride and triamterene) including in combination 
products with thiazide or loop diuretics 
• Potassium supplements, e.g., potassium chloride 
• Salt substitutes 
• Non-steroidal anti-inflammatory drugs (NSAIDs) 
• Cyclo-oxygenase-2 (COX-2) inhibitors 
• Trimethoprim and trimethoprim-containing combination products, such as Bactrim® and 
Septra® (trimethoprim/sulfamethoxazole fixed combination) 
• Herbal Supplements: 
• For example, Noni juice, alfalfa (Medicago sativa), dandelion (Taraxacum officinale), 
horsetail (Equisetum arvense), nettle (Urtica dioica), milkweed, lily of the valley, Siberian 
ginseng, hawthorn berries 
• Repeat serum potassium measurement within 3 to 5 days 
• If serum potassium remains > 5.3 and ≤ 5.5 mEq/L, regularly monitor serum potassium 
levels to ensure stability (suggested once monthly) 
• Consider down-titration of study medication, according to investigator medical judgment 
if he/she believes that adjustment/elimination of concomitant medications is not possible 
or does not alleviate the side effects of concern 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 patient and treat hyperkalemia as clinically indicated 
• Apply all measures outlined for serum potassium > 5.3 and < 6.0 mEq/L 
• If serum potassium < 5.5 mEq/L, consider resumption of study drug at lower dose with 
repeat potassium within 5 days 

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15 
Appendix 3: Guidelines for the management of blood 
pressure 
Guidelines 
• Investigator should monitor blood pressure closely 
• If symptomatic hypotension occurs: 
• Correct any treatable cause, e.g. hypovolemia 
• 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 
• 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 5.5.5 should be adhered to as much as possible. 
 
16 
Appendix 4: Guidelines for the management of renal 
dysfunction 
General principles: 
Glomerular filtration rate in HF patients depends on intrinsic renal function and on a balance 
between afferent and efferent glomerular arterial tonicity. This tonicity is partly regulated by a 
stimulation of angiotensin II and could be affected by either study medication. Moreover, renal 
dysfunction may develop or may deteriorate in some patients after study drug administration. 
These recommendations have been developed to guide the investigators in managing patients 
with renal dysfunction after randomization. 
Two types of response to serum creatinine increase are described: 
Surveillance situation 
If, at any time after randomization, eGFR decreases by ≥ 25% from baseline (or if serum 
creatinine concentration increase to 2.5 mg/dL [221 µmol/L]), the investigator will check for 
potentially reversible causes of renal dysfunction such as: 
• Non-steroidal anti-inflammatory drug intake, antibiotics, or other treatments known to 
affect creatininemia 
• Volume decrease, including that resulting from excessive dosing of diuretics 
• Urinary infection 
• Urinary tract obstruction 
• Study medication 
Action situation 
If a patient’s eGFR decreases by ≥ 40% from baseline (or if serum creatinine concentration rises 
above 3 mg/dL (265 µmol/L), the investigator will check for potentially reversible causes of 
renal dysfunction (see above). 

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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. 
 
17 
Appendix 5: Specific Renal Alert Criteria and Actions 
Table 17-1          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 patient 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 patient 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. 

Novartis 
Amended Protocol Version 02 (Clean) 
Confidential 
Page 83 
Protocol No. CLCZ696BUS08 
 
 
 
 
 

Novartis 
Amended Protocol Version 02 (Clean) 
Confidential 
Page 84 
Protocol No. CLCZ696BUS08